Microbiology Papers in Press. Published August 18, 2014 as doi:10.1099/mic.0.081794-0
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Sporothrix schenckii complex biology: environment and fungal pathogenicity
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Téllez MDa, Batista-Duharte Ab,c,d*, Portuondo Dc, Quinello Cc, Bonne-Hernández Rd, Carlos IZc*
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a
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* Corresponding authors
Faculty of Chemical Engineering. Oriente University. Ave Las Americas, Santiago de Cuba, Cuba, b Immunotoxicology Laboratory, Toxicology and Biomedicine Center (TOXIMED), Medical Science University, Autopista Nacional Km. 1 1/2 CP 90400, Santiago de Cuba, Cuba c Faculty of Pharmaceutical Sciences. Universidade Estadual Paulista Julio Mesquita Filho, UNESP. Rua Expedicionarios do Brasil 1621-CEP:14801-902, Araraquara, SP, Brazil, d Universidade Federal de São Paulo, São Paulo-SP, Brasil, d CAPES/Brasil Grant. Foreigner Visiting Professor Program.
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Profa. Dra. Iracilda Zeppone Carlos: Faculty of Pharmaceutical Sciences of Araraquara. Universidade
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Estadual Paulista Julio Mesquita Filho, UNESP. Araraquara, São Paulo. Brazil. CEP:14801-902
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Phone 55 16 3301-5712. E-mail: [email protected]
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Prof Dr. Alexander Batista-Duharte: Phone 55 16 3301-5713. E-mail: [email protected]
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Abstract
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Sporothrix schenckii is a complex of various species of fungus found in soils, plants, decaying
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vegetables and other outdoor environment. It is the etiological agent of sporotrichosis in humans and
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several animals. Humans and animals can acquire the disease through traumatic inoculation of the
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fungus into subcutaneous tissue. Despite the importance of sporotrichosis as a disease, which is
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currently regarded as an emergent disease in several countries, the factors driving its increasing
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medical importance are still largely unknown. There are only a few studies addressing the influence of
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the environment on the virulence of these pathogens. However, some recent discoveries made in
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studies of the biology of S. schenckii are demonstrating that adverse conditions in its natural habitats
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can trigger the expression of different virulence factors that confer survival advantages in both animal
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hosts and in the environment. In this review, we provide updates on the important advances in the
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understanding of the biology of S. schenckii and the modification of their virulence linked to
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demonstrated or putative environmental factors.
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Keywords: Sporotrichosis, Sporothrix schenckii complex, virulence, environmental, ‘dual use’
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Word count of summary: 170
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Word count of main text: 6689
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Total number of tables: 1
Total number of figures: 1
1
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1. Introduction
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Sporotrichosis is an acute or chronic granulomatous mycosis of humans and mammals that has a
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worldwide distribution. Initially the causal agent of this disease was thought to be a unique thermally
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dimorphic fungus Sporothrix schenckii; however, it has been recently proposed, based on physiologic
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and molecular aspects, that S. schenckii is a complex of various species (Lopes-Bezerra, 2006;
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Marimon et al., 2007; Marimon et al., 2008; Evangelista et al., 2014). Sporotrichosis was originally
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described in 1898 by Schenck at the Johns Hopkins Hospital in Baltimore, who recognized that the
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infection was most likely due to a previously undescribed fungal pathogen (Schenck, 1898). Two years
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later, Hektoen and Perkins confirmed these observations in a report of a second case and a detailed
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morphological description of the pathogen, which included studies involving laboratory animals
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(Hektoen and Perkins 1900). Other cases in the United States and western Europe were recognized,
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especially in France, where large numbers of cases were reported in the early 20th century (de
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Beurmann, 1912).
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Recently, S. schenckii has received particular attention due to the increased number of infections
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caused worldwide. Currently, the presence the S. schenckii complex and cases of sporotrichosis have
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been reported from all of the continents (Madrid et al., 2009; Barros et al., 2010) and in different
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geographic regions, such as tropical and subtropical regions. Some areas have declared sporotrichosis
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an emerging health problem, with a growing interest for sanitary authorities (Feeney et al., 2007; Hay
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and Morris-Jones, 2008; López-Romero et al., 2011; Messias, 2013). Sporotrichosis is now the most
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common subcutaneous mycosis in the Americas (especially Brazil, Mexico, Peru, Colombia and
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Uruguay) and also in Japan, India and South Africa (Carrada-Bravo et al., 2013). A particular
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geographical area called Abancay, in the south central Peruvian highlands, is considered a
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hyperendemic area, with an estimated incidence of approximately 50–60 cases per 100,000 inhabitants
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per year (Bustamante and Campos, 2001). Meanwhile in Brazil there are increasing reports of
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sporotrichosis in areas where the disease was rare decades ago, with an intriguing zoonotic
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transmission by cats (Borges et al., 2013; Rodrígues et al., 2013a,b). In Europe, sporotrichosis is less
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common, although it was also a common disease in France in 1900 but declined after two decades.
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Currently, sporotrichosis is intermittently reported in several others countries, such as Italy, Spain,
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Portugal, United Kingdom and Turkey (Criseo et al., 2008; Ojeda et al., 2011; Dias et al., 2011;
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Gürcan et al., 2007). Other interesting observation is that from the beginning of the AIDS (Acquired
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Immunodeficiency Syndrome) era, new clinical forms of disseminated sporothrichosis have been
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reported, including cerebral, endocardial and ocular involvement (Galhardo et al., 2010; Ramos-e-
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Silva et al., 2012; Silva-Vergara et al., 2012). 2
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A presence or even an abundance of the fungus in nature is not enough to explain the development of
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the disease. Although the fungus is frequently isolated in environmental and commercial samples, it is
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unclear why sporotrichosis has a low incidence. However, the different local emerging outbreaks
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reaching sometimes epidemic proportions lead to questions regarding the relevance of the host in the
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development of the disease (López-Romero et al., 2011), the virulence associated with genetic
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polymorphisms in the S. schenckii complex (Sasaki et al., 2014), and other environmentally associated
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factors not sufficiently studied yet.
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The aim of this work is to provide an update on the recent advances in the understanding of Sporothrix
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schenckii complex biology, addressing different ways through which environmental factors may
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modify the virulence of the fungus, as a possible contribution to the sporotrichosis outbreaks.
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2- The Sporothrix schenkii complex and sporotrichosis
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The genus Sporothrix is a species-rich taxon of Ascomycetes, which varies according to the ecological
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niche, frequency, distribution and virulence. Some of these fungi have the potential to survive in
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mammalian hosts and are able to cause damage in multiple species of animals, including humans (de
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Hoo, 1974; Fernandes et al., 2013). S. schenckii is recognized as a cryptic species complex including
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Sporothrix brasiliensis, Sporothrix globosa, Sporothrix mexicana, Sporothrix luriei, Sporothrix pallida
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(formerly Sporothrix albicans) and S. schenckii sensu strict (Marques et al 2014). With the exception
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of S. pallida, the other Sporothrix species have been reported to cause sporotrichosis in humans and
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animals (Lopes-Bezerra, 2006; Marimon et al., 2007, Marimon et al., 2008, Romeo and Criseo, 2013;
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Evangelista et al., 2014).
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The fungi belonging to the S. schenckii complex are ascomycetous dimorphic organisms (Ascomycota,
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Pyrenomycetes, Ophiostomatales, Ophiostomataceae), naturally
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living and decayed vegetation, animal excreta, and soils plentiful in cellulose, with a pH range of
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3.5 to 9.4, a mean temperature of 31°C, and a relative humidity above 92%. This
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phenotypically characterized by the ability to produce conidias in its filamentous form, and
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cigar-shaped yeast-like
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humans (Lopes-Bezerra, 2006).
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Sporotrichosis affects humans and other mammals, such as cats, dogs, rats, armadillos, and horses. As
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the fungus is abundant in soil, wood and moss, most infections occur following minor skin trauma in
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people with outdoor occupations or hobbies, such as gardening, farming, hunting or other activities
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involving close contact with vegetation and soil. The zoonotic transition from ill or carrier animals
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(mainly cats) to man is gaining a growing importance. Similarly, an inoculation may also occur after
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motor vehicle accidents and in laboratory personnel handling of Sporothrix-infected specimens (Barros
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et al., 2007; Hay et al., 2008; Romeo and Criseo; 2013).
cells when cultured at
found
in
substrates
such as
fungus is
35–37°C or as the infectious form in animals and
3
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Human disease has different clinical manifestations and can be classified into fixed cutaneous,
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lymphocutaneous, disseminated cutaneous, and extracutaneous or systemic sporotrichosis. The fixed
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cutaneous sporotrichosis is located in the skin and is restricted to the injury site without lymphatic
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involvement. The lymphocutaneous sporotrichosis is the most common manifestation and is
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characterized by papular and nodular, superficial ulcers and/or vegetative plaque lesions in the skin
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and along the trajectory of the draining lymph vessels. The disseminated cutaneous form consists of
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multiple and distant lesions in the skin due to hematogenous dissemination or multiple inoculations of
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the fungus. In the extracutaneous or systemic sporotrichosis, multiple cutaneous and visceral lesions
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involving the liver, joints, spleen, bones, marrow bones, lungs, eyes, testis and central nervous system
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associated with cellular immunodeficiency have been described (Edwards et al., 2000; Rocha et al.,
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2001; Ramos-e-Silva et al., 2012). Primary pulmonary sporotrichosis is another clinical type of this
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infection caused by the inhalation of infectious conidia in contaminated environments. (Aung et al.,
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2013).
111 112 113
3-The response of the Sporothrix schenkii complex to changing environmental conditions
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mammalian host is not a requisite for fungal survival and virulence (Steenbergen et al., 2004). This
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phenomenon is called by Casadewall ‘ready-made’ virulence (Casadewall et al., 2003). The influence
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of different environmental contaminants, on pathogenic or non-pathogenic fungi has been studied
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(Zafar et al., 2007; Gadd, 1993; Valix, 2001, 2003; Anahid et al., 2011). S. schenkii complexes are
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present in nature in diverse environmental conditions, including polluted environments (Cooke and
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Foter 1958; Dixon et al., 1991; Ulfig, 1994; Ulfig et al., 1996; Kacprzak, 2005; Pečiulytė 2010; Chao
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et al., 2012; Yazdanparast et al., 2013), in a wide pH range from 2.2 to 12.5 (Tapia et al., 1993;
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Ferreira et al., 2009) the floor of swimming pools (Staib 1983), desiccated mushrooms (Kazanas,
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1987), fleas, ants and horse hair (Carrada-Bravo, 2013). Moreover, specific indoor environments also
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select for certain stress-tolerant fungi and can drive their evolution towards acquiring medically
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important traits (Gostinčar et al., 2011).
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3.1 Physical factors: S. schenkii is able to resist extreme conditions, such as very low temperatures for
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several years (Pasarell and Mcginnis, 1992; Mendoza et al., 2005), extreme osmotic pressure
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(Castellani, 1967; Borba, 1992; De Capriles, 1993; Mendoza et al., 2005; Ferreira et al., 2009 ) and.
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Some studies have revealed that different levels of ultraviolet light (UV) exposure by S. schenckii
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strains resulted in a conserved viability, although with a high frequency of morphological variants,
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depending on the strain and UV dose. The main morphological variants were smaller colonies or
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changes in shape. Stable and non-stable morphological variants were found in the population, and the
The origin and maintenance of virulence in dimorphic fungi is enigmatic because an interaction with a
4
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reversion of the mutant phenotype was always to the wild-type phenotype (Torres-Guerrero
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and Arenas-López; 1998). In another study, the gamma radiation effects on the yeast cells of S.
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schenckii were analyzed, showing that yeast cells remained viable up to 9.0 kGy; however, synthetic
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protein metabolism was strongly affected, while a dose of 7.0 kGy retained viability, metabolic
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activity, and morphology but abolished the capacity to produce infection (de Souza et al., 2011).
