Alpha proteobacteria of genus Anaplasma (Rickettsiales: Anaplasmataceae): Epidemiology and characteristics of Anaplasma species related to veterinary and public health importance.

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REVIEW ARTICLE

Alpha proteobacteria of genus Anaplasma (Rickettsiales: Anaplasmataceae): Epidemiology and characteristics of Anaplasma species related to veterinary and public health importance FARHAN AHMAD ATIF* Department of Animal Sciences, University College of Agriculture, University of Sargodha, Sargodha-40100, Pakistan (Received 11 November 2015; revised 21 January 2016; accepted 26 January 2016; first published online 2 March 2016) SUMMARY

The Anaplasma species are important globally distributed tick-transmitted bacteria of veterinary and public health importance. These pathogens, cause anaplasmosis in domestic and wild animal species including humans. Rhipicephalus, Ixodes, Dermacentor and Amblyomma genera of ticks are the important vectors of Anaplasma. Acute anaplasmosis is usually diagnosed upon blood smear examination followed by antibodies and nucleic acid detection. All age groups are susceptible but prevalence increases with age. Serological cross-reactivity is one of the important issues among Anaplasma species. They co-exist and concurrent infections occur in animals and ticks in same geographic area. These are closely related bacteria and share various common attributes which should be considered while developing vaccines and diagnostic assays. Movement of susceptible animals from non-endemic to endemic regions is the major risk factor of bovine/ovine anaplasmosis and tick-borne fever. Tetracyclines are currently available drugs for clearance of infection and treatment in humans and animals. Worldwide vaccine is not yet available. Identification, elimination of reservoirs, vector control (chemical and biological), endemic stability, habitat modification, rearing of tick resistant breeds, chemotherapy and tick vaccination are major control measures of animal anaplasmosis. Identification of reservoirs and minimizing the high-risk tick exposure activities are important control strategies for human granulocytic anaplasmosis. Key words: Epidemiology, distribution, control, Anaplasma species. INTRODUCTION

The Anaplasma species are gram negative obligate intracellular bacteria that infect diverse cell types, worldwide (Berger, 2014). These are important tick-associated bacteria of veterinary and public health significance; cause anaplasmosis in various animal species and humans. The genus Anaplasma comprises of A. marginale, A. marginale subsp. centrale, A. ovis, A. bovis, A. platys, A. phagocytophilum and Aegyptianella pullorum. The A. bovis, A. platys and A. phagocytophilum species previously belong to genus Ehrlichia now included in genus Anaplasma after reclassification based on 16SrRNA and groEl genes in 2001 (Dumler et al. 2001). Anaplasma marginale, A. marginale subsp. centrale, and A. bovis cause bovine anaplasmosis. Anaplasma ovis is the agent of ovine/caprine anaplasmosis. Anaplasma marginale, A. marginale subsp. centrale, and A. ovis infect erythrocytes. Anaplasma platys infects canine platelets, responsible for canine infectious cyclic anaplasmosis. Anaplasma bovis infects monocytes of ruminants

(Sreekumar et al. 1996; Rar and Golovljova, 2011; Zobba et al. 2014); whereas A. phagocytophilum is a zoonotic pathogen that infect a wide range of vertebrate hosts including domestic and wild animals, birds, reptiles, rodents and humans infecting granulocytes (Foggie, 1951). Nevertheless, A. centrale is the least pathogenic among Anaplasma species. The distribution of A. centrale is limited to Mediterranean countries such as Turkey, Italy and Tunisia (Aktas et al. 2011; Zobba et al. 2014; Belkahia et al. 2015a). In terms of developing vaccines and diagnostic assays, it is important to know the similarities of closely related organisms. Currently, limited reviews are available on these intracellular blood-borne pathogens. Therefore, there is a need to provide updated information on ecology, epidemiology and major similarities of all Anaplasma species of family Anaplasmataceae for effective prevention and control of anaplasmosis in animals and humans. ANAPLASMA PHAGOCYTOPHILUM

* Corresponding author: Department of Animal Sciences, University College of Agriculture, University of Sargodha, Sargodha-40100, Pakistan. E-mail: [email protected]

Anaplasma phagocytophilum is a hetero-genetic zoonotic tick-borne bacteria of diverse hosts, mainly

