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Cell Microbiol. Author manuscript; available in PMC 2016 September 01. Published in final edited form as: Cell Microbiol. 2015 September ; 17(9): 1286–1294. doi:10.1111/cmi.12484.

Innate Immunity against Leishmania Infections Prajwal Gurung1 and Thirumala-Devi Kanneganti1,* 1Department

of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

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Leishmaniasis is a major health problem that affects more than 300 million people throughout the world. The morbidity associated with the disease causes serious economic burden in Leishmania endemic regions. Despite the morbidity and economic burden associated with Leishmaniasis, this disease rarely gets noticed and is still categorized under neglected tropical diseases. The lack of research combined with the ability of Leishmania to evade immune recognition has rendered our efforts to design therapeutic treatments or vaccines challenging. Herein, we review the literature on Leishmania from innate immune perspective and discuss potential problems as well as solutions and future directions that could aid in identifying novel therapeutic targets to eliminate this parasite.

Keywords Leishmania; Complement; TLR; NLR

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Introduction

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More than 12 million people are currently infected with Leishmania and 2 million new cases of Leishmaniasis are reported every year (Kedzierski, 2010, Alvar et al., 2012, CDC, 2013). Leishmania is a protozoan parasite transmitted to mammalian hosts by the bite of infected Phlebotomine sandflies (Sacks et al., 2002, Kaye et al., 2011). Leishmania have two major stages, promastigotes and amastigotes. Promastigotes, which have elongated slender body and flagella on its anterior end, are very motile and found within the gut and salivary gland of the sandfly. Amastigotes on the other hand are round in shape, do not have exterior flagella and live intracellularly in mammalian cells such as the macrophages. Promastigotes transform into amastigotes in a mammalian host and amastigotes transform into promastigotes in a sandfly. More than 20 different Leishmania spp. are known to cause disease in humans (Pearson et al., 1996). The clinical outcome of infection with Leishmania depends on both the parasite species and the host’s immune system. Leishmania spp. such as L. major, L. mexicana, L. amazonensis and L. brasilliensis are the cause of localized cutaneous infection of the skin called cutaneous Leishmaniasis

*

Correspondence should be addressed to: Thirumala-Devi Kanneganti, Department of Immunology, St Jude Children’s Research Hospital, MS #351, 570, St. Jude Place, Suite E7004, Memphis TN 38105-2794, Tel: (901) 595-3634; Fax. (901) 595-5766. [email protected]. The authors declare no competing financial interests.

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(Reithinger et al., 2007, David et al., 2009). L. major account for majority of the cutaneous infections and these milder self-healing skin lesions can often lead to painful skin ulcers and prolonged persistence without proper treatment. Mucocutaneous Leishmaniasis is a severe form of localized infection of the mucocutaneous sites (such as lips and nostrils) usually instigated by L. brasilliensis, L. panamensis and L. guyanensis (David et al., 2009, Kaye et al., 2011). These infections are associated with high morbidity and potentially life threatening if untreated (Murray et al., 2005). Finally, the most severe and fatal disease is caused by L. donovani and L. infantum. Infection with these Leishmania spp. results in systemic infection of the host called visceral Leishmaniasis (Chappuis et al., 2007). Visceral Leishmaniasis accounts for the majority of 70,000 deaths attributed to Leishmaniasis (Murray et al., 2005).

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One of the major problems with Leishmania infections is the ability of these parasites to evade and subvert host immune responses. These qualities allow these parasites to persist and establish chronic infections. In addition, the lack of Leishmania research has tremendously affected the potential for therapeutic intervention or vaccines. Innate immune responses are critical in rapidly clearing the invading pathogens and further shaping the adaptive immune responses critical for sterile immunity. In this review, we focus on the current understanding of innate immune responses, particularly the complement system and pathogen recognition receptors (PRRs), that are triggered during Leishmania infections and the immune evasion strategies utilized by Leishmania to persist in the host (Figure 1).

The Complement Cascade

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Complement system is a group of more than 30 soluble proteins in the blood plasma that are involved in rapid clearance of invading pathogens from the body (Dunkelberger et al., 2010). Three major pathways can activate the complement system: Classical, Lectin and Alternative pathway. Antibodies binding to the pathogen initiate Classical pathway, whereas the binding of mannose binding lectin (MBL) and ficolins activate Lectin pathway. In contrast, Alternative pathway does not require antibody or lectin binding and is directly activated by the pathogens. All of these pathways result in common activation of C3 convertase that cleaves C3 to generate C3b. C3b deposition on to the pathogen surface then induces the deposition of C5b-C6-C7-C8-C9 (C5b-9 membrane attack complex-MAC) complex that promotes lysis of the target pathogen. In addition C3b acts as an opsonin and promote phagocytosis of the pathogen by neutrophils and macrophages.

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Leishmania is an obligate intracellular parasite and thus needs an intracellular niche to survive and propagate. In this regards, one of the first barrier that these parasites face are the complement system. Indeed complement systems are very effective in clearing Leishmania and as little as 1/120 concentration of normal human serum (NHS) is cytotoxic for L. major parasites (Hoover et al., 1984a, Hoover et al., 1985). In vitro experiments, where Leishmania promastigotes (L. major, L. amazonensis, L. infantum, L. donovani) were cultured with NHS demonstrated that 85–90% of these parasites are lysed within 2.5 minutes of serum contact (Dominguez et al., 2002). Although there is some debate to which complement pathways are critical for clearance of Leishmania parasites, evidence for the involvement of all three major pathways exists. Alternative complement pathway is widely

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accepted as the major pathway that is involved in Leishmania clearance (Hoover et al., 1984a, Mosser et al., 1984, Hoover et al., 1985, Mosser et al., 1986, Puentes et al., 1989). NHS mediated clearance of parasites was shown to be independent of antibodies or C4 (both required for classical pathway) and mediated by Alternative pathway that required the formation of C5b-9 MAC (Hoover et al., 1984b, Mosser et al., 1984). However, IgM antiLeishmania antibodies induced activation of Classical pathway has also been shown to be important for Leishmania promastigotes agglutination and killing (Pearson et al., 1980, Navin et al., 1989). Whereas classical complement pathway is activated rapidly, the alternative pathway activation is delayed during NHS mediated killing of Leishmania (Dominguez et al., 2002). Furthermore, the Classical pathway seems to be specific for Leishmania promastigotes (Pearson et al., 1980), while the Alternative pathway kills the Leishmania amastigotes (Hoover et al., 1984a). Finally, serum MBL binds L. major and L. mexicana promastigotes suggesting the possible contribution of Lectin pathway in killing of Leishmania (Green et al., 1994). Importantly, in vivo studies lacking C5 complement component