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3.2 Metals: Microorganisms, including fungi, have been shown to possess an ability to survive by
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adapting or mutating at high concentrations of toxic heavy metals. In general, two mechanisms have
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been proposed for heavy metal tolerance in fungi: 1) extracellular sequestration with chelation and
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cell-wall binding, mainly employed in the avoidance of metal entry and 2) intracellular physical
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sequestration of metal by binding to metallothioneins (MT) sequestered as insoluble phosphates or
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removed from the cell via transporters such as CadA, ZntA or PbrA, preventing the damage caused by
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metals to sensitive cellular targets and reducing the metal burden in the cytosol. (Anahid et al., 2011;
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Jarosławiecka and Piotrowska-Seget, 2014). Most fungi synthesize siderophores that chelate iron,
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which is ultimately taken up as a siderophore-iron complex (Kosman et al., 2003). The capacity to
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accumulate iron is critical for the survival of fungal pathogens in different conditions (Schaible et al.,
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2004). Unlike other fungi, such as S. cerevisiae (Kaplan et al., 2006), S. schenckii is capable of
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producing its own siderophores in response to low iron availability (Pérez-Sánchez et al., 2010). This
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mechanism can be involved in the pathogenicity and survival under conditions of environmental stress
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or inside the host.
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3.3 Chemical contaminants: Environmental fungi can biodegrade aromatic hydrocarbons in their own
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habitat (Cerniglia 1997). An interesting report revealed that several fungi, including S. schenckii, were
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isolated from air biofilters exposed to hydrocarbon-polluted gas streams and assimilated volatile
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aromatic hydrocarbons as the sole source of carbon and energy. The data in this report show that many
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volatile-hydrocarbon-degrading strains are closely related to, or in some cases clearly conspecific with,
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the very restricted number of human-pathogenic fungal species causing severe mycoses, especially
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neurological infections, in immunocompetent individuals (Prenafeta-Boldu et al., 2006). In addition,
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the effect of fungicides against several environmental pathogenic fungi was evaluated, and S. schenkii
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had the greatest resistance to these products compared to the other fungi (Morehart and Larsh, 1967).
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3.4 Other microorganisms: A phenomenon insufficiently studied is the interaction of the pathogenic
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fungi with other microorganisms in the neighborhood. Chaturvedi et al. evaluated the in vitro
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interactions between colonies of Blastomyces dermatitidis and six other zoopathogenic fungi. The
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interactions were found to range from neutral with H. capsulatum and C. albicans to strongly
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antagonistic with Microsporum gypseum, Pseudallescheria boydii, and Sporothrix schenckii and
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included lysis by Cryptococcus neoformans (Chaturvedi et al., 1988). In another study, Cryptococcus 5
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neoformans was shown to interact with macrophages, slime molds, and amoebae in a similar manner,
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suggesting that fungal pathogenic strategies may arise from environmental interactions with
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phagocytic microorganisms (Steenbergen et al., 2003). In another interesting report, Steenbergen et al.,
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examined the interactions of three dimorphic fungi, Blastomyces dermatitidis, Histoplasma
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capsulatum, and S. schenckii, with the soil amoeba, Acanthameobae castellanii. The ingestion of the
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yeast by this amoeba resulted in amoeba death and fungal growth. For each fungal species, the
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exposure of yeast cells to amoebae resulted in an increase in hyphal cells (Steenbergen et al., 2004).
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The biochemical events during phagocytosis by either A. castellanii or immune phagocytes appear
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similar, suggesting that the ‘respiratory burst’ enzyme(s) responsible for oxyradical generation in these
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two cell types is structurally related (Davis et al., 1991). Thus, soil amoebae may contribute to the
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selection and maintenance of pathogenic dimorphic fungi in the environment, conferring these
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microbes with the capacity for virulence in mammals.
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Despite that are necessary more studies evaluating the influence of different environmental factors on
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the physiology and pathogenicity of the S. schenkii complex, all the available data suggest that the
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strategies that pathogenic fungi acquire to survive this environmental competition may, in turn,
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provide the ability to infect animals and may further allow the emergence of opportunistic pathogens
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from these microenvironments (Baumgardner, 2012) (Figure 1).
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4. Fungal elements involved in environmental resistance and pathogenicity
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Although is known that many external influences can affect the pathogenicity of the S. schenkii
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complex as environmental pathogenic fungi, these influences and mechanisms have not been
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sufficiently studied in this complex. However, the presence of the same molecules interacting with
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environmental toxins described in other fungus (Casadewall et al., 2003) is a good reason to
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hypothesize that similar mechanism may be acting to face these extreme conditions. As Casadewall
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reported for C. neoformans (Casadewall et al., 2003), several virulence factors in S. schenckii also
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appear to have ‘dual use’ capabilities for the survival in both animal hosts and in the environment
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(Table 1).
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4.1 Dimorphism: The dimorphic fungi comprise a group of important human pathogens and represent
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a family of seven phylogenetically related ascomycetes that include Blastomyces dermatitidis,
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Coccidioides immitis, Coccidioides posadasii, Histoplasma capsulatum, Paracoccidioides brasiliensis,
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Penicillium marneffei and Sporothrix schenckii. These fungi possess the unique ability to switch
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between mold and yeast in response to thermal stimuli and other environmental conditions. In the
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environment, they grow as mold that produces conidia or infectious spores, which, when transmitted to
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humans or other susceptible mammalian hosts, are capable of converting to pathogenic yeasts that
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cause serious infection (Klein and Tebbets 2007). 6
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The dimorphism in the S. schenckii complex has also been associated with the ability to adapt to
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environmental changes and to yield an increased virulence (Nemecek et al., 2006; Gauthier et al.,
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2008). This fungus exhibits mycelium morphology in its saprophytic phase at 25°C in laboratory
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conditions and a yeast morphology in host tissues at 35-37°C. On the other hand, in the environment
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with different grades of temperatures they are able to keep the mycelial form. The formation of yeast
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cells was thought to be a requisite for the pathogenicity of S. schenckii; however, the mechanisms that
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regulate the dimorphic switch remain unclear. Some recent findings have begun to clarify these
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mechanisms.
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The principal intracellular receptors of environmental signals are the heterotrimeric G proteins, and
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they are involved in fungal dimorphism and pathogenicity. Valentín-Berríos et al. described a new G
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protein α subunit gene in S. schenckii: ssg-2, and they demonstrated that the SSG-2 Gα subunit of
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40.90 kDa interacts with the cytosolic phospholipase A2 (cPLA2), participating in the control of the
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dimorphism in this fungus (Valentín-Berríos et al., 2009).
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The yeast-to-mycelium transition is dependent on calcium uptake (Serrano et al., 1990; Rivera-
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Rodríguez et al., 1992). In S. schenckii, a Ca2+/Calmodulin-dependent protein kinase (CaMK)
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encoded by the calcium/calmodulin kinase I (sscmk1) gene (GenBank accession no. AY823266) was
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described (Valle-Aviles et al., 2007). Experiments using different inhibitors of the CaMK pathway
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showed that they inhibited the transition from yeast cells to hyphae, which suggests a
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calcium/calmodulin pathway is involved in the regulation of the dimorphism in S. schenckii (Valle-
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Aviles et al., 2007). Similarly, RNAi technology was used to silence the expression of the sscmk 1
220
gene. The RNAi transformants were unable to grow as yeast cells at 35°C and showed a decreased
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tolerance to this temperature (Rodriguez-Caban et al., 2011).
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The mitogen-activated protein kinase (MAPK) cascade and cyclic AMP (cAMP) signaling pathways
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are known to be involved in fungal morphogenesis and pathogenic development. The MAPK and
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cAMP pathways are both activated by an upstream branch, two-component histidine protein kinase
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(HPK) phospho-relay system (Hou et al., 2013). Nemecek et al. reported that a long-sought regulator
226
controls the switch from a non-pathogenic mold form to a pathogenic yeast form in dimorphic fungi.
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They found that DRK1, a hybrid dimorphism-regulating histidine kinase, functions as a global
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regulator of the dimorphism and virulence in B. dermatitidis and H. capsulatum and is required for the
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phase transition from mold to yeast, expression of virulence genes, and pathogenicity in vivo.
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(Nemecek et al., 2006). More recently, Hou et al. developed a molecular cloning, characterization and
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differential expression of DRK1 in S. schenckii. In this report, quantitative real-time RT-PCR revealed
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that SsDRK1 was more highly expressed in the yeast stage compared with the mycelial stage, which
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indicated that SsDRK1 may be involved in the dimorphic switch in S. schenckii (Hou et al., 2013). 7
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Zhang et al. reported other proteins involved in the dimorphism process. The Ste20-related kinases are
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involved in signaling through the mitogen-activated protein kinase pathways and in morphogenesis
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through the regulation of cytokinesis and actin-dependent polarized growth (Zhang et al., 2013). The
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expression of other proteins that may affect biosynthetic and metabolic processes were found by
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Zhang’s group, such as Cullin-3, CdcH and 4-coumarate-CoA ligase. The expression of these genes
239
was detected predominantly in the yeast form and due to the yeast phase, which is the form of S.
240
schenckii found in the host; the expression of these genes could reflect the ability of the yeast phase to
241
adapt to growth-limiting environments. They also demonstrated an upregulation of the Hsp70
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chaperone Hsp88 in the development of the yeast phase of S. schenckii at 37°C; however, the precise
243
role of this gene remains unclear (Zhang et al., 2012).
244
Lipids are thought to play important roles in the regulation of the dimorphism and virulence in
245
pathogenic fungi. Generally, the ratio of phospholipid/ergosterol is less than 1 in the yeast form and 2-
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20 in the mycelial form cells in C. albicans and S. schenckii. During the transition from the yeast to
247
mycelial
248
whereas phosphatidylcholine increases. Phospho-lipase D is activated during this transition (Kitajma,
249
2000).
250
Phorbol-12-myristate-13-acetate (PMA), a tumor promoting agent and PKC activator, was found to
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stimulate germ tube formation and germ tube growth by yeast cells induced to undergo a transition to
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the mycelium form in a concentration-dependent manner. PMA also had a stimulatory effect on DNA
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and RNA synthesis in cells induced to undergo the yeast to mycelium transition and was found to
254
inhibit cell duplication and bud formation in yeast cells induced to re-enter the budding cycle. In
255
contrast, Polymyxin B, an inhibitor of PKC, inhibited germ tube formation by yeast cells. This
256
inhibition could be overcome if PMA or calcium were added to the medium, suggesting that the
257
inhibition obtained in the presence of this antibiotic was due to the inhibition of PKC. These results
258
support the involvement of PKC in the control of the dimorphic expression in S. schenckii (Colon-
259
Colon and Rodriguez-del Valle, 1993).
260
4.2 Genetic polymorphism: Recently, there has been an increasing interest in studying the biology of
261
the S. schenckii complex, and particular attention has been focused on its molecular phylogeny, which
262
has improved our knowledge of the taxonomy, pathogenic characteristics and the epidemiology of this
263
pathogenic fungus. Recent studies have shown important differences in the virulence and drug
264
resistance profiles among different species in the S. schenckii complex. S. brasiliensis is the most
265
virulent species in comparison with S. globosa and S. mexicana, which show little or no virulence in
266
murine models (Fernández-Silva et al., 2012; Fernandes et al., 2013). In addition, the test for
267
susceptibility to antifungal drugs showed that S. schenckii s. str. and S. brasiliensis were highly
forms,
phosphatidylinositol
and
8
phosphatidylserine
are
reduced,
268
susceptible to most of the antifungals tested in vitro in comparison with the more resistant, S. globosa
269
and S. mexicana species (Marimon et al., 2008). These and other observations suggest that possible
270
genetic differences may be involved.
271
The genomic organization and chromosome number in different species in the S. schenckii complex
272
remain unknown. However, sequencing studies in the calmodulin-encoding gene in the different
273
members of the S. schenkii complex have offered valuable information for elucidating the relationships
274
and differences among these species and their role in pathogenic manifestations (Romeo et al., 2011).
275
A recent study revealed a high diversity in the calmodulin gene (regulated by Ca+2) of S. schenckii. In
276
contrast, S. brasiliensis and S. globosa appeared to be more homogenous, with a low genetic diversity.
277
The electrophoretic karyotype profiles of S. brasiliensis isolates showed less variability than those
278
observed in S. schenckii sensu strictus isolates (Sasaki et al., 2014). These results were consistent with
279
the phylogenetic data, where the variability among isolates within the species was less frequent in S.
280
brasiliensis than in S. schenckii sensu strictus (Marimon et al., 2006; 2007; Rodrigues et al., 2013).
281
Future studies are necessary to determine the role of different genes from the species of the S.