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Farhan Ahmad Atif

transmitted by Ixodes, Dermacentor, Haemaphysalis, Amblyomma, Hyalomma, Rhipicephalus species of ticks (Jiang et al. 2011; Clark, 2012; M’ghirbi et al. 2012; Chastagner et al. 2013; Szekeres et al. 2015). This has been detected in Asia, Europe, Africa and America (Kawahara et al. 2006; M’ghirbi et al. 2012; Kang et al. 2013; Djiba et al. 2013; Stuen et al. 2013a; Borthakur et al. 2014; Razzaq et al. 2015; Table 1). Prevalence varies from region to region depending upon tick exposure, immunity and age (CDC, 2013). Infection in domestic ruminants is generally known as tick-borne fever, responsible for significant economic losses especially in Northern Europe (Stuen, 2007; Grøva et al. 2011). Clinical findings High fever, dullness, in-appetence, sudden drop in milk production, low weight gain, coughing, abortion, stillbirth and low fertility in sheep and reduced semen quality in rams are important clinical signs in cattle and sheep (CFSPH, 2013) but clinical signs differ among variants/strains involved. Less severe cases recover within few days and death is unusual outcome (Grøva et al. 2011; CFSPH, 2013). The TBF may develop concurrent infections with Borrelia burgdorferi and/or A. marginale and followed by secondary infections (tick pyemia and pasteurellosis) (Hofmann-Lehmann et al. 2004; Berger, 2014). Co-infection may alter disease pathogenesis and complicate diagnosis resulting in more severe clinical disease. These factors affect treatment and prognosis as well. Coinfected dogs with B. burgdorferi further predispose to Bartonella vinsonii subs. berkhoffii infection (Grab et al. 2007). Single A. phagocytophilum infected dogs and cats show generalized non-specific signs (CFSPH, 2013). Horses (>3 years) develop sever disease including fever, depression anorexia, icterus, ataxia, petechial hemorrhages and distal limb edema with severe myopathy (CFSPH, 2013). Fever, headache, myalgias and chills are the important clinical findings of human anaplasmosis (CFSPH, 2013). Leucopenia (marked neutropenia), thrombocytopenia, anaemia and/or elevated liver enzymes are common hematological and biochemical finding in humans and animals (especially dogs and cats) (Bakken et al. 1994; Aguero-rosenfeld et al. 1996; CFSPH, 2013; Ravnik et al. 2011; Dondi et al. 2014; Savidge et al. 2016; Khatat et al. 2015). Bacterium show purple colour mulberry-like micro-colonies after staining with Romanowsky stain called Morulae (Rikihisa, 2011). Enlargement of spleen (4–5 times) with subscapular bleeding is the most significant postmortem finding of tick-borne fever in sheep, reindeer and roe deer (Gordon et al. 1932; Øverås et al. 1993; Stuen, 2003).

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Epidemiology Infection has been noticed in cattle, sheep, goat, horse, donkey, dog, cat and wild ruminants (Table 1). Anaplasma phagocytophilum is most commonly been found in red deer, roe deer, fallow deer with highest prevalence (10–98%) in red deer and roe deer population (Hulínská et al. 2004; Zeman and Pecha, 2008; Scharf et al. 2011; Hapunik et al. 2011; Overzier et al. 2013). Exact reservoir hosts for A. phagocytophilum in animals and humans are not known to date. However, the pathogen has been detected in sika deer, white-tailed deer, Korean water deer, chamois, European bison, wild boar, Alpine ibex, mouflon, mule deer, elk, ilama, alpaca, Swedish moose and birds (Table 1). Small mammals: Dusky-footed wood rats, white-footed mice, vole, eastern chipmunk, squirrel, Virginia opossum and striped skunk. Insectivorous mammals: Shrew, hedgehog. Reptiles and snakes: Northern alligator lizard and Pacific gopher snake. Others: Gray fox, cotton tail rabbit, American black bear, timber wolf, raccoon and European brown bear (Table 1). High-risk outdoor behaviour (such as gardening and hiking), immunocompromised individuals (cancer treatments, HIV infection and prior organ transplants) and blood transfusion are important risk factors for human granulocytic anaplasmosis (HGA) (Leiby and Gill, 2004; Zhang et al. 2014; Atif, 2015). Higher degree of genetic, pathogenic and host tropisms exist in A. phagocytophilum isolates (Baráková et al. 2014). The 16S rRNA, p44, groEL heat-shock protein, msp4 and ankA genes are important genetic markers to study genetic diversity (Granquist et al. 2010a; Silaghi et al. 2011a, b). Transmission: Ixodes (I.) ricinus is the major vector in Europe; I. pacificus in Western USA; Dermacentor (D.) occidentalis and D. variabilis in California (Holden et al. 2003; Lane et al. 2010; Rejmanek et al. 2011); I. scapularis in Eastern USA (Lovrich et al. 2011; Roellig and Fang, 2012); Amblyomma americanum and I. scapularis in Southern USA; I. spinipalpis in North Colorado (USA) (Zeidner et al. 2000); I. scapularis and D. albipictus in Canada (Baldridge et al. 2009); I. persulcatus, I. nipponensis, I. ovatus, D. silvarum, Haemaphysalis (H.) douglasii, H. megaspinosa, H. japonica, H. longicornis in Asia (China, Korea, Japan, Russia; Table 2); I. ricinus, I. spinipalpis, Hyalomma (Hy.) marginatum, Hy. Detritum in North Africa (Algeria, Tunisia and Morocco) (Sarih et al. 2005; M’ghirbi et al. 2012); R. turanicus, Rhipicephalus kohlsi in Israel (Keysary et al. 2007). The pathogen has also been detected in I. persulcatus, H. concinna, D. reticulates and I. ventalloi ticks (Table 2). As mentioned above, A. phagocytophilum has been detected in various tick species, but the