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Tremendous selective pressure to survive the complement pathway mediated killing has resulted in the evolution of several immune evasion strategies that are employed by Leishmania. The two major virulence factors of Leishmania are glycocalyx component lipophosphoglycan (LPG) and the metalloprotease leishmanolysin GP63. L. major parasites lacking these glycocalyx receptors are highly susceptible to complement killing (Joshi et al., 2002, Spath et al., 2003b, Yao et al., 2013). Genetic deletion of GP63 in L. major parasite does not impact its growth in sandflies or culture; however, these promastigotes are highly susceptible to complement killing and the disease induced by these Gp63−/− L. major are delayed in comparison to WT L. major (Joshi et al., 2002). More remarkably, L. major parasites deficient in either LPG alone (Lpg1−/−) or all phoshoglycans (Lpg2−/−) are highly attenuated in their ability to infect mice in vivo (Spath et al., 2000, Spath et al., 2003b). Furthermore, LPG-deficient L. major also fail to survive within the sandfly’s gut demonstrating their important role in survival (Sacks et al., 2000). Interestingly, Lpg5A/Bdeficient L. major (that also lacks all phosphoglycans) did not phenocopy Lpg2−/− L. major phenotype, suggesting other LPG2-dependent mechanisms might be important for virulence (Capul et al., 2007). Furthremore, it is important to note that the role of LPG might also be context dependent. Especially, in L. mexicana, LPG-deficiency did not impact the virulence factors of this parasite in their ability to infect mice in vivo (Ilg, 2000, Ilg et al., 2001). However, L. mexicana deficient in all glycoconjugates such as GPI anchors, proteophosphoglycans, lipophosphoglycans and glycoinositolphospholipids (due to deletion of GDPMP gene) are highly avirulent and cannot establish an infection in vivo, suggesting a possible role for other glycoconjugates in this species (Garami et al., 2001). LPG is developmentally regulated in Leishmania and is the major acceptor of C3b (Puentes et al., 1988, McConville et al., 1992). LPG in metacyclic promastigotes (MP) is essential for resistance to killing by complement pathway. Although the MP-LPG bound C3b and initiated the C5b-9 MAC complex, the complex does not reach the Leishmania membrane and is spontaneously released as soluble C5b-9 complex (Puentes et al., 1990). Furthermore, more recent study have shown that stationary phase Leishmania promastigotes inhibited

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deposition of C3b and its derivatives deposition on its surface (Ramer-Tait et al., 2012). Similarly, GP63 facilitate robust C3 deposition on the Leishmania surface but inactivate C3b (iC3b), totally inhibiting the formation of subsequent C5b-9 MAC complex (Brittingham et al., 1995). LPG and GP63 facilitate C3b opsonization, which promotes phagocytosis through C3b receptor CD11b (also known as CR3/Mac-1) (Mosser et al., 1985, Law, 1988, Ueno et al., 2009). In addition, both LPG and GP63 can directly bind to cell surface receptors such as the mannose and fibronectin receptor and promote their uptake (Wilson et al., 1986, Rizvi et al., 1988). Thus, LPG and GP63-mediated entry into the host cells protect Leishmania from the complement cascade killing. In support, mice deficient in CD11b are slightly resistant to L. major infection in vivo, further substantiating the importance of CD11b for perpetuating the disease (Carter et al., 2009). While rapid CD11b-dependent phagocytosis of Leishmania is required for parasite persistence within the host, FcγRdependent Leishmania phagocytosis is required for clearance and protection from disease (Woelbing et al., 2006). These studies highlight the constant “tug-of-war” between the mammalian host and Leishmania to get an evolutionary edge in survival. Now that most of the complement component deficient mice are available, thorough study of Leishmania infection in the context of complete germline genetic deficiency of these complement components will be required to uncover the complex interaction between the complement system and Leishmania and identify possible novel checkpoints that can be targeted.

Pattern Recognition Receptors

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The major innate immune cells that respond to Leishmania infection are neutrophils and macrophages. These cells are equipped with several germline encoded pattern recognition receptors (PRRs) that help them to sample the host environment from invading pathogens. In addition to the membrane bound toll-like receptors (TLRs) and C-type lectin like receptors (CLRs), recent advances in science has seen a dramatic progress in our understanding of the cytoplasmic PRR that include Nod-like receptors (NLR), Aim2-like receptors (ALR), RIG-I like receptors (RLRs) and several cytoplasmic DNA sensors. Despite all these advancements, our understanding on TLRs and cytoplasmic PRRs that recognize and respond to Leishmania are rather limited which is discussed below. Toll like receptors

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There are ten TLRs in human and 12 TLRs in mouse that are functional (Kawai et al., 2011). Most of these TLRs utilize the common adaptor MyD88 for signal transduction with the exception of TLR3 that utilizes the adaptor TRIF and TLR4 that utilizes both MyD88 and TRIF. Mice deficient in MyD88 are highly susceptible to L. major infections. C57BL/6 WT mice infected with L. major develop footpad lesions that peak around 4–5 weeks and are cleared by 8–10 weeks post infection. However, C57BL/6 mice deficient in MyD88 develop non-healing footpad lesions that progressively worsen over the course of infection (de Veer et al., 2003, Debus et al., 2003, Muraille et al., 2003). Indeed, disease progression following L. major infection in the MyD88−/− mice is comparable to disease progression observed in highly susceptible BALB/c mice (Muraille et al., 2003). Mechanistically, MyD88 regulates the expression of IL-12, which is severely dampened in MyD88−/− mice

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(de Veer et al., 2003, Debus et al., 2003, Muraille et al., 2003). To this end, rIL-12 treatment of MyD88−/− mice protected these mice from L. major infection (Muraille et al., 2003).