282
schenckii complex in the virulence, drug resistance and environmental resistance. Changes in the
283
expression of such genes might be beneficial to S. schenckii survival from the natural environment to
284
within a host during infection. Comparative genomics and transcriptomics analysis between highly
285
pathogenic Sporothrix species and species with reduced or absent pathogenicity certainly will
286
accelerate the discovery of new proteins for diagnostics, drug targets and vaccines (Romeo and Criseo,
287
2013).
288
4.3 Cell wall: The fungal wall protects the cell from drastic changes in the external environment; it is
289
the first point of contact with the host (Mora-Montes et al., 2009). The S. schenckii cell wall is
290
composed of glucans, galactomannans, rhamnomannans, chitin, glycoproteins, glycolipids and melanin
291
(Travassos et al., 1977; Travassos and Lloyd 1980; Lopes-Bezerra et al., 2006; López-Romero et al.,
292
2011). Despite are necessary more studies to know their detailed structure, it seems to be that a proper
293
wall cell composition is required for supporting external stress and for virulence (Madrid et al., 2010;
294
López-Esparza et al., 2013).
295
4.4 Melanin: An interesting mechanism to resist environmental adverse conditions is the production of
296
melanin, also implicated in the pathogenesis of several important human fungal pathogens. Several
297
types of melanin have been described in the fungal kingdom but the majority is derived from 1.8-
298
dihydroxynaphthalene (DHN) and is known as DHN-melanin (Helene et al., 2012). Melanin has been
299
referred to as 'fungal armor,' due to the ability of the polymer to protect microorganisms against a
300
broad range of toxic insults, warranting the survival of fungi in the environment and during infection
301
(Gómez and Nosanchuk, 2003). Melanization reduces the susceptibility to enzymatic degradation, the 9
302
toxicity from heavy metals, ultraviolet and nuclear radiation, extremes of temperature, oxygen and
303
nitrogen free radicals, which may afford the fungus protection against similar insults in
304
the environment (Wang and Casadevall 1994 a, b; Rosas and Casadewall 1997, 2001, Taborda et al.,
305
2008, Gessler et al., 2014). Melanin also reduces the susceptibilities of pathogenic fungi to different
306
antifungal drugs (van Duin et al., 2003; Nosanchuk and Casadevall 2006) and to different immune
307
mechanisms in the host, especially phagocytosis (Steenbergen et al., 2004).
308
S. schenckii produces melanin or melanin-like compounds in vitro. While melanin is an important
309
virulence factor in other pathogenic fungi, this pigment also has a similar role in the pathogenesis of
310
sporotrichosis (Morris-Jones et al., 2003). Melanized cells of the wild-type S. schenckii and the albino
311
grown on scytalone-amended medium were less susceptible to killing by chemically generated
312
oxygen- and nitrogen-derived radicals and by UV light than were the conidia of mutant strains. Wild
313
type melanized conidia and the scytalone-treated albino were also more resistant to phagocytosis and
314
killing by human monocytes and murine macrophages than were the unmelanized conidia of two
315
mutants (Romero-Martinez et al., 2000). Similar to C. neoformans and P. brasiliensis, S. schenckii can
316
utilize phenolic compounds to augment melanin production, which may be associated with a
317
concomitant increase in the protection against unfavorable conditions in both the environment and
318
during infection (Almeida-Paes et al., 2009).
319
4.5 The expression of adhesins: The adhesion ability of a fungus is important in the colonization of
320
different environmental extracts and in the host is essential for colonization and the establishment of
321
infection. Specific microbial adhesins mediate adherence to host tissues by participating in
322
sophisticated interactions with some of the host proteins that compose the extracellular matrix
323
(Teixeira et al., 2013). The adhesion-encoding genes are not constitutively expressed. Instead,
324
adhesion is under tight transcriptional control by several interacting regulatory pathways. The switch
325
from non-adherence to adherence may allow yeasts to adapt to stress (Verstrepen and Klis, 2006). The
326
adhesion genes are activated by diverse environmental triggers such as carbon and/or nitrogen
327
starvation, changes in pH or ethanol levels (Verstrepen et al., 2003; Sampermans et al., 2005). Fungi
328
need to adhere to the appropriate host tissues to establish an infection site. Apart from being a stress-
329
defense mechanism, adhesion is also crucial for fungal pathogenesis: (Verstrepen and Klis, 2006).
330
The outermost layer of the cell wall of S. schenckii has molecules involved in the adhesion of the
331
fungus to host tissues and has a central role in host-pathogen interactions, mediating several
332
interactions associated with the pathogenesis of this microorganism processes. It has been reported that
333
S. schenckii adhered to fibronectin and laminin in soluble and immobilized forms (Lima et al., 1999,
334
2001, 2004) and that this is a key step for the transposition of the endothelial barrier (Figueiredo et al.,
335
2007). Independently, Ruiz-Baca et al. (2008) and Nascimento characterized a 70 kDa glycoprotein 10
336
(gp70) on the cell wall of S. schenckii that mediates the adhesion of the fungus to the dermal and
337
subendothelial matrix. This gp70 and another protein with a slightly lower molecular mass (67 kDa)
338
were detected from different isolates. This variation might be related to differences in glycosylation
339
(Teixeira et al., 2009). Interestingly, sera obtained from patients with sporotrichosis reacted mainly
340
with the 40 and 70 kDa antigens (Scott and Muchmore, 1989; Lopes-Alves et al., 1994). In addition,
341
hyperimmune sera of mice infected with S. schenckii reacted with gp 70 (Birth and Adams, 2005), and
342
monoclonal antibodies specific for gp70 were protective against experimental infection (Nascimento et
343
al., 2008). Moreover, recently the Lopes-Becerra´s group reported that reduced level of gp70
344
expression was found in virulent S. brasiliensis and S schenckii strains, while a high expression of this
345
molecule is associated with a lower virulence profile of the strains. This would be other evidence this
346
antigen induces a protective host response (Castro et al., 2013).
347
In other pathogenic microorganism, Staphylococcus aureus, many molecules involved in adhesion are
348
also involved in
349
adhesion (Zecconi and Scali, 2013). However, in the case of the S. schenckii complex, the role of their
350
adhesins as immune evasion factors is unknown.
351
4.6 Enzyme production: The Pires de Camargo group studied the different enzymatic activities
352
related to fungal virulence of 151 Brazilian S. schenckii isolates from 5 different geographic regions of
353
Brazil. All (100%) of the S. schenckii isolates presented urease and DNase activities. Only three
354
(15.78%) isolates (one from the North and two from the Southeast region) showed gelatinase activity,
355
and five (26.31%) isolates (one from the North, three from the Northeast, and one from the Southeast
356
region) showed proteinase activities of 0.68, 0.88, 0.85, 0.55, and 0.78, respectively. Additionally,
357
only four (21.05%) isolates (one from the North, one from the Central West, and two from the
358
Southeast region) showed caseinase activities of 0.75, 0.87, 0.89, and 0.87, respectively (Ferreira et al.,
359
2009). Another report of isolates from Venezuela confirmed the urease activity (Mendoza et al., 2005),
360
while another study in India reported that all of the mycelial forms of S. schenckii could split urea
361
(Ghosh et al., 2002).
362
However, Fernandes et al. from the same group of Pires de Camargo, also found that while the “highly
363
virulent” S. schenckii isolates show a profile of secreted enzymes (proteinase, caseinase, gelatinase,
364
DNase and urease), most of these enzymes were not observed in the hypervirulent species S.
365
brasiliensis (Fernandes et al., 2009). This observation indicates that the mechanisms promoting
366
pathogenesis are much more complex, perhaps not conserved among closely related Sporothrix species
367
and most likely involve different virulence factors to evade the host immune system (Romeo and
368
Criseo, 2013).
different immune evasion mechanisms, not related to the specific process of
11
369
An interesting enzyme present in S. schenkii complex is the nitroreductase, a member of a group of
370
enzymes that reduces the wide range of nitroaromatic compounds and has potential industrial
371
applications (Stopiglia et al., 2013). Nitroreductase activity has been detected in a diverse range of
372
bacteria and in yeast (Lee et al., 2008; Xu et al., 2007; Aviv et al., 2014). A recent study in an
373
emergent Salmonella enterica serovar Infantis strain, demonstrated that the fixation of adaptive
374
mutations in the DNA gyrase (gyrA) and nitroreductase (nfsA) genes, conferred resistance to
375
quinolones and nitrofurans and contributes to stress tolerance and pathogenicity of this bacteria (Aviv
376
et al., 2014). The possible role of the nitroreductase in the S. schenckii tolerance to environmental
377
adverse conditions and in the host, the resistance to oxidative stress, to antifungal drug and other
378
aspects involved in the pathogeny are matters needing to be studied.
379
Additionally, the recent finding in S. schenkii of intracellular molecules and signals associated with the
380
heterotrimeric G protein alpha subunit SSG-1, involved in the response to different external adverse
381
conditions, help to explain how this fungus is able to survive under external stress (environmental and
382
inside the host) (Valentín-Berríos et al., 2009; Pérez-Sánchez et al., 2010).
383
5. Infections of an alternative host
384
Sporothrichosis is a human mycosis; however, ultimately there is an alarming increase in the
385
frequency of infections in domestic animals, principally in cats, which has led to an increase in the
386
relevant importance from an epidemiological perspective (Smilack; Reed et al., 1993; De Lima et al.,
387
2001; Barros et al., 2008; Lloret et al., 2013). Its ease of transmission to cohabitant humans and other
388
animals, especially by bites and scratches, makes it a significant zoonosis (Read et al., 1982; Nusbaum
389
et al., 1983; Dunstan et al., 1986). Cats develop disseminated skin ulcers, with often fatal infection
390
(Lloret et al., 2013). The fungus is spread from an ulcer or from bites and scratches. The propensity of
391
cats to transmit the infection to humans may be attributable to the large number of organisms
392
associated with the lesions in most infected cats (Yegneswaran et al., 2009).
393
However, there are reports of the presence of S. schenckii in samples from the nails of apparently
394
healthy domestic cats (Schubach et al., 2001, 2002). The cat habit of digging holes and covering their
395
excrements with soil and sand, and sharpening its nails on trees, woods or trunks, are most likely
396
responsible for the carriage of the fungus on its nails and claws, even as healthy carriers (Carrada-
397
Bravo and Olvera Macías 2013). These healthy carriers can be important in the dissemination of the
398
fungus and the occurrence of sporothrichosis cases when the conditions are favorable. Human
399
infections have also been associated with insect stings, fish handling, and the bites or scratches from
400
birds, dogs, squirrels, horses, reptiles, parrots and rodents, even though clinical symptoms may not be
401
present in these animals (Werner and Werner, 1994; Kauffman, 1999; Liu and Lin, 2001; Ranjana et
402
al., 2001; Haddad et al., 2002; Barros et al., 2011; Carrada-Bravo and Olvera-Macías, 2013). 12
403 404
6. The ability to escape from host immune mechanisms
405
Members of the S. schenckii complex are able to produce localized infections in immunocompetent
406
hosts. They have developed different mechanisms permitting the escape from host immunological
407
mechanisms.
408
6.1 Phagocytosis inhibition: It has long been reported that phagocytosis is an important defense
409
mechanisms against S. schenckii (Cunningham et al., 1979; Oda et al., 1982). The recognition of the
410
fungus is mediated by molecules such as Toll-like receptors (TLRs): TLR2 (Negrini et al., 2013;
411
2014), TLR4 (Sassa et al., 2012) and carbohydrate receptors (Guzman-Beltran et al., 2012). Sialic acid
412
residues are expressed at the cell surface of S. schenckii (Alviano et al., 1982). These residues protect
413
unopsonized fungal cells from phagocytosis by resident mouse peritoneal macrophages. The enzymatic
414
removal of sialic acids from the external layers of S. schenckii envelopes renders yeast cells more
415
susceptible to phagocytosis (Oda et al., 1982; Alviano et al., 1999). Other in vitro studies have shown
416
that galactomanan, ramnomanan and a lipid extract purified from the fungal cell wall are able to inhibit
417
the phagocytosis of S. schenckii yeast by peritoneal macrophages (Oda et al., 1983; Carlos et al.,
418
2003).
419
Several processes associated with phagocytosis, such as the cytotoxicity mediated by reactive oxygen
420
and nitrogen species (ROS and NO), are involved in the destruction of invading organisms, and their
421
virulence may be related to a differential susceptibility to these mediators (Fernandez et al., 2000;
422
Carlos et al., 2009; Sassa et al., 2012; Xiao-Hui et al., 2008). A study demonstrated that the S.