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Epidemiology and characteristics of Anaplasma species related to veterinary and public health importance

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Table 1. Detection of Anaplasma phagocytophilum from different vertebrate hostsa Animalsb

Country

Prevalence

Methodc

References

Domestic animals Cattle

Guatemala

51%

Teglas et al. (2005)

Cattle Cattle

Italy Algeria

1·7% 71·4%

Cattle

China

6·4%

Cattle

USA (Connecticut)

Sheep

Norway

12·0% 4·0% 37·5%

nPCRd (16S rRNA) RLBe PCR (23S rRNA) nPCRd (16S rRNA) ELISA IFA

Sheep

Italy

11·5%

Sheep

Germany

4·0%

Sheep

2·8%

Sheep

Czech Republic, Slovakia Republic Denmark

Sheep

China

28·8%

Sheep Goat Goat Dog Dog Dog Dog Dog Dog Dog Dog Dog Cat Cat Cat Cat Cat Horse Horse

Turkey Switzerland Turkey USA California USA (South) USA (Mid-Atlantic) USA (Northeast) USA (Midwest) USA (West) Canada Caribbean Brazil USA (Connecticut) USA Northeast USA Mid Atlantic USA South USA Midwest Pakistan Poland

11·1% 5·6% 5·8% 7·6% 2·1% 5·4% 13% 1·9% 2·0% 1·1% 3·4% 7·1% 33·3% 1·3% 2·3% 0·1% 0·1% 7·1% 2·63%

Horse

Slovakia

2·56%

Horse

Ukraine

0·0%

Donkey Donkey

Spain Italy

100% 4·0 %

Brazil

20%

Poland

10·2%

Roe deer (Capreolus capreolus)

USA

98·9%

Roe deer (Capreolus capreolus) Fallow deer (Dama dama)

Austria UK

52·6% 21%

nPCRd (16S rRNA) PCR (16S rRNA, AnkA) nPCRd (16S rRNA) qPCRf (msp2) qPCRf (msp2)

Sika deer (Cervus nippon) Sika deer (Cervus nippon yesoensis) White tailed deer (Odocoileus virginianus)

Japan Japan USA (Minnesota)

46% NA 46·6%

nPCRd PCR PCR (msp2)

Wild ruminants Brazilian brown brocket deer (Mazama gouazoubira) Red deer (Cervus elaphus)

11·6%

nPCRd (16S rRNA, msp4) PCR (16S rRNA) nPCRd (16S rRNA) PCR PCR (16S rRNA) nPCRd (16S rRNA) PCR (msp4) qPCRf (msp2) PCR (msp4) qPCRf (msp2) ELISA kit ELISA kit ELISA kit ELISA kit ELISA kit ELISA kit ELISA kit qPCRf (msp2) PCR (msp2) ELISA kit ELISA kit ELISA kit ELISA kit PCR-RFLP nPCRd (16S rRNA) nPCRd (16S rRNA) nPCRd (16S rRNA) PCR (msp4) PCR (16S rRNA/ msp4)