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MyD88 is a common adaptor protein that functions downstream of several TLRs. LPG of several Leishmania spp. activates MAP kinase and induces IL-12 and TNF-α production in a MyD88 dependent manner, identifying LPG as a potential ligand. In vitro studies with L. donovani infection of macrophages suggested that TLR2 as well as TLR3 are both involved in immune responses, specifically production of TNF-α and nitric oxide, both important for protective immunity against Leishmania (Flandin et al., 2006). Furthermore, transfection studies (293T cells transfected with several TLRs) demonstrated that TLR2 is the receptor for LPG (de Veer et al., 2003). Studies in human neutrophils suggest that TLR2 can directly bind LPG to promote signaling events (Becker et al., 2003). More recently, it was demonstrated that anti-TLR2 antibody could inhibit LPG-induced NF-κB signaling events, suggesting LPG as the direct ligand for TLR2 (Srivastav et al., 2012). However, LPGdeficient L. donovani (Lpg1−/−) still activates macrophage in a TLR2 dependent manner suggesting TLR2 can also recognize other phosphoglycan moieties on Leishmania. Interestingly, Tlr2−/− mice are resistant to Leishmania infections as a result of increased IL-12 production (Vargas-Inchaustegui et al., 2009, Guerra et al., 2010). These results suggest that Leishmania LPG utilizes TLR2 to evade host immune responses.

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Glycoproteins and glycosphingophospholipids from L. donovani have both been suggested as potential ligands for TLR4 based on their ability to induce effector proteins such as reactive oxygen species and IL-12 (Karmakar et al., 2012, Paul et al., 2012). In accord, Tlr4−/− mice are highly susceptible to Leishmania spp. infections and show increased parasite load at all time points (Kropf et al., 2004a, Kropf et al., 2004b). Interestingly, these Tlr4−/− mice are able to ultimately clear the parasitic infection (unlike MyD88−/− mice that develop progressive lesions (Muraille et al., 2003)), suggesting roles for other TLRs as well. Indeed, TLR9 has now emerged as another important TLR involved in providing immunity against Leishmania infections. TLR9 recognizes Leishmania spp. DNA to increase IL-12 production and specific lysis of target cells through NK cell activation (Liese et al., 2007, Schleicher et al., 2007). Moreover, Tlr9−/− mice show increased susceptibility to Leishmania spp. infection, with increased footpad lesion and increased Leishmania titers (Liese et al., 2007, Weinkopff et al., 2013). Similar to Tlr4−/− mice, the disease in Tlr9−/− mice eventually resolves over time. These independent studies highlight the redundancy in the TLR that are involved in providing protection against Leishmania spp. infection.

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While in vitro studies have insinuated at possible role for TLR3 in immunity against Leishmania (Flandin et al., 2006), in vivo studies with Tlr3−/− mice have not been done and will be interesting. TLR3 requires its adaptor TRIF for signaling, which has also been suggested to play redundant roles with MyD88 during in vitro Leishmania infections (Gallego et al., 2011). Study by Schamber-Reis et al showed that nucleic acid sensing by multiple TLRs during Leishmania infection is a major resistance factor (Schamber-Reis et al., 2013). While, Tlr3-, Tlr7- or Tlr9-single deficiency showed some susceptibility to Leishmania infection in vivo, triple deficiency in all these three TLRs rendered these mice highly susceptible to Leishmaina infections comparable to Myd88-deficient mice. This study clearly shows redundancy between TLRs in promoting immune responses against Cell Microbiol. Author manuscript; available in PMC 2016 September 01.

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Leishmania infections. Furthermore, the role of TLR5 in immunity against Leishmania infection is still unknown and whether it plays redundant roles will other TLRs will need to be investigated.

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It is clear from the reviewed literature that TLR4 and TLR9 play an important role in immunity to recognize and respond against Leishmania. Interestingly, Leishmania hijacks TLR2, which evolved similarly as TLR4 and TLR9 to respond against Leishmania. Indeed, recognition of Leishmania LPG seems to promote Leishmania growth by inhibiting IL-12 production. Thus, during L. donovani infection, blockade of TLR2 signaling by anti-TLR2 antibody provide significant protection by reducing parasite burden (Murray et al., 2013). Mechanistically, L. donovani induce robust expression of A20 (a deubiquitinating enzyme) (Srivastav et al., 2012). A20 blocks TRAF6 Lys63 ubiquitination and signaling through TLR2. Moreover, Leishmania LPG signaling through TLR2 inhibits TLR9 expression and anti-leishmanial responses (Srivastava et al., 2013). Leishmania also utilizes several other host proteins to regulate TLR signaling. Study by Gupta et al. shows that L. donovani inhibits TRAF3 degradation, an important step required for TLR4 signaling, by targeting Ubc13 (Gupta et al., 2014). In addition, L. amazonensis negatively regulates TLR4 signaling by degrading intracellular signaling proteins such as STAT1/STAT2, ERK1/2 and IRF1 (Xin et al., 2008), while L. major inhibitor of serine peptidase 2 has been shown to inhibit TLR4 activation by neutrophil elastase (Faria et al., 2011).

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TLRs serve as the first line defense for innate immune cells and are critically important for protection against Leishmania infections; thus it is not surprising that Leishmania has evolved to evade and manipulate the immune system to hijack these immune responses to survive within the host. The importance of TLR signaling in protection against Leishmania infections is further solidified by studies that have directly targeted several TLR using specific agonists. Indeed, activation of TLR2, TLR4 and TLR9 with their respective agonists have all resulted in significant protection from Leishmania spp. induced pathogenesis and parasitic burden (Raman et al., 2010, Chandel et al., 2014, Huang et al., 2015). These studies argue the role for TLR stimulation as a potential vaccine therapy. Nod like receptors

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While the TLRs guard the extracellular milieu and endosomal compartments, cytoplasmic pattern recognition receptors patrol danger in the cytoplasm. NLRs are the best studied cytoplasmic PRRs that sense both pathogens associated and danger associated molecular patterns. So far 22 NLR in human and 34 NLR in mouse has been identified (Harton et al., 2002). These NLR have myriad functions ranging from MHC regulation to both positive and negative regulation of various signaling pathways. However, one of the most important discoveries relating to NLRs has been the discovery of inflammasomes. NLRP1b, NLRP3 and NLRC4 have been shown to form a multimeric protein complex along with common adaptor molecule ASC and cysteine protease caspase-1 called the inflammasomes (Martinon et al., 2002, Mariathasan et al., 2004, Kanneganti et al., 2006, Mariathasan et al., 2006, Martinon et al., 2006, Kanneganti, 2015). Inflammasomes are central for cleavage and activation of pyrogenic cytokines, IL-1β and IL-18. NLRs and inflammasomes are linked to several autoimmune and inflammatory diseases as well as infections (Davis et al., 2011).