423
schenckii catalase is involved in the defense against the ROS induced by environmental changes in
424
vitro, and they proposed that catalase, as a main component of antioxidant defense, may contribute to
425
the survival of S. schenckii during infection. Moreover, it is known that ergosterol is the major sterol
426
observed in fungal membranes (Weete, 1989), while ergosterol peroxide, the putative product of the
427
H2O2 dependent enzymatic oxidation of ergosterol (Bates et al.,
428
membrane of S. schenckii, which could inactivate or scavenge toxic oxygen products that are formed
429
in phagocytic cells (Basaga, 1990; Sgarbi et al., 1997). It is conceivable that in S. schenckii, ergosterol
430
peroxide is formed as a protective mechanism to evade reactive oxygen species during phagocytosis
431
(Sgarbi et al., 1997).
432
Carlos et al. studied the effect of three different components of the S. schenckii wall cell (a lipid
433
extract, exoantigens and the alkali-insoluble fraction) and observed a drastic inhibition of the
434
phagocytosis of yeast in murine peritoneal macrophages previously treated with a lipid extract. This
435
inhibitory effect was associated with a high production of Tumor Necrosis Factor alpha (TNF-α) and
436
Nitric oxide (NO) (Carlos et al., 2003). Studies performed in our laboratory demonstrated a high 13
1976), is a constituent of the
437
fungal burden in a murine model of S. schenckii infection during the 2nd and 4th after a previous high
438
production of NO (unpublished data). Similarly, Niedbala et al. reported that NO induces a population
439
of CD4(+)CD25(+)Foxp3(-) regulatory T cells (NO-Tregs) that suppress the functions of
440
CD4(+)CD25(-) effector T cells in vitro and in vivo (Niedbala et al., 2007; 2011). The helper 17
441
(Th17) cells are important in antifungal mechanisms (Hernández-Santos and Gaffen, 2012).
442
Interestingly, recently it was discovered that NO-Tregs suppressed Th17 but not Th1 cell
443
differentiation and function, suggesting a differential suppressive function between NO-Tregs and
444
natural Tregs (nTregs) (Niedbala et al., 2013). In addition, severe infection promotes the release of
445
proinflammatory mediators, including TNF-α and NO, with the subsequent induction of molecules,
446
such as IL-10, Fas L and CTLA-4, which lead to the suppression of the T cell response (Fernandes et
447
al., 2008).
448
6.2
449
proteases have been intensively investigated as potential virulence factors. It is evident that secreted
450
proteases are important for the virulence of dermatophytes because these fungi grow exclusively in the
451
stratum corneum, nails or hair, which constitutes their sole nitrogen and carbon sources (Monod et al.,
452
2002). The proteases secreted by C. albicans are involved in the adherence process and penetration of
453
tissues and in interactions with the immune system, thereby stimulating inflammatory process in the
454
infected host. (Wu 2013, Pietrella, 2013). S. schenckii produces proteases that are able to cleave
455
different subclasses of human IgG, suggesting a sequential production of antigens and molecules that
456
could interact and interfere with the immune response of the host (da Rosa et al., 2009). Other effects
457
of proteases secreted by S schenckii are being investigated.
458
6.3
459
infections with S. schenkii reveal a transitory early immunosuppression, favoring a fungal burden.
460
Studies performed by Carlos et al. demonstrate the production of interleukin-1 (IL-1) and TNF by
461
adherent peritoneal cells from BALB/c mice, which was measured at week 2, 4, 6, 8 and 10 after
462
intravenous inoculation with 106 S. schenckii yeasts. Compared with age-matched controls, IL-1 and
463
TNF production by adherent peritoneal cells from S. schenckii-infected mice was reduced severely at
464
week 4 and 6 of infection and was greater than normal at weeks 8 and 10. Moreover, between week 4
465
and 6 of infection, there was a depression of the delayed type hypersensitivity response to a specific
466
whole soluble antigen and an increase in fungal multiplication in the livers and spleens of the infected
467
mice. Thus, the deficits of cell-mediated immunity in the mice with systemic S. schenckii infection
468
may derive, in part, from an impaired amplification of the immune response due to the abnormal
469
generation of IL-1 and TNF (Carlos et al., 1994). Other reports have demonstrated that, although nitric
470
oxide NO is an essential mediator in the in vitro killing of S. schenckii by macrophages, the activation
Production of proteases: Many species of human pathogenic fungi secrete proteases. Fungal
Transitory early immunosuppression: Different reports derived from mouse models of
14
471
of the NO system in vivo contributes to the immunosuppression and cytokine balance during the early
472
phases of infection with S. schenckii (Fernandes et al., 2008).
473
6.4
474
called exoantigen (ExoAg), has been identified as an important virulence factor for sporotrichosis
475
(Nascimento et al., 2008; Teixeira et al., 2009). The main immunogenic proteins of the cell wall (gp 70
476
and gp 40) are present in the ExoAg, and it is thought that the secretion of this outer component can
477
distract several immune mechanisms and serve as a fungal evasion mechanism (Carlos et al., 2009).
478
This hypothesis needs to be confirmed.
479
6.5
480
localized lymphocutaneous disease in the immunocompetent host, while it frequently results in
481
disseminated disease in the immunocompromised patient. Disseminated sporotrichosis occurs in
482
individuals with impaired cellular immunity, such as in cases of neoplasia, transplantation, diabetes,
483
and especially acquired immunodeficiency syndrome (AIDS) (Wroblewska et al., 2005; Silva-Vergara
484
et al., 2012; Freitas et al., 2012). The extracutaneous forms of sporotrichosis without skin
485
manifestations and no previous history of traumatic injuries have been described in renal transplant
486
recipients not treated with antifungal prophylaxis (Gewehr et al., 2013). Additionally, this disease has
487
been described in a patient with X-linked chronic granulomatous disease (CGD) (Trotter et al., 2014).
488
Interestingly, more than 20 cases of sporotrichosis meningitis have been reported, several of these
489
were associated with immunosuppression (Silva-Vergara et al., 2005; Vilela et al., 2007; Galhardo et
490
al., 2010).
491
4. Concluding remarks and future perspectives
492
The vast majority of human pathogenic fungi are environmental fungi, which normally live outside the
493
human body and can cause infections in certain susceptible hosts. These fungi have most likely gained
494
their pathogenic potential in environmental niches, which resemble certain aspects of the host body. In
495
these environmental niches, fungi acquire the capacity to adhere to surfaces, form biofilms, compete
496
with bacteria, acquire all necessary nutrients and deal with changes in temperature, UV radiations, pH,
497
osmolarity, environmental chemical contaminants, meteorological factors and other physical, chemical
498
and biological stress factors. In addition, these fungi may be challenged by amoebae, which share
499
many characteristics with human phagocytes (Davis et al., 1991). Thus, in nature or in animal hosts,
500
fungal cells must respond efficiently to changing environmental conditions in order to survive (Pérez-
501
Sánchez et al., 2010).
502
The S. schenkii complex uses signal transduction pathways to sense the environment and to adapt
503
quickly to changing conditions (Rodriguez-Caban et al., 2011). Despite these findings, little is known
504
about the genetic mechanisms of virulence and drug resistance in the S. schenckii complex. The
The liberation of exo-antigens: A peptide-polysaccharide released from the fungal cell wall,
Opportunistic infections in immunodeficient hosts: Infection with S. schenckii causes a
15
505
ecological niches occupied by the S. schenckii complex are extraordinarily complex and variable and
506
most likely include biologic elements such as other fungi, viruses, bacteria, animals, protists, algae and
507
plants; together with physical (e.g., temperature, humidity, radiations) and chemical components (pH,
508
metals, hydrocarbons, pesticides, etc.).
509
The chronic effect of some of these components including heavy metals, UV radiations and pesticides
510
with immunotoxic effects in potential hosts, such as cats and other animals and outdoor workers such
511
as farmers and gardeners, can contribute to the occurrence of fungal infection. The understanding of
512
the interactions between fungi and their potential hosts in the environment is in its infancy; however,
513
initial observations suggest that this will be an extremely rich area of investigation for exploring the
514
fundamental questions of fungal pathogenesis (Casadewall et al., 2003; Prenafeta-Boldu et al., 2006).
515
This knowledge will contribute to the design of new strategies for the control of sporothrichosis.
516 517
Competing Interests: The authors declare that no competing interests exist.
518 519 520 521
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947
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948
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949 950 951
Table 1. Some attributes of S. schenckii complex with demonstrated or putative effects in the protection against environmental stressors and as virulence factor in the host (dual use) 952 953 Functi on
Attribute
In the environment
In the host
Sel ected references
Cell wall
Pr otects the cell from drasti c changes in
Protects the cel l from
Oda et al., ., 1983; Carlos et
the external environment
aggressive conditions in the
al.,
host ti ssue
2010; López-Esparza et al., 2013
Mel anin
Ultraviol et shi elding, extreme
Resistant to phagocytosis and
Almeida-Paes et al.,
temperature
oxidative kil ling by phagocytic
Romero-Martinez et al.,
cells. Antifungal drug
2000
resi stance
Morris-Jones et al.,
Pr otection against oxidative kil ling by
Protection against oxidat ive
Sgarbi et al.,
soil amoebas?
killing by phagocytic cells
Myceli um morphology in its saprophytic
Yeast morphology in host
Nemecek et al.,
phase
tissues at 35-37°C
Gauthi er et al.,
Romeo and Criseo 2013
protection, reduced
susceptibility to enzymatic degradation
Ergosterol
Dimorphism
Genetic polymorphism
Adhesins
954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975
2003; Madrid et al., .
Generation of strain diversity to survive
Antifungal drug resistance.
to environmental str ess?
Different vir ulence profile
2009
2003
1997
2006; 2008
In other fungi, adhesi on genes are
Adhesion to the dermal and
Verstrepen et al.,
activated by diverse environmental
subendothelial matrix,
Samper mans et al. ,
triggers like carbon and/or nitrogen
transposition of the
Figueiredo et al., .,2007;
starvati on, changes in pH or ethanol
endothelial barri er,
Lima et al. , . ,1999, 2001,
levels.
Immunomodulators
2004; Ruiz-Baca et al., .
2003;
2005;
2008; Nascimento et al., . , 2008; Teixeira et al., Pr oteinase
Nutritional function
Catalase
Pr otection against ROS of soil amoebas?
Superoxide dismutase
Pr otection against oxygen derived
Tissue damage; degradation of
De Rosa et al .,
antibodi es
et al.,
Protection agai nst ROS of host
Davis et al.,
phagocytes
et al.,
Intracellular growth
Pérez-Sánchez et al.,
2002
1991; Xiao-Hui
2008;
oxidants? Nitroreductase
Tolerance to environmental
Resistance to NO in
Stopiglia et al., 2013
contaminants?
phagocytes?
Aviv et al., 2014
Siderophores
Iron uptake in the environmental
Iron uptake inside the host
SSG-1
Survival under conditions of stress and nutrient li mitation inside the human host or the envi ronment .
976 29
2013
2009; Monod
2010
Pérez-Sánchez et al.,
2010
Pérez-Sánchez et al.,
2010
977 978 979 980 981 982 983 984 985 986 987 988
Fig 1. Environmental stressor promotes Sporothrix schenckii virulence.The origin of virulence in S. schenckii should be related to interactions of the pathogen with different environmental challengers
present in their natural habitat. These adaptive changes permit to acquire survival capacity tending to a higher virulence. * Dimorphism, Genetic polymorphism, Cell wall, Melanin, Expression of adhesins, Enzyme production.
30
Environment
Cell wall
Melanin
Ergosterol
Host tissue
Genetic polymorphism Dimorphism Adhesins Catalase Superoxide dismutase Proteinases SSG-1
Extreme temperatures, pH, osmotic pressure and humidity. radiations, chemicals. soil amoebas.