Ceci et al. (2014) Dahmani et al. (2015) Yang et al. (2015a) Magnarelli et al. (2002) Stuen et al. (2013a) Torina et al. (2010) Scharf et al. (2011) Derdáková et al. (2011) Kiilerich et al. (2009) Yang et al. (2015a) Öter et al. (2015) Silaghi et al. (2011a) Öter et al. (2015) Henn et al. (2007) Qurollo et al. (2014) Qurollo et al. (2014) Qurollo et al. (2014) Qurollo et al. (2014) Qurollo et al. (2014) Qurollo et al. (2014) Qurollo et al. (2014) Santos et al. (2013) Levin et al. (2002) Hegarty et al. (2015) Hegarty et al. (2015) Hegarty et al. (2015) Hegarty et al. (2015) Razzaq et al. (2015) Slivinska et al. (2016) Slivinska et al. (2016) Slivinska et al. (2016) Naranjo et al. (2006) Torina et al. (2008)

Silveira et al. (2012) Hapunik et al. (2011) Overzier et al. (2013) Silaghi et al. (2011b) Robinson et al. (2009) Jilintai et al. (2009) Ybañez et al. (2012) Johnson et al. (2011)


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Table 1. (Cont.) Animalsb

Country

Prevalence

Methodc d

Black tailed deer (Odocoileus hemoniuscolumbianus) Korean water deer (Hydropotes inermis argyropus) Mongolian gazelle (Procapra gutturosa)

USA (California)

26·7%

Korea

63·6%

China

65·2%

Mule deer (Odocoileus hemonius hemonius) Wild cervidesh

USA (California)

83·3%

Spain

64·2%

European bison (Bison bonasus)

Poland

58%

Swedish moose (Alces alces)

Sweden

36·6%

Alpine ibex (Capra ibex) Chamois (Rupicapra rupicapra) Mouflon (Ovis musimon) Elk (Cervus elaphus nannodes)

Austria Austria Austria USA (California)

16·7% 26·1% 50·0% 31·0%

Yaks

China

35·0%

USA (California)

9·4%

qPCRf (msp2)

USA (Connecticut)

20·0– 46·8% 2·6%

PCR (msp2)

Small mammals Dusky-footed wood rat (Neatoma fuscipes) White-footed mice (Peromyscus leucopus) East-European field vole (Microtus rossiaemeridionalis) Eastern chipmunk (Tamias striatus)

nPCR (16S rRNA) nPCRd (16S rRNA) PCR (16S rRNA) nPCRd (16S rRNA) qPCRf (16S rRNA) nPCRd (16S rRNA) qPCRf (16S rRNA) qPCRf qPCRf (msp2) qPCRf (msp2) nPCRd (16S rRNA) nPCRd (16S rRNA)

References Foley et al. (1998) Kang et al. (2011) Li et al. (2014) Foley et al. (1998) García-Pérez et al. (2015) Scharf et al. (2011) Malmsten et al. (2014) Silaghi et al. (2011b) Silaghi et al. (2011b) Silaghi et al. (2011b) Foley et al. (1998) Yang et al. (2013) Rejmanek et al. (2011) Johnson et al. (2011)

USA Russia (Minnesota) USA (California)

4·3% 11·1%

nPCRd (16S rRNA) nPCRd (16S rRNA) qPCRf (msp2)

USA (California)

25·0%

qPCRf (msp2)

USA (Minnesota) Germany

17·2% 85·4%

PCR qPCRf

Southern Hungary

5·1–6·6%

Multiplex qPCRf,g

Szekeres et al. (2015)

USA (California) USA (California)

9·1% 33·3%

qPCRf (msp2) qPCRf (msp2)

Nieto et al. (2009) Nieto et al. (2009)

USA (California)

20·0%

qPCRf (msp2)

Nieto et al. (2009)

USA (California) Italy

9·0% 16·6%

Gabriel et al. (2009) Ebani et al. (2011)

Red fox (Vulpes vulpes) spleen

Hungary

12·5%

Red fox (Vulpes vulpes)

Romania

2·55%

American black bear (Ursus americanus)

USA (California)

4·0%

qPCRf (msp2) nPCRd (16S rRNA) qPCRf (16S rDNA) PCR (16S rRNA) qPCRf (msp2)