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However, our knowledge on the roles of NLR in immunity against Leishmania infections is almost non-existent with the exception of few studies on NLRP3.

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IL-1α, IL-1β and IL-18, cytokines tightly regulated by the inflammasomes, have been shown to be involved in Leishmania infections with conflicting results. IL-1α and IL-1β promote Leishmaniasis during L. major infection of susceptible BALB/c mice (Voronov et al., 2010). Specifically, both Il1a−/− and Il1b−/− mice are resistant to L. major infection and exhibit delayed nodule development and death. Furthermore, the absence of IL-1 receptor antagonist rendered these mice highly susceptible to L. major infection confirming the role of IL-1 signaling in promoting disease (Voronov et al., 2010). However, infection of resistant C57BL/6 mice with L. major reveals no role for IL-1α and IL-1β (Kautz-Neu et al., 2011). Interestingly, prophylactic recombinant IL-1α treatment locally at the site of infection provide robust protection from L. major induced inflammation and parasitic burden in both susceptible BALB/c and resistant C57BL/6 mice (Von Stebut et al., 2003). Similar conflicting results are also available for IL-18. While Il18−/− mice are resistant to L. major and L. mexicana infections in susceptible BALB/c background, Il18−/− mice on a resistant C57BL/6 background are highly susceptible (Wei et al., 1999, Monteforte et al., 2000, Wei et al., 2004, Bryson et al., 2008). Altogether, these studies suggest that IL-1 and IL-18 signaling are pathogenic in BALB/c mice, but protective in C57BL/6 mice. More importantly, these studies confirm a role for IL-1 signaling axis during Leishmania infection in vivo.

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NLRP3 inflammasome is one of the major regulators of IL-1β and IL-18 both in vitro and in vivo (Gurung et al., 2015b). Lima Junior et al. demonstrate an important protective role for NLRP3 inflammasome during L. amazonenesis infection of resistant C57BL/6 mice in vivo (Lima-Junior et al., 2013). In vitro experiments show that most Leishmania spp. including L. amazonensis, L. braziliensis and L. mexicana induce caspase-1 activation and IL-1β production in a NLRP3 inflammasome-depenent manner (Lima-Junior et al., 2013). Furthermore, Nlrp3−/−, Asc−/− and Casp1−/− mice are all highly susceptible to L. amazonensis infection when compared to C57BL/6 WT control mice signifying the importance of NLRP3 inflammasome in providing protection. Mechanistically, IL-1β signals through IL-1R/MyD88 signaling axis to induce nitric oxide production and promote Leishmania killing in macrophages (Lima-Junior et al., 2013).

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Interestingly, a more recent report on the role of NLRP3 during L. major infection in a susceptible BALB/c background shows a pathogenic role for this inflammasome (Gurung et al., 2015a). Similar to the study by Lima Junior et al, L. major infection of WT BALB/c macrophages also induces caspase-1 activation and subsequent IL-1β and IL-18 production. NLRP3, ASC and caspase-1 are all required for L. major induced caspase-1 activation, IL-1β and IL-18 production establishing NLRP3 inflammasome as the critical complex. However, this is where the similarities end. While BALB/c WT mice infected with L. major display severe footpad swelling and parasite burden, Nlrp3−/−, Asc−/− and Casp1−/− mice exhibit significantly reduced footpad swelling and parasite burden implying a pathogenic role for NLRP3 inflammasome in a BALB/c background (Gurung et al., 2015a). In-depth mechanistic studies reveal IL-18 as the pathogenic cytokine that promotes L. major survival by skewing T cell responses (Gurung et al., 2015a). Cell Microbiol. Author manuscript; available in PMC 2016 September 01.

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Although contrasting, these two studies on NLRP3 inflamamsomes confirm previous studies with IL-1β and IL-18. As discussed above, it is apparent that the IL-1 and IL-18 signaling axis seems to promote Leishmania growth in BALB/c mice and inhibit Leishmania growth in C57BL/6 mice. Thus, it is not surprising that NLRP3 inflammasome, which control these critical cytokines (IL-1 and IL-18), also promote Leishmania growth in BALB/c mice and inhibit Leishmania growth in C57BL/6 mice. While our review was in submission, new study by Shio et al showed that GP63 of Leishmania actively inhibits NLRP3 inflammasome activation and secretion of IL-1β (Shio et al., 2015). Mechanistically, GP63-inhibited Leishmania induced ROS production, which is required for NLRP3 inflammasome activation. Furthermore, GP63 also induced cleavage of NLRP3 suggesting a more direct role for this metalloprotease in regulating the NLRP3 inflammasome. This study further confirms the importance of GP63 as a virulence factor that can also regulate the cytoplasmic signaling within the cells. More research is needed to investigate whether LPG and other glycocalyx moieties are also involved in the modulation of these cytoplasmic sensors.

Perspectives and Conclusions

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Leishmania is a complex protozoan parasite that has evolved to evade and survive the host immune responses. Every Leishmania spp. infection manifests an entirely different disease state in the host. Furthermore, the genetic background of the host determinates the immune response that is generated against Leishmania. These variables have made it extremely difficult to achieve consensus among different studies, which has negatively impacted generation of potential therapeutics for treatment of Leishmania. For mouse studies, it will be important to study different backgrounds together to understand what impact genetic makeup of the host has on the immune response against a particular Leishmania spp. of interest. These types of comparative studies should eliminate background specific bias and further encourage generalized mechanisms that can be targeted for future therapeutics. More importantly, natural mode/dose of infection has been shown to be critical to understand the actual events during infection and could be important to our understanding of the discrepancies between various systems that we have encountered as well (Belkaid et al., 1998, Belkaid et al., 2000).