Siderophore s
Sporothrix schenckii complex (Constitutive and inducible virulence factors)
Adhesion, resistant to phagocytosis and killing by phagocytic cells, tissue damage, degradation of antibodies, iron uptake, immunosupresion, antifungal drug resistance
1
Sporothrix schenckii complex biology: environment and fungal pathogenicity
2
Téllez MDa, Batista-Duharte Ab,c,d*, Portuondo Dc, Quinello Cc, Bonne-Hernández Rd, Carlos IZc*
3 4 5 6 7 8
a
9
* Corresponding authors
Faculty of Chemical Engineering. Oriente University. Ave Las Americas, Santiago de Cuba, Cuba, b Immunotoxicology Laboratory, Toxicology and Biomedicine Center (TOXIMED), Medical Science University, Autopista Nacional Km. 1 1/2 CP 90400, Santiago de Cuba, Cuba c Faculty of Pharmaceutical Sciences. Universidade Estadual Paulista Julio Mesquita Filho, UNESP. Rua Expedicionarios do Brasil 1621-CEP:14801-902, Araraquara, SP, Brazil, d Universidade Federal de São Paulo, São Paulo-SP, Brasil, d CAPES/Brasil Grant. Foreigner Visiting Professor Program.
10
Profa. Dra. Iracilda Zeppone Carlos: Faculty of Pharmaceutical Sciences of Araraquara. Universidade
11
Estadual Paulista Julio Mesquita Filho, UNESP. Araraquara, São Paulo. Brazil. CEP:14801-902
12
Phone 55 16 3301-5712. E-mail: [email protected]
13
Prof Dr. Alexander Batista-Duharte: Phone 55 16 3301-5713. E-mail: [email protected]
14
Abstract
15
Sporothrix schenckii is a complex of various species of fungus found in soils, plants, decaying
16
vegetables and other outdoor environment. It is the etiological agent of sporotrichosis in humans and
17
several animals. Humans and animals can acquire the disease through traumatic inoculation of the
18
fungus into subcutaneous tissue. Despite the importance of sporotrichosis as a disease, which is
19
currently regarded as an emergent disease in several countries, the factors driving its increasing
20
medical importance are still largely unknown. There are only a few studies addressing the influence of
21
the environment on the virulence of these pathogens. However, some recent discoveries made in
22
studies of the biology of S. schenckii are demonstrating that adverse conditions in its natural habitats
23
can trigger the expression of different virulence factors that confer survival advantages in both animal
24
hosts and in the environment. In this review, we provide updates on the important advances in the
25
understanding of the biology of S. schenckii and the modification of their virulence linked to
26
demonstrated or putative environmental factors.
27
Keywords: Sporotrichosis, Sporothrix schenckii complex, virulence, environmental, ‘dual use’
28
Word count of summary: 170
29
Word count of main text: 6689
30
Total number of tables: 1
Total number of figures: 1
1
31
1. Introduction
32
Sporotrichosis is an acute or chronic granulomatous mycosis of humans and mammals that has a
33
worldwide distribution. Initially the causal agent of this disease was thought to be a unique thermally
34
dimorphic fungus Sporothrix schenckii; however, it has been recently proposed, based on physiologic
35
and molecular aspects, that S. schenckii is a complex of various species (Lopes-Bezerra, 2006;
36
Marimon et al., 2007; Marimon et al., 2008; Evangelista et al., 2014). Sporotrichosis was originally
37
described in 1898 by Schenck at the Johns Hopkins Hospital in Baltimore, who recognized that the
38
infection was most likely due to a previously undescribed fungal pathogen (Schenck, 1898). Two years
39
later, Hektoen and Perkins confirmed these observations in a report of a second case and a detailed
40
morphological description of the pathogen, which included studies involving laboratory animals
41
(Hektoen and Perkins 1900). Other cases in the United States and western Europe were recognized,
42
especially in France, where large numbers of cases were reported in the early 20th century (de
43
Beurmann, 1912).
44
Recently, S. schenckii has received particular attention due to the increased number of infections
45
caused worldwide. Currently, the presence the S. schenckii complex and cases of sporotrichosis have
46
been reported from all of the continents (Madrid et al., 2009; Barros et al., 2010) and in different
47
geographic regions, such as tropical and subtropical regions. Some areas have declared sporotrichosis
48
an emerging health problem, with a growing interest for sanitary authorities (Feeney et al., 2007; Hay
49
and Morris-Jones, 2008; López-Romero et al., 2011; Messias, 2013). Sporotrichosis is now the most
50
common subcutaneous mycosis in the Americas (especially Brazil, Mexico, Peru, Colombia and
51
Uruguay) and also in Japan, India and South Africa (Carrada-Bravo et al., 2013). A particular
52
geographical area called Abancay, in the south central Peruvian highlands, is considered a
53
hyperendemic area, with an estimated incidence of approximately 50–60 cases per 100,000 inhabitants
54
per year (Bustamante and Campos, 2001). Meanwhile in Brazil there are increasing reports of
55
sporotrichosis in areas where the disease was rare decades ago, with an intriguing zoonotic
56
transmission by cats (Borges et al., 2013; Rodrígues et al., 2013a,b). In Europe, sporotrichosis is less
57
common, although it was also a common disease in France in 1900 but declined after two decades.
58
Currently, sporotrichosis is intermittently reported in several others countries, such as Italy, Spain,
59
Portugal, United Kingdom and Turkey (Criseo et al., 2008; Ojeda et al., 2011; Dias et al., 2011;
60
Gürcan et al., 2007). Other interesting observation is that from the beginning of the AIDS (Acquired
61
Immunodeficiency Syndrome) era, new clinical forms of disseminated sporothrichosis have been
62
reported, including cerebral, endocardial and ocular involvement (Galhardo et al., 2010; Ramos-e-
63
Silva et al., 2012; Silva-Vergara et al., 2012). 2
64
A presence or even an abundance of the fungus in nature is not enough to explain the development of
65
the disease. Although the fungus is frequently isolated in environmental and commercial samples, it is
66
unclear why sporotrichosis has a low incidence. However, the different local emerging outbreaks
67
reaching sometimes epidemic proportions lead to questions regarding the relevance of the host in the
68
development of the disease (López-Romero et al., 2011), the virulence associated with genetic
69
polymorphisms in the S. schenckii complex (Sasaki et al., 2014), and other environmentally associated
70
factors not sufficiently studied yet.
71
The aim of this work is to provide an update on the recent advances in the understanding of Sporothrix
72
schenckii complex biology, addressing different ways through which environmental factors may
73
modify the virulence of the fungus, as a possible contribution to the sporotrichosis outbreaks.
74
2- The Sporothrix schenkii complex and sporotrichosis
75
The genus Sporothrix is a species-rich taxon of Ascomycetes, which varies according to the ecological
76
niche, frequency, distribution and virulence. Some of these fungi have the potential to survive in
77
mammalian hosts and are able to cause damage in multiple species of animals, including humans (de
78
Hoo, 1974; Fernandes et al., 2013). S. schenckii is recognized as a cryptic species complex including
79
Sporothrix brasiliensis, Sporothrix globosa, Sporothrix mexicana, Sporothrix luriei, Sporothrix pallida
80
(formerly Sporothrix albicans) and S. schenckii sensu strict (Marques et al 2014). With the exception
81
of S. pallida, the other Sporothrix species have been reported to cause sporotrichosis in humans and
82
animals (Lopes-Bezerra, 2006; Marimon et al., 2007, Marimon et al., 2008, Romeo and Criseo, 2013;
83
Evangelista et al., 2014).
84
The fungi belonging to the S. schenckii complex are ascomycetous dimorphic organisms (Ascomycota,
85
Pyrenomycetes, Ophiostomatales, Ophiostomataceae), naturally
86
living and decayed vegetation, animal excreta, and soils plentiful in cellulose, with a pH range of
87
3.5 to 9.4, a mean temperature of 31°C, and a relative humidity above 92%. This
88
phenotypically characterized by the ability to produce conidias in its filamentous form, and
89
cigar-shaped yeast-like
90
humans (Lopes-Bezerra, 2006).
91
Sporotrichosis affects humans and other mammals, such as cats, dogs, rats, armadillos, and horses. As
92
the fungus is abundant in soil, wood and moss, most infections occur following minor skin trauma in
93
people with outdoor occupations or hobbies, such as gardening, farming, hunting or other activities
94
involving close contact with vegetation and soil. The zoonotic transition from ill or carrier animals
95
(mainly cats) to man is gaining a growing importance. Similarly, an inoculation may also occur after
96
motor vehicle accidents and in laboratory personnel handling of Sporothrix-infected specimens (Barros
97
et al., 2007; Hay et al., 2008; Romeo and Criseo; 2013).
cells when cultured at
found
in
substrates
such as
fungus is
35–37°C or as the infectious form in animals and
3
98
Human disease has different clinical manifestations and can be classified into fixed cutaneous,
99
lymphocutaneous, disseminated cutaneous, and extracutaneous or systemic sporotrichosis. The fixed
100
cutaneous sporotrichosis is located in the skin and is restricted to the injury site without lymphatic
101
involvement. The lymphocutaneous sporotrichosis is the most common manifestation and is
102
characterized by papular and nodular, superficial ulcers and/or vegetative plaque lesions in the skin
103
and along the trajectory of the draining lymph vessels. The disseminated cutaneous form consists of
104
multiple and distant lesions in the skin due to hematogenous dissemination or multiple inoculations of
105
the fungus. In the extracutaneous or systemic sporotrichosis, multiple cutaneous and visceral lesions
106
involving the liver, joints, spleen, bones, marrow bones, lungs, eyes, testis and central nervous system
107
associated with cellular immunodeficiency have been described (Edwards et al., 2000; Rocha et al.,
108
2001; Ramos-e-Silva et al., 2012). Primary pulmonary sporotrichosis is another clinical type of this
109
infection caused by the inhalation of infectious conidia in contaminated environments. (Aung et al.,
110
2013).
111 112 113
3-The response of the Sporothrix schenkii complex to changing environmental conditions
114
mammalian host is not a requisite for fungal survival and virulence (Steenbergen et al., 2004). This
115
phenomenon is called by Casadewall ‘ready-made’ virulence (Casadewall et al., 2003). The influence
116
of different environmental contaminants, on pathogenic or non-pathogenic fungi has been studied
117
(Zafar et al., 2007; Gadd, 1993; Valix, 2001, 2003; Anahid et al., 2011). S. schenkii complexes are
118
present in nature in diverse environmental conditions, including polluted environments (Cooke and
119
Foter 1958; Dixon et al., 1991; Ulfig, 1994; Ulfig et al., 1996; Kacprzak, 2005; Pečiulytė 2010; Chao
120
et al., 2012; Yazdanparast et al., 2013), in a wide pH range from 2.2 to 12.5 (Tapia et al., 1993;
121
Ferreira et al., 2009) the floor of swimming pools (Staib 1983), desiccated mushrooms (Kazanas,
122
1987), fleas, ants and horse hair (Carrada-Bravo, 2013). Moreover, specific indoor environments also
123
select for certain stress-tolerant fungi and can drive their evolution towards acquiring medically
124
important traits (Gostinčar et al., 2011).
125
3.1 Physical factors: S. schenkii is able to resist extreme conditions, such as very low temperatures for
126
several years (Pasarell and Mcginnis, 1992; Mendoza et al., 2005), extreme osmotic pressure
127
(Castellani, 1967; Borba, 1992; De Capriles, 1993; Mendoza et al., 2005; Ferreira et al., 2009 ) and.
128
Some studies have revealed that different levels of ultraviolet light (UV) exposure by S. schenckii
129
strains resulted in a conserved viability, although with a high frequency of morphological variants,
130
depending on the strain and UV dose. The main morphological variants were smaller colonies or
131
changes in shape. Stable and non-stable morphological variants were found in the population, and the
The origin and maintenance of virulence in dimorphic fungi is enigmatic because an interaction with a
4
132
reversion of the mutant phenotype was always to the wild-type phenotype (Torres-Guerrero
133
and Arenas-López; 1998). In another study, the gamma radiation effects on the yeast cells of S.
134
schenckii were analyzed, showing that yeast cells remained viable up to 9.0 kGy; however, synthetic
135
protein metabolism was strongly affected, while a dose of 7.0 kGy retained viability, metabolic
136
activity, and morphology but abolished the capacity to produce infection (de Souza et al., 2011).