European brown bear (Ursus arctos)

Slovakia

24·3%

Wild boar (Sus scrofa) Timber wolf (Canis lupus occidentalis)

Slovenia Austria

Raccoon (Nyctereutes procyonoides) Cottontail rabbit (S. floridanus)

Germany USA (Massachusetts)

6·3% Case report 23·0% 27·0%

Eastern grey squirrel (Sciurus carolinensis) Northern flying squirrel (Glaucomys sabrinus) Short-tailed shrew (Blarina spp.) European hedgehog (Erinaceus europaeus) Yellow-necked mouse [Apodemus (Ap.)] flavicollis), Striped field mouse (Ap. agrarius), Bank vole (Myodes glareolus), Common vole (Microtus arvalis), House mouse (Mus musculus) Reptiles and Snakes Western fence lizard (S. occidentalis) Northern alligator lizard (Elgaria coeruleus) Pacific gopher snake (Pituophis catenifer) Other animals Gray fox (Urocyon cinereoargenteus) Red fox (Vulpes vulpes)

PCR (16S rDNA) qPCRf Blood smear /PCR qPCRf (msp2) nPCRd (16S rRNA)

Rar et al. (2011) Walls et al. (1997) Nieto and Foley (2008) Rejmanek et al. (2011) Johnson et al. (2011) Silaghi et al. (2012)

Tolnai et al. (2015) Dumitrache et al. (2015) Drazenovich et al. (2006) Víchová et al. (2010) Zele et al. (2012) Leschnik et al. (2012) Härtwig et al. (2014) Goethert and Telford (2003a)



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Table 1. (Cont.) Animalsb Hare (Leparus europaeus) Birds Eurasian collared doves (Streptopelia decaocto) Eurasian eagle owls (Bubo bubo) House sparrow (Passer domesticus)

a b c d e f g h

Country

Prevalence

Methodc

References

Czech Republic

12·5%

PCR (16S rRNA)

Hulínská et al. (2004)

China (south west)

3·5%

Yang et al. (2015b)

China (south west)

15·4%

Spain

6·0%

nPCRd (16S rRNA) nPCRd (16S rRNA) PCR

Yang et al. (2015b) de la Fuente et al. (2005)

Detection of A. phagocytophilum from 1998 to 2015. Organism detected in tissue or blood specimen. In parenthesis target gene has been mentioned. Nested PCR. Reverse line blot hybridization. Real time PCR. Commercial kit. Species involved were not available.

vector competence of I. ricinus, I. pacificus, I. scapularis and I. spinipalpis has so far been proved (Woldehiwet, 2010). Identification of reservoir hosts and competent vectors are the important research area that needs to be explored. There are reports of mechanical transmission by deer ked (Lipoptena cervi) from Cervides (Víchová et al. 2011). Similarly, transplacental (lambs and calves), perinatal, nosocomial and blood transfusions associated transmissions has been reported (Bakken et al. 1994; Horowitz et al. 1998; Dhand et al. 2007; Zhang et al. 2008; Annen et al. 2012; Henniger et al. 2013; Reppert et al. 2013). The epidemiology of anaplasmosis is further complicated by these modes of transmissions. Diagnosis Anaplasma phagocytophilum is rarely diagnosed only on the basis of clinical signs; usually laboratory tests are required for confirmation. Intra-cytoplasmic inclusions can be observed in granulocytes in peripheral blood smear (Fig. 1). Disease can be confirmed by electron microscopy of blood or organs smears, cell culture or immune-histochemistry (Lepidi et al. 2000; Stuen et al. 2013b). The “SNAP®4Dx® ELISA” (dog), also detect antibodies for sheep and horse (Granquist et al. 2010b; Hansen et al. 2010); “MegaFLUO® ANAPLASMA phagocytophilum” (dog, horse) and “ImmunoRun Canine Anaplasma Antibody Detection kit” (dog) are commercially available diagnostic kits for in-house detection of A. phagocytophilum antibodies in plasma or serum; as per specifications of manufacturer. The indirect immunofluorescence assay is the gold standard for HGA (Center for Disease Control and Prevention) (CDC, 2013). Conventional, real-time and nested PCR techniques has been developed for blood and