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Our understanding of innate immunity against Leishmania spp. is still at its infancy. While the complement system is one of the oldest innate immune pathways to be discovered, we still lack enough knowledge about the precise roles of complement components during Leishmania infections. While in vivo study of C5-deficient mice showed no role for complement in controlling L. major infection in vivo (Spath et al., 2003a), a separate study that depleted whole complement system in BALB/c mice using cobra venom anticomplement protein challenge showed a profound role for complement in controlling L. amazonensis infection in vivo (Laurenti et al., 2004). Thus, comprehensive in vivo studies with Leishmania infections of mice lacking individual components of complement (C3b−/−, C5b−/−, C5a−/− etc.) will be invaluable in unraveling the molecular underpinnings of how complement are involved. The TLR field has shown a lot of promise in that agonists that specifically target TLRs provide protective immunity against Leishmania infections (Raman et al., 2010, Chandel et al., 2014, Huang et al., 2015). In depth mechanistic studies are still required to test not only the known TLR such as TLR2, TLR4 and TLR9 but also other Cell Microbiol. Author manuscript; available in PMC 2016 September 01.

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TLRs such as TLR3, TLR5 and TLR7 whose role in Leishmania infections in vivo are yet to be defined. Finally, studying the cytoplasmic PRRs and their role during Leishmania infections is necessitated. It is very surprising that only two studies on cytoplasmic PRR and their role in Leishmania infections exist to date (Lima-Junior et al., 2013, Gurung et al., 2015a). Cytoplasmic sensors comprise of several proteins that can regulate signaling pathway, form inflammasomes, sense RNA, sense DNA as well as regulate MHC expression. Studies of these cytoplasmic molecules will increase our understanding of innate immune interactions with Leishmania and identify numerous potential therapeutic targets.

Acknowledgments

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We tried to incorporate most of the works, but sincerely apologize to authors whose work was not referenced in here. PG is a postdoctoral fellow supported by Paul Barrett Endowed Fellowship from St. Jude Children’s Research Hospital. This work was supported in part by grants from the National Institute of Health (Grants AR056296, CA163507 and AI101935) and the American Lebanese Syrian Associated Charities (ALSAC) to T-D.K.

References

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Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PloS one. 2012; 7:e35671. [PubMed: 22693548] Becker I, Salaiza N, Aguirre M, Delgado J, Carrillo-Carrasco N, Kobeh LG, et al. Leishmania lipophosphoglycan (LPG) activates NK cells through toll-like receptor-2. Molecular and biochemical parasitology. 2003; 130:65–74. [PubMed: 12946842] Belkaid Y, Kamhawi S, Modi G, Valenzuela J, Noben-Trauth N, Rowton E, et al. Development of a natural model of cutaneous leishmaniasis: powerful effects of vector saliva and saliva preexposure on the long-term outcome of Leishmania major infection in the mouse ear dermis. The Journal of experimental medicine. 1998; 188:1941–1953. [PubMed: 9815271] Belkaid Y, Mendez S, Lira R, Kadambi N, Milon G, Sacks D. A natural model of Leishmania major infection reveals a prolonged “silent” phase of parasite amplification in the skin before the onset of lesion formation and immunity. Journal of immunology. 2000; 165:969–977. Brittingham A, Morrison CJ, McMaster WR, McGwire BS, Chang KP, Mosser DM. Role of the Leishmania surface protease gp63 in complement fixation, cell adhesion, and resistance to complement-mediated lysis. Journal of immunology. 1995; 155:3102–3111. Bryson KJ, Wei XQ, Alexander J. Interleukin-18 enhances a Th2 biased response and susceptibility to Leishmania mexicana in BALB/c mice. Microbes and infection/Institut Pasteur. 2008; 10:834–839. [PubMed: 18538609] Capul AA, Hickerson S, Barron T, Turco SJ, Beverley SM. Comparisons of mutants lacking the Golgi UDP-galactose or GDP-mannose transporters establish that phosphoglycans are important for promastigote but not amastigote virulence in Leishmania major. Infection and immunity. 2007; 75:4629–4637. [PubMed: 17606605] Carter CR, Whitcomb JP, Campbell JA, Mukbel RM, McDowell MA. Complement receptor 3 deficiency influences lesion progression during Leishmania major infection in BALB/c mice. Infection and immunity. 2009; 77:5668–5675. [PubMed: 19797068] CDC. Center for Disease Control and Prevention. Parasites-Leishmaniasis. Global Health - Division of Parasitic Diseases and Malaria; 2013. http://www.cdc.gov/parasites/leishmaniasis/epi.html Chandel HS, Pandey SP, Shukla D, Lalsare K, Selvaraj SK, Jha MK, Saha B. Toll-like receptors and CD40 modulate each other’s expression affecting Leishmania major infection. Clinical and experimental immunology. 2014; 176:283–290. [PubMed: 24387292] Chappuis F, Sundar S, Hailu A, Ghalib H, Rijal S, Peeling RW, et al. Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nature reviews. Microbiology. 2007; 5:873–882. [PubMed: 17938629] David CV, Craft N. Cutaneous and mucocutaneous leishmaniasis. Dermatologic therapy. 2009; 22:491–502. [PubMed: 19889134]