137
3.2 Metals: Microorganisms, including fungi, have been shown to possess an ability to survive by
138
adapting or mutating at high concentrations of toxic heavy metals. In general, two mechanisms have
139
been proposed for heavy metal tolerance in fungi: 1) extracellular sequestration with chelation and
140
cell-wall binding, mainly employed in the avoidance of metal entry and 2) intracellular physical
141
sequestration of metal by binding to metallothioneins (MT) sequestered as insoluble phosphates or
142
removed from the cell via transporters such as CadA, ZntA or PbrA, preventing the damage caused by
143
metals to sensitive cellular targets and reducing the metal burden in the cytosol. (Anahid et al., 2011;
144
Jarosławiecka and Piotrowska-Seget, 2014). Most fungi synthesize siderophores that chelate iron,
145
which is ultimately taken up as a siderophore-iron complex (Kosman et al., 2003). The capacity to
146
accumulate iron is critical for the survival of fungal pathogens in different conditions (Schaible et al.,
147
2004). Unlike other fungi, such as S. cerevisiae (Kaplan et al., 2006), S. schenckii is capable of
148
producing its own siderophores in response to low iron availability (Pérez-Sánchez et al., 2010). This
149
mechanism can be involved in the pathogenicity and survival under conditions of environmental stress
150
or inside the host.
151
3.3 Chemical contaminants: Environmental fungi can biodegrade aromatic hydrocarbons in their own
152
habitat (Cerniglia 1997). An interesting report revealed that several fungi, including S. schenckii, were
153
isolated from air biofilters exposed to hydrocarbon-polluted gas streams and assimilated volatile
154
aromatic hydrocarbons as the sole source of carbon and energy. The data in this report show that many
155
volatile-hydrocarbon-degrading strains are closely related to, or in some cases clearly conspecific with,
156
the very restricted number of human-pathogenic fungal species causing severe mycoses, especially
157
neurological infections, in immunocompetent individuals (Prenafeta-Boldu et al., 2006). In addition,
158
the effect of fungicides against several environmental pathogenic fungi was evaluated, and S. schenkii
159
had the greatest resistance to these products compared to the other fungi (Morehart and Larsh, 1967).
160
3.4 Other microorganisms: A phenomenon insufficiently studied is the interaction of the pathogenic
161
fungi with other microorganisms in the neighborhood. Chaturvedi et al. evaluated the in vitro
162
interactions between colonies of Blastomyces dermatitidis and six other zoopathogenic fungi. The
163
interactions were found to range from neutral with H. capsulatum and C. albicans to strongly
164
antagonistic with Microsporum gypseum, Pseudallescheria boydii, and Sporothrix schenckii and
165
included lysis by Cryptococcus neoformans (Chaturvedi et al., 1988). In another study, Cryptococcus 5
166
neoformans was shown to interact with macrophages, slime molds, and amoebae in a similar manner,
167
suggesting that fungal pathogenic strategies may arise from environmental interactions with
168
phagocytic microorganisms (Steenbergen et al., 2003). In another interesting report, Steenbergen et al.,
169
examined the interactions of three dimorphic fungi, Blastomyces dermatitidis, Histoplasma
170
capsulatum, and S. schenckii, with the soil amoeba, Acanthameobae castellanii. The ingestion of the
171
yeast by this amoeba resulted in amoeba death and fungal growth. For each fungal species, the
172
exposure of yeast cells to amoebae resulted in an increase in hyphal cells (Steenbergen et al., 2004).
173
The biochemical events during phagocytosis by either A. castellanii or immune phagocytes appear
174
similar, suggesting that the ‘respiratory burst’ enzyme(s) responsible for oxyradical generation in these
175
two cell types is structurally related (Davis et al., 1991). Thus, soil amoebae may contribute to the
176
selection and maintenance of pathogenic dimorphic fungi in the environment, conferring these
177
microbes with the capacity for virulence in mammals.
178
Despite that are necessary more studies evaluating the influence of different environmental factors on
179
the physiology and pathogenicity of the S. schenkii complex, all the available data suggest that the
180
strategies that pathogenic fungi acquire to survive this environmental competition may, in turn,
181
provide the ability to infect animals and may further allow the emergence of opportunistic pathogens
182
from these microenvironments (Baumgardner, 2012) (Figure 1).
183
4. Fungal elements involved in environmental resistance and pathogenicity
184
Although is known that many external influences can affect the pathogenicity of the S. schenkii
185
complex as environmental pathogenic fungi, these influences and mechanisms have not been
186
sufficiently studied in this complex. However, the presence of the same molecules interacting with
187
environmental toxins described in other fungus (Casadewall et al., 2003) is a good reason to
188
hypothesize that similar mechanism may be acting to face these extreme conditions. As Casadewall
189
reported for C. neoformans (Casadewall et al., 2003), several virulence factors in S. schenckii also
190
appear to have ‘dual use’ capabilities for the survival in both animal hosts and in the environment
191
(Table 1).
192
4.1 Dimorphism: The dimorphic fungi comprise a group of important human pathogens and represent
193
a family of seven phylogenetically related ascomycetes that include Blastomyces dermatitidis,
194
Coccidioides immitis, Coccidioides posadasii, Histoplasma capsulatum, Paracoccidioides brasiliensis,
195
Penicillium marneffei and Sporothrix schenckii. These fungi possess the unique ability to switch
196
between mold and yeast in response to thermal stimuli and other environmental conditions. In the
197
environment, they grow as mold that produces conidia or infectious spores, which, when transmitted to
198
humans or other susceptible mammalian hosts, are capable of converting to pathogenic yeasts that
199
cause serious infection (Klein and Tebbets 2007). 6
200
The dimorphism in the S. schenckii complex has also been associated with the ability to adapt to
201
environmental changes and to yield an increased virulence (Nemecek et al., 2006; Gauthier et al.,
202
2008). This fungus exhibits mycelium morphology in its saprophytic phase at 25°C in laboratory
203
conditions and a yeast morphology in host tissues at 35-37°C. On the other hand, in the environment
204
with different grades of temperatures they are able to keep the mycelial form. The formation of yeast
205
cells was thought to be a requisite for the pathogenicity of S. schenckii; however, the mechanisms that
206
regulate the dimorphic switch remain unclear. Some recent findings have begun to clarify these
207
mechanisms.
208
The principal intracellular receptors of environmental signals are the heterotrimeric G proteins, and
209
they are involved in fungal dimorphism and pathogenicity. Valentín-Berríos et al. described a new G
210
protein α subunit gene in S. schenckii: ssg-2, and they demonstrated that the SSG-2 Gα subunit of
211
40.90 kDa interacts with the cytosolic phospholipase A2 (cPLA2), participating in the control of the
212
dimorphism in this fungus (Valentín-Berríos et al., 2009).
213
The yeast-to-mycelium transition is dependent on calcium uptake (Serrano et al., 1990; Rivera-
214
Rodríguez et al., 1992). In S. schenckii, a Ca2+/Calmodulin-dependent protein kinase (CaMK)
215
encoded by the calcium/calmodulin kinase I (sscmk1) gene (GenBank accession no. AY823266) was
216
described (Valle-Aviles et al., 2007). Experiments using different inhibitors of the CaMK pathway
217
showed that they inhibited the transition from yeast cells to hyphae, which suggests a
218
calcium/calmodulin pathway is involved in the regulation of the dimorphism in S. schenckii (Valle-
219
Aviles et al., 2007). Similarly, RNAi technology was used to silence the expression of the sscmk 1
220
gene. The RNAi transformants were unable to grow as yeast cells at 35°C and showed a decreased
221
tolerance to this temperature (Rodriguez-Caban et al., 2011).
222
The mitogen-activated protein kinase (MAPK) cascade and cyclic AMP (cAMP) signaling pathways
223
are known to be involved in fungal morphogenesis and pathogenic development. The MAPK and
224
cAMP pathways are both activated by an upstream branch, two-component histidine protein kinase
225
(HPK) phospho-relay system (Hou et al., 2013). Nemecek et al. reported that a long-sought regulator
226
controls the switch from a non-pathogenic mold form to a pathogenic yeast form in dimorphic fungi.
227
They found that DRK1, a hybrid dimorphism-regulating histidine kinase, functions as a global
228
regulator of the dimorphism and virulence in B. dermatitidis and H. capsulatum and is required for the
229
phase transition from mold to yeast, expression of virulence genes, and pathogenicity in vivo.
230
(Nemecek et al., 2006). More recently, Hou et al. developed a molecular cloning, characterization and
231
differential expression of DRK1 in S. schenckii. In this report, quantitative real-time RT-PCR revealed
232
that SsDRK1 was more highly expressed in the yeast stage compared with the mycelial stage, which
233
indicated that SsDRK1 may be involved in the dimorphic switch in S. schenckii (Hou et al., 2013). 7
234
Zhang et al. reported other proteins involved in the dimorphism process. The Ste20-related kinases are
235
involved in signaling through the mitogen-activated protein kinase pathways and in morphogenesis
236
through the regulation of cytokinesis and actin-dependent polarized growth (Zhang et al., 2013). The
237
expression of other proteins that may affect biosynthetic and metabolic processes were found by
238
Zhang’s group, such as Cullin-3, CdcH and 4-coumarate-CoA ligase. The expression of these genes
239
was detected predominantly in the yeast form and due to the yeast phase, which is the form of S.
240
schenckii found in the host; the expression of these genes could reflect the ability of the yeast phase to
241
adapt to growth-limiting environments. They also demonstrated an upregulation of the Hsp70
242
chaperone Hsp88 in the development of the yeast phase of S. schenckii at 37°C; however, the precise
243
role of this gene remains unclear (Zhang et al., 2012).
244
Lipids are thought to play important roles in the regulation of the dimorphism and virulence in
245
pathogenic fungi. Generally, the ratio of phospholipid/ergosterol is less than 1 in the yeast form and 2-
246
20 in the mycelial form cells in C. albicans and S. schenckii. During the transition from the yeast to
247
mycelial
248
whereas phosphatidylcholine increases. Phospho-lipase D is activated during this transition (Kitajma,
249
2000).
250
Phorbol-12-myristate-13-acetate (PMA), a tumor promoting agent and PKC activator, was found to
251
stimulate germ tube formation and germ tube growth by yeast cells induced to undergo a transition to
252
the mycelium form in a concentration-dependent manner. PMA also had a stimulatory effect on DNA
253
and RNA synthesis in cells induced to undergo the yeast to mycelium transition and was found to
254
inhibit cell duplication and bud formation in yeast cells induced to re-enter the budding cycle. In
255
contrast, Polymyxin B, an inhibitor of PKC, inhibited germ tube formation by yeast cells. This
256
inhibition could be overcome if PMA or calcium were added to the medium, suggesting that the
257
inhibition obtained in the presence of this antibiotic was due to the inhibition of PKC. These results
258
support the involvement of PKC in the control of the dimorphic expression in S. schenckii (Colon-
259
Colon and Rodriguez-del Valle, 1993).
260
4.2 Genetic polymorphism: Recently, there has been an increasing interest in studying the biology of
261
the S. schenckii complex, and particular attention has been focused on its molecular phylogeny, which
262
has improved our knowledge of the taxonomy, pathogenic characteristics and the epidemiology of this
263
pathogenic fungus. Recent studies have shown important differences in the virulence and drug
264
resistance profiles among different species in the S. schenckii complex. S. brasiliensis is the most
265
virulent species in comparison with S. globosa and S. mexicana, which show little or no virulence in
266
murine models (Fernández-Silva et al., 2012; Fernandes et al., 2013). In addition, the test for
267
susceptibility to antifungal drugs showed that S. schenckii s. str. and S. brasiliensis were highly
forms,
phosphatidylinositol
and
8
phosphatidylserine
are
reduced,
268
susceptible to most of the antifungals tested in vitro in comparison with the more resistant, S. globosa
269
and S. mexicana species (Marimon et al., 2008). These and other observations suggest that possible
270
genetic differences may be involved.
271
The genomic organization and chromosome number in different species in the S. schenckii complex
272
remain unknown. However, sequencing studies in the calmodulin-encoding gene in the different
273
members of the S. schenkii complex have offered valuable information for elucidating the relationships
274
and differences among these species and their role in pathogenic manifestations (Romeo et al., 2011).
275
A recent study revealed a high diversity in the calmodulin gene (regulated by Ca+2) of S. schenckii. In
276
contrast, S. brasiliensis and S. globosa appeared to be more homogenous, with a low genetic diversity.
277
The electrophoretic karyotype profiles of S. brasiliensis isolates showed less variability than those
278
observed in S. schenckii sensu strictus isolates (Sasaki et al., 2014). These results were consistent with
279
the phylogenetic data, where the variability among isolates within the species was less frequent in S.
280
brasiliensis than in S. schenckii sensu strictus (Marimon et al., 2006; 2007; Rodrigues et al., 2013).