tissue samples targeting 16S rRNA, groEL, msp4, ankA and p44 genes of A. phagocytophilum (Chen et al. 1994; Courtney et al. 2004; Alberti et al. 2005). There is no such test available that can differentiate persistent and chronic Anaplasma infections. Treatment Ovine granulocytic anaplasmosis can be treated and possibly eliminated by long acting oxytetracycline at 10–20 mg kg−1 (Stuen and Bergstrom, 2001). Similarly, oxytetracycline is also effective against horses and other ruminants (Atif et al. 2012b; Siska et al. 2013; The Merck Veterinary Manual, 2014); whereas doxycycline showed efficacy against feline and canine granulocytic anaplasmosis (CFSPH, 2013). Oxytetracycline, rifampin, doxycycline hyclate and levofloxacin are effective against HGA (Goodman et al. 1996; Wormser et al. 2006; Zeidner et al. 2008; CDC, 2013; Bakken and Dumler 2015). ANAPLASMA BOVIS

Anaplasma bovis infects monocytes of diverse hosts. This has been described for the first time in cattle in 1936 (Donatien and Lestoquard, 1936). Since it has been reported from Spain, Italy, India, China, Korea, Japan, America, Brazil, Tunisia and South Africa from domestic and wild animals (Sakamoto et al. 2010; Harrison et al. 2011; Sashika et al. 2011; Chirayath et al. 2012; Liu et al. 2012; Ceci et al. 2014; Li et al. 2015a; Yang et al. 2015a; Hwang et al. 2015; Belkahia et al. 2015a; GarcíaPérez et al. 2015; Ben Said et al. 2015; Table 3). Clinical findings Anaplasma bovis infection is characterized by fever, drop in milk production, weakness, obvious weight


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Table 2. Detection of Anaplasma phagocytophilum in different tick species Countries

Tick species

References

Hungary Austria Russia Latvia/Estonia

Ixodes ricinus, Dermacentor reticulatus, Haemaphysalis concinna Ixodes ricinus Ixodes persulcatus Ixodes persulcatus

France

Rhipicephalus bursa, Rhipicephalus sanguineus, Rhipicephalus turanicus, Dermacentor marginatus, Hyalomma marginatum Ixodes ricinus, Hyalomma marginatum, Hyalomma Detritum, Ixodes spinipalpis Ixodes scapularis, Dermacentor albipictus Ixodes scapularis

Szekeres et al. (2015) Glatz et al. (2014) Rar et al. (2011) Paulauskas et al. (2012); Rar et al. (2011) Chastagner et al. (2013)

Algeria/Tunisia/ Morocco Canada USA (East) USA (West) USA (North) USA (South) USA (California) Israel China Korea Japan

Sarih et al. (2005); M’ghirbi et al. (2012) Baldridge et al. (2009) Lovrich et al. (2011); Roellig and Fang (2012) Ixodes pacificus Rejmanek et al. (2011) Ixodes spinipalpis Zeidner et al. (2000) Amblyomma americanum, Ixodes scapularis Clark (2012) Dermacentor occidentalis, Dermacentor variabilis Holden et al. (2003); Lane et al. (2010); Rejmanek et al. (2011) Hyalomma spp., Rhipicephalus turanicus, Rhipicephalus kohlsi Keysary et al. (2007) Ixodes persulcatus, Dermacentor silvarum, Haemaphysalis long- Cao et al. (2006); Jiang et al. (2011) icornis, Haemaphysalis concinna Haemaphysalis longicornis, Ixodes nipponensis Chae et al. (2008) Ixodes persulcatus, Haemaphysalis, megaspinosa, Ixodes ovatus, Wuritu et al. (2009); Yoshimoto Haemaphysalis douglasii et al. (2010); Ybañez et al. (2012)

rabbit and eastern rock sengi (Table 3). The first molecular phylogenetic study of A. bovis was performed in Japan using groEL and gltA genes (Ybañez et al. 2014). Prevalence of A. bovis varies from region to region depending upon the test method and specie type. Prevalence in domestic ruminants range from 3·94·8 to 39·9% and 9 to 15% in wild Cervids (Red deer and Sika deer) (Ceci et al. 2014; Belkahia et al. 2015a; Li et al. 2015a; Yang et al. 2015a; Njiiri et al. 2015; Table 3). Transmission: Haemaphysalis megaspinosa, H. shimoga, H. punctata, H. longicornis, H. leporispalustris and Rhipicephalus sanguineus species of ticks are important vector of A. bovis (Table 4) but the vector competence of ticks needs to be further evaluated. Fig. 1. Anaplasma phagocytophilum in dog’s granulocyte (Sainz et al. 2015); magnification 100×.