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Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annual review of immunology. 2011; 29:707–735. de Veer MJ, Curtis JM, Baldwin TM, DiDonato JA, Sexton A, McConville MJ, et al. MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll-like receptor 2 signaling. European journal of immunology. 2003; 33:2822–2831. [PubMed: 14515266] Debus A, Glasner J, Rollinghoff M, Gessner A. High levels of susceptibility and T helper 2 response in MyD88-deficient mice infected with Leishmania major are interleukin-4 dependent. Infection and immunity. 2003; 71:7215–7218. [PubMed: 14638820] Dominguez M, Moreno I, Lopez-Trascasa M, Torano A. Complement interaction with trypanosomatid promastigotes in normal human serum. The Journal of experimental medicine. 2002; 195:451–459. [PubMed: 11854358] Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell research. 2010; 20:34–50. [PubMed: 20010915] Faria MS, Reis FC, Azevedo-Pereira RL, Morrison LS, Mottram JC, Lima AP. Leishmania inhibitor of serine peptidase 2 prevents TLR4 activation by neutrophil elastase promoting parasite survival in murine macrophages. Journal of immunology. 2011; 186:411–422. Flandin JF, Chano F, Descoteaux A. RNA interference reveals a role for TLR2 and TLR3 in the recognition of Leishmania donovani promastigotes by interferon-gamma-primed macrophages. European journal of immunology. 2006; 36:411–420. [PubMed: 16369915] Gallego C, Golenbock D, Gomez MA, Saravia NG. Toll-like receptors participate in macrophage activation and intracellular control of Leishmania (Viannia) panamensis. Infection and immunity. 2011; 79:2871–2879. [PubMed: 21518783] Garami A, Ilg T. Disruption of mannose activation in Leishmania mexicana: GDP-mannose pyrophosphorylase is required for virulence, but not for viability. The EMBO journal. 2001; 20:3657–3666. [PubMed: 11447107] Green PJ, Feizi T, Stoll MS, Thiel S, Prescott A, McConville MJ. Recognition of the major cell surface glycoconjugates of Leishmania parasites by the human serum mannan-binding protein. Molecular and biochemical parasitology. 1994; 66:319–328. [PubMed: 7808481] Guerra CS, Silva RM, Carvalho LO, Calabrese KS, Bozza PT, Corte-Real S. Histopathological analysis of initial cellular response in TLR-2 deficient mice experimentally infected by Leishmania (L.) amazonensis. International journal of experimental pathology. 2010; 91:451–459. [PubMed: 20586817] Gupta P, Giri J, Srivastav S, Chande AG, Mukhopadhyaya R, Das PK, Ukil A. Leishmania donovani targets tumor necrosis factor receptor-associated factor (TRAF) 3 for impairing TLR4-mediated host response. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2014; 28:1756–1768. [PubMed: 24391131] Gurung P, Karki R, Vogel P, Watanabe M, Bix M, Lamkanfi M, Kanneganti TD. An NLRP3 inflammasome-triggered Th2-biased adaptive immune response promotes leishmaniasis. The Journal of clinical investigation. 2015a; 125:1329–1338. [PubMed: 25689249] Gurung P, Lukens JR, Kanneganti TD. Mitochondria: diversity in the regulation of the NLRP3 inflammasome. Trends in molecular medicine. 2015b; 21:193–201. [PubMed: 25500014] Harton JA, Linhoff MW, Zhang J, Ting JP. Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. Journal of immunology. 2002; 169:4088–4093. Hoover DL, Berger M, Hammer CH, Meltzer MS. Complement-mediated serum cytotoxicity for Leishmania major amastigotes: killing by serum deficient in early components of the membrane attack complex. Journal of immunology. 1985; 135:570–574. Hoover DL, Berger M, Nacy CA, Hockmeyer WT, Meltzer MS. Killing of Leishmania tropica amastigotes by factors in normal human serum. Journal of immunology. 1984a; 132:893–897. Hoover DL, Nacy CA. Macrophage activation to kill Leishmania tropica: defective intracellular killing of amastigotes by macrophages elicited with sterile inflammatory agents. Journal of immunology. 1984b; 132:1487–1493.

Cell Microbiol. Author manuscript; available in PMC 2016 September 01.

Gurung and Kanneganti

Page 11

Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Huang L, Hinchman M, Mendez S. Coinjection with TLR2 agonist Pam3CSK4 reduces the pathology of leishmanization in mice. PLoS neglected tropical diseases. 2015; 9:e0003546. [PubMed: 25738770] Ilg T. Lipophosphoglycan is not required for infection of macrophages or mice by Leishmania mexicana. The EMBO journal. 2000; 19:1953–1962. [PubMed: 10790362] Ilg T, Demar M, Harbecke D. Phosphoglycan repeat-deficient Leishmania mexicana parasites remain infectious to macrophages and mice. The Journal of biological chemistry. 2001; 276:4988–4997. [PubMed: 11071892] Joshi PB, Kelly BL, Kamhawi S, Sacks DL, McMaster WR. Targeted gene deletion in Leishmania major identifies leishmanolysin (GP63) as a virulence factor. Molecular and biochemical parasitology. 2002; 120:33–40. [PubMed: 11849703] Kanneganti TD. The inflammasome: firing up innate immunity. Immunological reviews. 2015; 265:1– 5. [PubMed: 25879279] Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature. 2006; 440:233– 236. [PubMed: 16407888] Karmakar S, Bhaumik SK, Paul J, De T. TLR4 and NKT cell synergy in immunotherapy against visceral leishmaniasis. PLoS pathogens. 2012; 8:e1002646. [PubMed: 22511870] Kautz-Neu K, Kostka SL, Dinges S, Iwakura Y, Udey MC, von Stebut E. IL-1 signalling is dispensable for protective immunity in Leishmania-resistant mice. Experimental dermatology. 2011; 20:76–78. [PubMed: 20955202] Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011; 34:637–650. [PubMed: 21616434] Kaye P, Scott P. Leishmaniasis: complexity at the host-pathogen interface. Nature reviews. Microbiology. 2011; 9:604–615. [PubMed: 21747391] Kedzierski L. Leishmaniasis Vaccine: Where are We Today? Journal of global infectious diseases. 2010; 2:177–185. [PubMed: 20606974] Kropf P, Freudenberg MA, Modolell M, Price HP, Herath S, Antoniazi S, et al. Toll-like receptor 4 contributes to efficient control of infection with the protozoan parasite Leishmania major. Infection and immunity. 2004a; 72:1920–1928. [PubMed: 15039311] Kropf P, Freudenberg N, Kalis C, Modolell M, Herath S, Galanos C, et al. Infection of C57BL/10ScCr and C57BL/10ScNCr mice with Leishmania major reveals a role for Toll-like receptor 4 in the control of parasite replication. Journal of leukocyte biology. 2004b; 76:48–57. [PubMed: 15039466] Laurenti MD, Orn A, Sinhorini IL, Corbett CE. The role of complement in the early phase of Leishmania (Leishmania) amazonensis infection in BALB/c mice. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas/Sociedade Brasileira de Biofisica … [et al. ]. 2004; 37:427–434. Law SK. C3 receptors on macrophages. Journal of cell science. Supplement. 1988; 9:67–97. [PubMed: 2978518] Liese J, Schleicher U, Bogdan C. TLR9 signaling is essential for the innate NK cell response in murine cutaneous leishmaniasis. European journal of immunology. 2007; 37:3424–3434. [PubMed: 18034422] Lima-Junior DS, Costa DL, Carregaro V, Cunha LD, Silva AL, Mineo TW, et al. Inflammasomederived IL-1beta production induces nitric oxide-mediated resistance to Leishmania. Nature medicine. 2013; 19:909–915. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004; 430:213–218. [PubMed: 15190255] Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006; 440:228–232. [PubMed: 16407890]