281
Future studies are necessary to determine the role of different genes from the species of the S.
282
schenckii complex in the virulence, drug resistance and environmental resistance. Changes in the
283
expression of such genes might be beneficial to S. schenckii survival from the natural environment to
284
within a host during infection. Comparative genomics and transcriptomics analysis between highly
285
pathogenic Sporothrix species and species with reduced or absent pathogenicity certainly will
286
accelerate the discovery of new proteins for diagnostics, drug targets and vaccines (Romeo and Criseo,
287
2013).
288
4.3 Cell wall: The fungal wall protects the cell from drastic changes in the external environment; it is
289
the first point of contact with the host (Mora-Montes et al., 2009). The S. schenckii cell wall is
290
composed of glucans, galactomannans, rhamnomannans, chitin, glycoproteins, glycolipids and melanin
291
(Travassos et al., 1977; Travassos and Lloyd 1980; Lopes-Bezerra et al., 2006; López-Romero et al.,
292
2011). Despite are necessary more studies to know their detailed structure, it seems to be that a proper
293
wall cell composition is required for supporting external stress and for virulence (Madrid et al., 2010;
294
López-Esparza et al., 2013).
295
4.4 Melanin: An interesting mechanism to resist environmental adverse conditions is the production of
296
melanin, also implicated in the pathogenesis of several important human fungal pathogens. Several
297
types of melanin have been described in the fungal kingdom but the majority is derived from 1.8-
298
dihydroxynaphthalene (DHN) and is known as DHN-melanin (Helene et al., 2012). Melanin has been
299
referred to as 'fungal armor,' due to the ability of the polymer to protect microorganisms against a
300
broad range of toxic insults, warranting the survival of fungi in the environment and during infection
301
(Gómez and Nosanchuk, 2003). Melanization reduces the susceptibility to enzymatic degradation, the 9
302
toxicity from heavy metals, ultraviolet and nuclear radiation, extremes of temperature, oxygen and
303
nitrogen free radicals, which may afford the fungus protection against similar insults in
304
the environment (Wang and Casadevall 1994 a, b; Rosas and Casadewall 1997, 2001, Taborda et al.,
305
2008, Gessler et al., 2014). Melanin also reduces the susceptibilities of pathogenic fungi to different
306
antifungal drugs (van Duin et al., 2003; Nosanchuk and Casadevall 2006) and to different immune
307
mechanisms in the host, especially phagocytosis (Steenbergen et al., 2004).
308
S. schenckii produces melanin or melanin-like compounds in vitro. While melanin is an important
309
virulence factor in other pathogenic fungi, this pigment also has a similar role in the pathogenesis of
310
sporotrichosis (Morris-Jones et al., 2003). Melanized cells of the wild-type S. schenckii and the albino
311
grown on scytalone-amended medium were less susceptible to killing by chemically generated
312
oxygen- and nitrogen-derived radicals and by UV light than were the conidia of mutant strains. Wild
313
type melanized conidia and the scytalone-treated albino were also more resistant to phagocytosis and
314
killing by human monocytes and murine macrophages than were the unmelanized conidia of two
315
mutants (Romero-Martinez et al., 2000). Similar to C. neoformans and P. brasiliensis, S. schenckii can
316
utilize phenolic compounds to augment melanin production, which may be associated with a
317
concomitant increase in the protection against unfavorable conditions in both the environment and
318
during infection (Almeida-Paes et al., 2009).
319
4.5 The expression of adhesins: The adhesion ability of a fungus is important in the colonization of
320
different environmental extracts and in the host is essential for colonization and the establishment of
321
infection. Specific microbial adhesins mediate adherence to host tissues by participating in
322
sophisticated interactions with some of the host proteins that compose the extracellular matrix
323
(Teixeira et al., 2013). The adhesion-encoding genes are not constitutively expressed. Instead,
324
adhesion is under tight transcriptional control by several interacting regulatory pathways. The switch
325
from non-adherence to adherence may allow yeasts to adapt to stress (Verstrepen and Klis, 2006). The
326
adhesion genes are activated by diverse environmental triggers such as carbon and/or nitrogen
327
starvation, changes in pH or ethanol levels (Verstrepen et al., 2003; Sampermans et al., 2005). Fungi
328
need to adhere to the appropriate host tissues to establish an infection site. Apart from being a stress-
329
defense mechanism, adhesion is also crucial for fungal pathogenesis: (Verstrepen and Klis, 2006).
330
The outermost layer of the cell wall of S. schenckii has molecules involved in the adhesion of the
331
fungus to host tissues and has a central role in host-pathogen interactions, mediating several
332
interactions associated with the pathogenesis of this microorganism processes. It has been reported that
333
S. schenckii adhered to fibronectin and laminin in soluble and immobilized forms (Lima et al., 1999,
334
2001, 2004) and that this is a key step for the transposition of the endothelial barrier (Figueiredo et al.,
335
2007). Independently, Ruiz-Baca et al. (2008) and Nascimento characterized a 70 kDa glycoprotein 10
336
(gp70) on the cell wall of S. schenckii that mediates the adhesion of the fungus to the dermal and
337
subendothelial matrix. This gp70 and another protein with a slightly lower molecular mass (67 kDa)
338
were detected from different isolates. This variation might be related to differences in glycosylation
339
(Teixeira et al., 2009). Interestingly, sera obtained from patients with sporotrichosis reacted mainly
340
with the 40 and 70 kDa antigens (Scott and Muchmore, 1989; Lopes-Alves et al., 1994). In addition,
341
hyperimmune sera of mice infected with S. schenckii reacted with gp 70 (Birth and Adams, 2005), and
342
monoclonal antibodies specific for gp70 were protective against experimental infection (Nascimento et
343
al., 2008). Moreover, recently the Lopes-Becerra´s group reported that reduced level of gp70
344
expression was found in virulent S. brasiliensis and S schenckii strains, while a high expression of this
345
molecule is associated with a lower virulence profile of the strains. This would be other evidence this
346
antigen induces a protective host response (Castro et al., 2013).
347
In other pathogenic microorganism, Staphylococcus aureus, many molecules involved in adhesion are
348
also involved in
349
adhesion (Zecconi and Scali, 2013). However, in the case of the S. schenckii complex, the role of their
350
adhesins as immune evasion factors is unknown.
351
4.6 Enzyme production: The Pires de Camargo group studied the different enzymatic activities
352
related to fungal virulence of 151 Brazilian S. schenckii isolates from 5 different geographic regions of
353
Brazil. All (100%) of the S. schenckii isolates presented urease and DNase activities. Only three
354
(15.78%) isolates (one from the North and two from the Southeast region) showed gelatinase activity,
355
and five (26.31%) isolates (one from the North, three from the Northeast, and one from the Southeast
356
region) showed proteinase activities of 0.68, 0.88, 0.85, 0.55, and 0.78, respectively. Additionally,
357
only four (21.05%) isolates (one from the North, one from the Central West, and two from the
358
Southeast region) showed caseinase activities of 0.75, 0.87, 0.89, and 0.87, respectively (Ferreira et al.,
359
2009). Another report of isolates from Venezuela confirmed the urease activity (Mendoza et al., 2005),
360
while another study in India reported that all of the mycelial forms of S. schenckii could split urea
361
(Ghosh et al., 2002).
362
However, Fernandes et al. from the same group of Pires de Camargo, also found that while the “highly
363
virulent” S. schenckii isolates show a profile of secreted enzymes (proteinase, caseinase, gelatinase,
364
DNase and urease), most of these enzymes were not observed in the hypervirulent species S.
365
brasiliensis (Fernandes et al., 2009). This observation indicates that the mechanisms promoting
366
pathogenesis are much more complex, perhaps not conserved among closely related Sporothrix species
367
and most likely involve different virulence factors to evade the host immune system (Romeo and
368
Criseo, 2013).
different immune evasion mechanisms, not related to the specific process of
11
369
An interesting enzyme present in S. schenkii complex is the nitroreductase, a member of a group of
370
enzymes that reduces the wide range of nitroaromatic compounds and has potential industrial
371
applications (Stopiglia et al., 2013). Nitroreductase activity has been detected in a diverse range of
372
bacteria and in yeast (Lee et al., 2008; Xu et al., 2007; Aviv et al., 2014). A recent study in an
373
emergent Salmonella enterica serovar Infantis strain, demonstrated that the fixation of adaptive
374
mutations in the DNA gyrase (gyrA) and nitroreductase (nfsA) genes, conferred resistance to
375
quinolones and nitrofurans and contributes to stress tolerance and pathogenicity of this bacteria (Aviv
376
et al., 2014). The possible role of the nitroreductase in the S. schenckii tolerance to environmental
377
adverse conditions and in the host, the resistance to oxidative stress, to antifungal drug and other
378
aspects involved in the pathogeny are matters needing to be studied.
379
Additionally, the recent finding in S. schenkii of intracellular molecules and signals associated with the
380
heterotrimeric G protein alpha subunit SSG-1, involved in the response to different external adverse
381
conditions, help to explain how this fungus is able to survive under external stress (environmental and
382
inside the host) (Valentín-Berríos et al., 2009; Pérez-Sánchez et al., 2010).
383
5. Infections of an alternative host
384
Sporothrichosis is a human mycosis; however, ultimately there is an alarming increase in the
385
frequency of infections in domestic animals, principally in cats, which has led to an increase in the
386
relevant importance from an epidemiological perspective (Smilack; Reed et al., 1993; De Lima et al.,
387
2001; Barros et al., 2008; Lloret et al., 2013). Its ease of transmission to cohabitant humans and other
388
animals, especially by bites and scratches, makes it a significant zoonosis (Read et al., 1982; Nusbaum
389
et al., 1983; Dunstan et al., 1986). Cats develop disseminated skin ulcers, with often fatal infection
390
(Lloret et al., 2013). The fungus is spread from an ulcer or from bites and scratches. The propensity of
391
cats to transmit the infection to humans may be attributable to the large number of organisms
392
associated with the lesions in most infected cats (Yegneswaran et al., 2009).
393
However, there are reports of the presence of S. schenckii in samples from the nails of apparently
394
healthy domestic cats (Schubach et al., 2001, 2002). The cat habit of digging holes and covering their
395
excrements with soil and sand, and sharpening its nails on trees, woods or trunks, are most likely
396
responsible for the carriage of the fungus on its nails and claws, even as healthy carriers (Carrada-
397
Bravo and Olvera Macías 2013). These healthy carriers can be important in the dissemination of the
398
fungus and the occurrence of sporothrichosis cases when the conditions are favorable. Human
399
infections have also been associated with insect stings, fish handling, and the bites or scratches from
400
birds, dogs, squirrels, horses, reptiles, parrots and rodents, even though clinical symptoms may not be
401
present in these animals (Werner and Werner, 1994; Kauffman, 1999; Liu and Lin, 2001; Ranjana et
402
al., 2001; Haddad et al., 2002; Barros et al., 2011; Carrada-Bravo and Olvera-Macías, 2013). 12
403 404
6. The ability to escape from host immune mechanisms
405
Members of the S. schenckii complex are able to produce localized infections in immunocompetent
406
hosts. They have developed different mechanisms permitting the escape from host immunological
407
mechanisms.
408
6.1 Phagocytosis inhibition: It has long been reported that phagocytosis is an important defense
409
mechanisms against S. schenckii (Cunningham et al., 1979; Oda et al., 1982). The recognition of the
410
fungus is mediated by molecules such as Toll-like receptors (TLRs): TLR2 (Negrini et al., 2013;
411
2014), TLR4 (Sassa et al., 2012) and carbohydrate receptors (Guzman-Beltran et al., 2012). Sialic acid
412
residues are expressed at the cell surface of S. schenckii (Alviano et al., 1982). These residues protect
413
unopsonized fungal cells from phagocytosis by resident mouse peritoneal macrophages. The enzymatic
414
removal of sialic acids from the external layers of S. schenckii envelopes renders yeast cells more
415
susceptible to phagocytosis (Oda et al., 1982; Alviano et al., 1999). Other in vitro studies have shown
416
that galactomanan, ramnomanan and a lipid extract purified from the fungal cell wall are able to inhibit
417
the phagocytosis of S. schenckii yeast by peritoneal macrophages (Oda et al., 1983; Carlos et al.,
418
2003).