loss, pale mucous membranes, enlargement of prescapular lymph nodes and death in stressed or naïve cattle (Losos, 1986; Sreekumar et al. 1996). Epidemiology Cattle and goats are the major reservoirs of this pathogen (Goethert and Telford, 2003b). Infection has also been detected in other animals including buffalo, dog, roe deer, red deer, sika deer, Korean water deer, Brazilian brown brocket deer, marsh deer, Mongolian gazelle, leopard cat, raccoon, cotton tail

Diagnosis Examination of Leishman’s stained peripheral blood smear of cow show acidophilic A. bovis elementary bodies in monocytes or lymphocytes with eosinophilia (Sreekumar et al. 1996; Chirayath et al. 2012). Nested PCR targeting 16S rRNA gene has been used for the detection of bacterial DNA in ticks, domestic and wild ruminants (Kawahara et al. 2006; Doan et al. 2013; Li et al. 2015a; Yang et al. 2015a). Treatment So far, there are no controlled treatment studies available for A. bovis. In a case study, infection has



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Table 3. Detection of Anaplasma bovis among vertebrate hosts from different countriesa Country

Animalsb

Prevalence

Methodc

References

Spain Italy India India India China China China China China

Roe deer (Capreolus capreolus) Cattle Cattle Water buffalo Cattle Goat Red deer (Cervus elaphus) Sika deer Cattle Mongolian gazelle (Procapra gutturosa) Korean Water Deer (Hydropotes inermis argyropus) Leopard cats (Prionailurus bengalensis euptilurus) Cattle Dog

4d 4·2% Case report Case report 4·7% 16·0% 9·0% 15·0% 4·8% 78·3·2%

qPCRe (16S rRNA) RLB assayf Blood smear Blood/lymph node smear nPCRg (16S rRNA) PCR (16S rRNA) PCR (16S rRNA) PCR (16S rRNA) PCR (16S rRNA) PCR (16S rRNA)

García-Pérez et al. (2015) Ceci et al. (2014) Chirayath et al. (2012) Sree Devi et al. (2011) Nair et al. (2013) Liu et al. (2012) Li et al. (2015a) Li et al. (2015a) Yang et al. (2015a) Li et al. (2014)

34·8%

nPCRg (16S rRNA)

Kang et al. (2011)

27·6%

PCR (16S rRNA)

Hwang et al. (2015)

NA 0·2%

Ooshiro et al. (2008) Sakamoto et al. (2010)

Raccoon (Procyon lotor) Cottontail rabbit (Sylvilagus floridanus) Brazilian brown brocket deer (Mazama gouazoubira) and Marsh deer (Blastocerus dichotomus) Cattle Sheep Goat Eastern rock sengi, (Elephantulus myurus)

94·7% 18%

PCR PCR (16S rRNA/DNA nucleotide sequencing) nPCRg PCR (16S rDNA)

3·4%

nPCRg

Sashika et al. (2011) Goethert and Telford (2003b) Silveira et al. (2012)

3·9% 42·7% 23·8% 28·6%

PCR (msp1b/msp4) nPCRg nPCRg PCR (16S rRNA)

Belkahia et al. (2015a) Ben Said et al. (2015) Ben Said et al. (2015) Harrison et al. (2011)

Korea Korea Japan Japan Japan USA Brazil

Tunisia Tunisia Tunisia South Africa

NA = not available. Detection of A. bovis from 2003–2015. b Organism detected in tissue or blood specimen. c In parenthesis target gene has been mentioned. d Number of animals found positive. e Real time PCR. f Reverse line blot hybridization. g Nested PCR. a

Table 4. Molecular detection of Anaplasma bovis in different tick species Country

Tick species

References

Israel

Rhipicephalus sanguineus Haemaphysalis leporispalustris Haemaphysalis megaspinosa Haemaphysalis shimoga Haemaphysalis punctata Haemaphysalis longicornis

Harrus et al. (2011)

USA Japan Thailand Spain Korea

Goethert and Telford (2003b) Sashika et al. (2011) Malaisri et al. (2015) Palomar et al. (2015) Doan et al. (2013)

been treated with oxytetracycline at the dose rate of 20 mg kg−1 intravenous along with 500 ml normal saline. This showed marked improvement in clinical signs (Chirayath et al. 2012).