Cell Microbiol. Author manuscript; available in PMC 2016 September 01.

Gurung and Kanneganti

Page 12

Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Molecular cell. 2002; 10:417–426. [PubMed: 12191486] Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006; 440:237–241. [PubMed: 16407889] McConville MJ, Turco SJ, Ferguson MA, Sacks DL. Developmental modification of lipophosphoglycan during the differentiation of Leishmania major promastigotes to an infectious stage. The EMBO journal. 1992; 11:3593–3600. [PubMed: 1396559] Monteforte GM, Takeda K, Rodriguez-Sosa M, Akira S, David JR, Satoskar AR. Genetically resistant mice lacking IL-18 gene develop Th1 response and control cutaneous Leishmania major infection. Journal of immunology. 2000; 164:5890–5893. Mosser DM, Burke SK, Coutavas EE, Wedgwood JF, Edelson PJ. Leishmania species: mechanisms of complement activation by five strains of promastigotes. Experimental parasitology. 1986; 62:394– 404. [PubMed: 3780933] Mosser DM, Edelson PJ. Activation of the alternative complement pathway by Leishmania promastigotes: parasite lysis and attachment to macrophages. Journal of immunology. 1984; 132:1501–1505. Mosser DM, Edelson PJ. The mouse macrophage receptor for C3bi (CR3) is a major mechanism in the phagocytosis of Leishmania promastigotes. Journal of immunology. 1985; 135:2785–2789. Muraille E, De Trez C, Brait M, De Baetselier P, Leo O, Carlier Y. Genetically resistant mice lacking MyD88-adapter protein display a high susceptibility to Leishmania major infection associated with a polarized Th2 response. Journal of immunology. 2003; 170:4237–4241. Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis. Lancet. 2005; 366:1561–1577. [PubMed: 16257344] Murray HW, Zhang Y, Zhang Y, Raman VS, Reed SG, Ma X. Regulatory actions of Toll-like receptor 2 (TLR2) and TLR4 in Leishmania donovani infection in the liver. Infection and immunity. 2013; 81:2318–2326. [PubMed: 23589575] Navin TR, Krug EC, Pearson RD. Effect of immunoglobulin M from normal human serum on Leishmania donovani promastigote agglutination, complement-mediated killing, and phagocytosis by human monocytes. Infection and immunity. 1989; 57:1343–1346. [PubMed: 2925255] Paul J, Karmakar S, De T. TLR-mediated distinct IFN-gamma/IL-10 pattern induces protective immunity against murine visceral leishmaniasis. European journal of immunology. 2012; 42:2087–2099. [PubMed: 22622993] Pearson RD, Sousa AQ. Clinical spectrum of Leishmaniasis. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 1996; 22:1–13. [PubMed: 8824958] Pearson RD, Steigbigel RT. Mechanism of lethal effect of human serum upon Leishmania donovani. Journal of immunology. 1980; 125:2195–2201. Puentes SM, Da Silva RP, Sacks DL, Hammer CH, Joiner KA. Serum resistance of metacyclic stage Leishmania major promastigotes is due to release of C5b-9. Journal of immunology. 1990; 145:4311–4316. Puentes SM, Dwyer DM, Bates PA, Joiner KA. Binding and release of C3 from Leishmania donovani promastigotes during incubation in normal human serum. Journal of immunology. 1989; 143:3743–3749. Puentes SM, Sacks DL, da Silva RP, Joiner KA. Complement binding by two developmental stages of Leishmania major promastigotes varying in expression of a surface lipophosphoglycan. The Journal of experimental medicine. 1988; 167:887–902. [PubMed: 3280727] Raman VS, Bhatia A, Picone A, Whittle J, Bailor HR, O’Donnell J, et al. Applying TLR synergy in immunotherapy: implications in cutaneous leishmaniasis. Journal of immunology. 2010; 185:1701–1710. Ramer-Tait AE, Lei SM, Bellaire BH, Beetham JK. Differential surface deposition of complement proteins on logarithmic and stationary phase Leishmania chagasi promastigotes. The Journal of parasitology. 2012; 98:1109–1116. [PubMed: 22662870] Reithinger R, Dujardin JC, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. The Lancet. Infectious diseases. 2007; 7:581–596. [PubMed: 17714672]

Cell Microbiol. Author manuscript; available in PMC 2016 September 01.