419
Several processes associated with phagocytosis, such as the cytotoxicity mediated by reactive oxygen
420
and nitrogen species (ROS and NO), are involved in the destruction of invading organisms, and their
421
virulence may be related to a differential susceptibility to these mediators (Fernandez et al., 2000;
422
Carlos et al., 2009; Sassa et al., 2012; Xiao-Hui et al., 2008). A study demonstrated that the S.
423
schenckii catalase is involved in the defense against the ROS induced by environmental changes in
424
vitro, and they proposed that catalase, as a main component of antioxidant defense, may contribute to
425
the survival of S. schenckii during infection. Moreover, it is known that ergosterol is the major sterol
426
observed in fungal membranes (Weete, 1989), while ergosterol peroxide, the putative product of the
427
H2O2 dependent enzymatic oxidation of ergosterol (Bates et al.,
428
membrane of S. schenckii, which could inactivate or scavenge toxic oxygen products that are formed
429
in phagocytic cells (Basaga, 1990; Sgarbi et al., 1997). It is conceivable that in S. schenckii, ergosterol
430
peroxide is formed as a protective mechanism to evade reactive oxygen species during phagocytosis
431
(Sgarbi et al., 1997).
432
Carlos et al. studied the effect of three different components of the S. schenckii wall cell (a lipid
433
extract, exoantigens and the alkali-insoluble fraction) and observed a drastic inhibition of the
434
phagocytosis of yeast in murine peritoneal macrophages previously treated with a lipid extract. This
435
inhibitory effect was associated with a high production of Tumor Necrosis Factor alpha (TNF-α) and
436
Nitric oxide (NO) (Carlos et al., 2003). Studies performed in our laboratory demonstrated a high 13
1976), is a constituent of the
437
fungal burden in a murine model of S. schenckii infection during the 2nd and 4th after a previous high
438
production of NO (unpublished data). Similarly, Niedbala et al. reported that NO induces a population
439
of CD4(+)CD25(+)Foxp3(-) regulatory T cells (NO-Tregs) that suppress the functions of
440
CD4(+)CD25(-) effector T cells in vitro and in vivo (Niedbala et al., 2007; 2011). The helper 17
441
(Th17) cells are important in antifungal mechanisms (Hernández-Santos and Gaffen, 2012).
442
Interestingly, recently it was discovered that NO-Tregs suppressed Th17 but not Th1 cell
443
differentiation and function, suggesting a differential suppressive function between NO-Tregs and
444
natural Tregs (nTregs) (Niedbala et al., 2013). In addition, severe infection promotes the release of
445
proinflammatory mediators, including TNF-α and NO, with the subsequent induction of molecules,
446
such as IL-10, Fas L and CTLA-4, which lead to the suppression of the T cell response (Fernandes et
447
al., 2008).
448
6.2
449
proteases have been intensively investigated as potential virulence factors. It is evident that secreted
450
proteases are important for the virulence of dermatophytes because these fungi grow exclusively in the
451
stratum corneum, nails or hair, which constitutes their sole nitrogen and carbon sources (Monod et al.,
452
2002). The proteases secreted by C. albicans are involved in the adherence process and penetration of
453
tissues and in interactions with the immune system, thereby stimulating inflammatory process in the
454
infected host. (Wu 2013, Pietrella, 2013). S. schenckii produces proteases that are able to cleave
455
different subclasses of human IgG, suggesting a sequential production of antigens and molecules that
456
could interact and interfere with the immune response of the host (da Rosa et al., 2009). Other effects
457
of proteases secreted by S schenckii are being investigated.
458
6.3
459
infections with S. schenkii reveal a transitory early immunosuppression, favoring a fungal burden.
460
Studies performed by Carlos et al. demonstrate the production of interleukin-1 (IL-1) and TNF by
461
adherent peritoneal cells from BALB/c mice, which was measured at week 2, 4, 6, 8 and 10 after
462
intravenous inoculation with 106 S. schenckii yeasts. Compared with age-matched controls, IL-1 and
463
TNF production by adherent peritoneal cells from S. schenckii-infected mice was reduced severely at
464
week 4 and 6 of infection and was greater than normal at weeks 8 and 10. Moreover, between week 4
465
and 6 of infection, there was a depression of the delayed type hypersensitivity response to a specific
466
whole soluble antigen and an increase in fungal multiplication in the livers and spleens of the infected
467
mice. Thus, the deficits of cell-mediated immunity in the mice with systemic S. schenckii infection
468
may derive, in part, from an impaired amplification of the immune response due to the abnormal
469
generation of IL-1 and TNF (Carlos et al., 1994). Other reports have demonstrated that, although nitric
470
oxide NO is an essential mediator in the in vitro killing of S. schenckii by macrophages, the activation
Production of proteases: Many species of human pathogenic fungi secrete proteases. Fungal
Transitory early immunosuppression: Different reports derived from mouse models of
14
471
of the NO system in vivo contributes to the immunosuppression and cytokine balance during the early
472
phases of infection with S. schenckii (Fernandes et al., 2008).
473
6.4
474
called exoantigen (ExoAg), has been identified as an important virulence factor for sporotrichosis
475
(Nascimento et al., 2008; Teixeira et al., 2009). The main immunogenic proteins of the cell wall (gp 70
476
and gp 40) are present in the ExoAg, and it is thought that the secretion of this outer component can
477
distract several immune mechanisms and serve as a fungal evasion mechanism (Carlos et al., 2009).
478
This hypothesis needs to be confirmed.
479
6.5
480
localized lymphocutaneous disease in the immunocompetent host, while it frequently results in
481
disseminated disease in the immunocompromised patient. Disseminated sporotrichosis occurs in
482
individuals with impaired cellular immunity, such as in cases of neoplasia, transplantation, diabetes,
483
and especially acquired immunodeficiency syndrome (AIDS) (Wroblewska et al., 2005; Silva-Vergara
484
et al., 2012; Freitas et al., 2012). The extracutaneous forms of sporotrichosis without skin
485
manifestations and no previous history of traumatic injuries have been described in renal transplant
486
recipients not treated with antifungal prophylaxis (Gewehr et al., 2013). Additionally, this disease has
487
been described in a patient with X-linked chronic granulomatous disease (CGD) (Trotter et al., 2014).
488
Interestingly, more than 20 cases of sporotrichosis meningitis have been reported, several of these
489
were associated with immunosuppression (Silva-Vergara et al., 2005; Vilela et al., 2007; Galhardo et
490
al., 2010).
491
4. Concluding remarks and future perspectives
492
The vast majority of human pathogenic fungi are environmental fungi, which normally live outside the
493
human body and can cause infections in certain susceptible hosts. These fungi have most likely gained
494
their pathogenic potential in environmental niches, which resemble certain aspects of the host body. In
495
these environmental niches, fungi acquire the capacity to adhere to surfaces, form biofilms, compete
496
with bacteria, acquire all necessary nutrients and deal with changes in temperature, UV radiations, pH,
497
osmolarity, environmental chemical contaminants, meteorological factors and other physical, chemical
498
and biological stress factors. In addition, these fungi may be challenged by amoebae, which share
499
many characteristics with human phagocytes (Davis et al., 1991). Thus, in nature or in animal hosts,
500
fungal cells must respond efficiently to changing environmental conditions in order to survive (Pérez-
501
Sánchez et al., 2010).
502
The S. schenkii complex uses signal transduction pathways to sense the environment and to adapt
503
quickly to changing conditions (Rodriguez-Caban et al., 2011). Despite these findings, little is known
504
about the genetic mechanisms of virulence and drug resistance in the S. schenckii complex. The
The liberation of exo-antigens: A peptide-polysaccharide released from the fungal cell wall,
Opportunistic infections in immunodeficient hosts: Infection with S. schenckii causes a
15
505
ecological niches occupied by the S. schenckii complex are extraordinarily complex and variable and
506
most likely include biologic elements such as other fungi, viruses, bacteria, animals, protists, algae and
507
plants; together with physical (e.g., temperature, humidity, radiations) and chemical components (pH,
508
metals, hydrocarbons, pesticides, etc.).
509
The chronic effect of some of these components including heavy metals, UV radiations and pesticides
510
with immunotoxic effects in potential hosts, such as cats and other animals and outdoor workers such
511
as farmers and gardeners, can contribute to the occurrence of fungal infection. The understanding of
512
the interactions between fungi and their potential hosts in the environment is in its infancy; however,
513
initial observations suggest that this will be an extremely rich area of investigation for exploring the
514
fundamental questions of fungal pathogenesis (Casadewall et al., 2003; Prenafeta-Boldu et al., 2006).
515
This knowledge will contribute to the design of new strategies for the control of sporothrichosis.
516 517
Competing Interests: The authors declare that no competing interests exist.
518 519 520 521
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Table 1. Some attributes of S. schenckii complex with demonstrated or putative effects in the protection against environmental stressors and as virulence factor in the host (dual use) 952 953 Functi on
Attribute
In the environment
In the host
Sel ected references
Cell wall
Pr otects the cell from drasti c changes in
Protects the cel l from
Oda et al., ., 1983; Carlos et
the external environment
aggressive conditions in the
al.,
host ti ssue
2010; López-Esparza et al., 2013
Mel anin
Ultraviol et shi elding, extreme
Resistant to phagocytosis and
Almeida-Paes et al.,
temperature
oxidative kil ling by phagocytic
Romero-Martinez et al.,
cells. Antifungal drug
2000
resi stance
Morris-Jones et al.,
Pr otection against oxidative kil ling by
Protection against oxidat ive
Sgarbi et al.,
soil amoebas?
killing by phagocytic cells
Myceli um morphology in its saprophytic
Yeast morphology in host
Nemecek et al.,
phase
tissues at 35-37°C
Gauthi er et al.,
Romeo and Criseo 2013
protection, reduced
susceptibility to enzymatic degradation
Ergosterol
Dimorphism
Genetic polymorphism
Adhesins
954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975
2003; Madrid et al., .
Generation of strain diversity to survive
Antifungal drug resistance.
to environmental str ess?
Different vir ulence profile
2009
2003
1997
2006; 2008
In other fungi, adhesi on genes are
Adhesion to the dermal and
Verstrepen et al.,
activated by diverse environmental
subendothelial matrix,
Samper mans et al. ,
triggers like carbon and/or nitrogen
transposition of the
Figueiredo et al., .,2007;
starvati on, changes in pH or ethanol
endothelial barri er,
Lima et al. , . ,1999, 2001,
levels.
Immunomodulators
2004; Ruiz-Baca et al., .
2003;
2005;
2008; Nascimento et al., . , 2008; Teixeira et al., Pr oteinase
Nutritional function
Catalase
Pr otection against ROS of soil amoebas?
Superoxide dismutase
Pr otection against oxygen derived
Tissue damage; degradation of
De Rosa et al .,
antibodi es
et al.,
Protection agai nst ROS of host
Davis et al.,
phagocytes
et al.,
Intracellular growth
Pérez-Sánchez et al.,
2002
1991; Xiao-Hui
2008;
oxidants? Nitroreductase
Tolerance to environmental
Resistance to NO in
Stopiglia et al., 2013
contaminants?
phagocytes?
Aviv et al., 2014
Siderophores
Iron uptake in the environmental
Iron uptake inside the host
SSG-1
Survival under conditions of stress and nutrient li mitation inside the human host or the envi ronment .
976 29
2013
2009; Monod
2010
Pérez-Sánchez et al.,
2010
Pérez-Sánchez et al.,
2010
977 978 979 980 981 982 983 984 985 986 987 988
Fig 1. Environmental stressor promotes Sporothrix schenckii virulence.The origin of virulence in S. schenckii should be related to interactions of the pathogen with different environmental challengers
present in their natural habitat. These adaptive changes permit to acquire survival capacity tending to a higher virulence. * Dimorphism, Genetic polymorphism, Cell wall, Melanin, Expression of adhesins, Enzyme production.
30
Environment
Cell wall
Melanin
Ergosterol
Host tissue
Genetic polymorphism Dimorphism Adhesins Catalase Superoxide dismutase Proteinases SSG-1
Extreme temperatures, pH, osmotic pressure and humidity. radiations, chemicals. soil amoebas.
Siderophore s
Sporothrix schenckii complex (Constitutive and inducible virulence factors)
Adhesion, resistant to phagocytosis and killing by phagocytic cells, tissue damage, degradation of antibodies, iron uptake, immunosupresion, antifungal drug resistance