Gurung and Kanneganti

Page 13

Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Rizvi FS, Ouaissi MA, Marty B, Santoro F, Capron A. The major surface protein of Leishmania promastigotes is a fibronectin-like molecule. European journal of immunology. 1988; 18:473–476. [PubMed: 2965651] Sacks D, Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice. Nature reviews. Immunology. 2002; 2:845–858. Sacks DL, Modi G, Rowton E, Spath G, Epstein L, Turco SJ, Beverley SM. The role of phosphoglycans in Leishmania-sand fly interactions. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97:406–411. [PubMed: 10618431] Schamber-Reis BL, Petritus PM, Caetano BC, Martinez ER, Okuda K, Golenbock D, et al. UNC93B1 and nucleic acid-sensing Toll-like receptors mediate host resistance to infection with Leishmania major. The Journal of biological chemistry. 2013; 288:7127–7136. [PubMed: 23325805] Schleicher U, Liese J, Knippertz I, Kurzmann C, Hesse A, Heit A, et al. NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs. The Journal of experimental medicine. 2007; 204:893–906. [PubMed: 17389237] Shio MT, Christian JG, Jung JY, Chang KP, Olivier M. PKC/ROS-Mediated NLRP3 Inflammasome Activation Is Attenuated by Leishmania Zinc-Metalloprotease during Infection. PLoS neglected tropical diseases. 2015; 9:e0003868. [PubMed: 26114647] Spath GF, Epstein L, Leader B, Singer SM, Avila HA, Turco SJ, Beverley SM. Lipophosphoglycan is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania major. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97:9258–9263. [PubMed: 10908670] Spath GF, Garraway LA, Turco SJ, Beverley SM. The role(s) of lipophosphoglycan (LPG) in the establishment of Leishmania major infections in mammalian hosts. Proceedings of the National Academy of Sciences of the United States of America. 2003a; 100:9536–9541. [PubMed: 12869694] Spath GF, Lye LF, Segawa H, Sacks DL, Turco SJ, Beverley SM. Persistence without pathology in phosphoglycan-deficient Leishmania major. Science. 2003b; 301:1241–1243. [PubMed: 12947201] Srivastav S, Kar S, Chande AG, Mukhopadhyaya R, Das PK. Leishmania donovani exploits host deubiquitinating enzyme A20, a negative regulator of TLR signaling, to subvert host immune response. Journal of immunology. 2012; 189:924–934. Srivastava S, Pandey SP, Jha MK, Chandel HS, Saha B. Leishmania expressed lipophosphoglycan interacts with Toll-like receptor (TLR)-2 to decrease TLR-9 expression and reduce antileishmanial responses. Clinical and experimental immunology. 2013; 172:403–409. [PubMed: 23600828] Ueno N, Bratt CL, Rodriguez NE, Wilson ME. Differences in human macrophage receptor usage, lysosomal fusion kinetics and survival between logarithmic and metacyclic Leishmania infantum chagasi promastigotes. Cellular microbiology. 2009; 11:1827–1841. [PubMed: 19702651] Vargas-Inchaustegui DA, Tai W, Xin L, Hogg AE, Corry DB, Soong L. Distinct roles for MyD88 and Toll-like receptor 2 during Leishmania braziliensis infection in mice. Infection and immunity. 2009; 77:2948–2956. [PubMed: 19364834] Von Stebut E, Ehrchen JM, Belkaid Y, Kostka SL, Molle K, Knop J, et al. Interleukin 1alpha promotes Th1 differentiation and inhibits disease progression in Leishmania major-susceptible BALB/c mice. The Journal of experimental medicine. 2003; 198:191–199. [PubMed: 12860932] Voronov E, Dotan S, Gayvoronsky L, White RM, Cohen I, Krelin Y, et al. IL-1-induced inflammation promotes development of leishmaniasis in susceptible BALB/c mice. International immunology. 2010; 22:245–257. [PubMed: 20181656] Wei XQ, Leung BP, Niedbala W, Piedrafita D, Feng GJ, Sweet M, et al. Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice. Journal of immunology. 1999; 163:2821–2828. Wei XQ, Niedbala W, Xu D, Luo ZX, Pollock KG, Brewer JM. Host genetic background determines whether IL-18 deficiency results in increased susceptibility or resistance to murine Leishmania major infection. Immunology letters. 2004; 94:35–37. [PubMed: 15234532]

Cell Microbiol. Author manuscript; available in PMC 2016 September 01.

Gurung and Kanneganti

Page 14

Author Manuscript

Weinkopff T, Mariotto A, Simon G, Hauyon-La Torre Y, Auderset F, Schuster S, et al. Role of Tolllike receptor 9 signaling in experimental Leishmania braziliensis infection. Infection and immunity. 2013; 81:1575–1584. [PubMed: 23439309] Wilson ME, Pearson RD. Evidence that Leishmania donovani utilizes a mannose receptor on human mononuclear phagocytes to establish intracellular parasitism. Journal of immunology. 1986; 136:4681–4688. Woelbing F, Kostka SL, Moelle K, Belkaid Y, Sunderkoetter C, Verbeek S, et al. Uptake of Leishmania major by dendritic cells is mediated by Fcgamma receptors and facilitates acquisition of protective immunity. The Journal of experimental medicine. 2006; 203:177–188. [PubMed: 16418399] Xin L, Li K, Soong L. Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes. Molecular immunology. 2008; 45:3371–3382. [PubMed: 18538399] Yao C, Gaur Dixit U, Barker JH, Teesch LM, Love-Homan L, Donelson JE, Wilson ME. Attenuation of Leishmania infantum chagasi metacyclic promastigotes by sterol depletion. Infection and immunity. 2013; 81:2507–2517. [PubMed: 23630964]

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Figure 1. Innate immune responses against Leishmania infections

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(A) Upon entry into the mammalian hosts, Leishmania parasites first come in contact with the complement system. Once the complement pathway is activated, C3b facilitates C5b-C9 membrane attack complex (MAC) on the Leishmania surface and lyses the parasite. Conversely, Leishmania virulence factor LPG inhibits MAC complex formation on the surface, while GP63 inactivates C3b (iC3b) and inhibits MAC complex. Opsonization of Leishmania by C3b and iC3b facilitates its uptake by CD11b and FcγR receptor on neutrophils and macrophages. (B) TLR2 and TLR4 on macrophage recognize Leishmania outside, whereas TLR3 and TLR9 recognizes Leishmania in the vacuole. Activation of TLRs activates the NFκB and MAP kinase signaling through MyD88 which is important for Leishmania clearance. In the cytoplasm, NLRP3 inflammasome senses Leishmania to produce IL-1β and IL-18, which can have diverse cellular functions depending on the genetic background of the host.

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Innate immunity against Leishmania infections.

Leishmaniasis is a major health problem that affects more than 300 million people throughout the world. The morbidity associated with the disease caus...
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