ANAPLASMA OVIS

Anaplasma ovis is an important intraerythrocytic tick-borne pathogen of goats, sheep and wild small ruminants worldwide (Shompole et al. 1989; Zaugg et al. 1996; Yabsley et al. 2005; de la Fuente et al. 2007; Yasini et al. 2012; Ybañez et al. 2014; Gharbi et al. 2015; Khan et al. 2015; Li et al. 2015a; Lee et al. 2015; Yang et al. 2015a; Table 5). Ovine anaplasmosis has been considered a problem for poor countries but scientists have also detected this bacterium in developed countries such as USA, Hungary, Greece, Italy, Spain, Portugal and Turkey (de la Fuente et al. 2006a; Hornok et al. 2007; de la Fuente et al. 2008; Torina et al. 2010; Renneker et al. 2013; Giadinis et al. 2015; Öter et al. 2015). The occurrence of A. ovis is not widespread in these countries yet, but the climate change and traditional farming (pasturage on meadows) may lead to the spread of this pathogen.


Farhan Ahmad Atif

Clinical findings Acute infection is characterized by fever, weakness, anaemia, pallor mucous membrane, lower milk production, weight loss, jaundice, abortion and often death (Shompole et al. 1989; Kocan et al. 2003). Anaplasma ovis does not cause clinical disease in cattle. Clinical disease cause great economic losses in resource limited countries where sheep and goat are the major component of livestock. The clinical signs are variable based on age, breed and health status of animal (Splitter et al. 1955; Shompole et al. 1989). Animals recovered from clinical disease become life-long carriers. Persistent infections may cause low weight gain (>14%) in lambs (Klabi, 2011). Splenectomized animals, intercurrent infections, malnutrition and pregnancy render animals more susceptible to anaplasmosis (Splitter et al. 1956). Epidemiology In recent years, its occurrence have been reported from all over the world such as Hungary, Greece, Italy, Spain, Portugal, USA, Turkey, Iran, Iraq, Tunisia, Sudan, Kenya, Pakistan, India, China and Korea (Table 5). Transmission: Anaplasma ovis is biologically transmitted by soft and hard tick species including R. bursa, Dermacentor andersoni, R. turanicus, Ornithodoros lahorensis and mechanically by biting Diptera. Nonetheless, sheep ked (Melophagus ovinus) has also been suspected to transmit A. ovis (Table 6). Diagnosis Acute disease is usually diagnosed on the basis of clinical signs, detection of organism in blood smear and hematology (Rassouli et al. 2015). This bacterium is deeply stained and appears dense, round bodies located at the centre or margins of the erythrocytes (Fig. 2). Treatment Oxytetracycline is the most effective drug followed by imidocarb dipropionate and diaminazene in sheep and goats (Ali et al. 2014). ANAPLASMA MARGINALE

Anaplasma marginale has been described by Sir Arnold Theiler in erythrocytes of cattle as “marginal points” (Theiler, 1910). Bovine anaplasmosis (BA) is caused by A. marginale, characterized by fever, severe anaemia, pale mucous membranes, jaundice, brownish urine, decreased milk production, abortion, hyper excitability, weight loss and mortality during acute phase of the infection (Richey and Palmer, 1990; Wanduragala and Ristic, 1993;

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Ooshiro et al. 2009; Jaswal et al. 2013). The BA is responsible for economic losses of 48·13 million USD in Tanzania and $26 million Australian dollars due to mortality in Australia (Kivaria, 2006; Sackett and Holmes, 2006). Hemolytic anaemia is the major clinical manifestation of A. marginale infection in cattle (Atif et al. 2012a). Animals recovered from clinical disease become life-long carriers (Palmer et al. 2006). Numerous strains of A. marginale exist. They differ in morphology, antigenic characteristics, protein sequence and biological transmission (Smith et al. 1986; Barbet et al. 1987; Kocan et al. 2003, 2004). Epidemiology The BA is widely distributed throughout the world especially in tropical and subtropical (400N–320S) regions, including Asia, Far East Asia, Central Asia, Southern Europe, America and Africa (Table 7). Increase in prevalence and distribution of anaplasmosis is due to increase in movement and transportation of cattle from endemic to nonendemic regions (Saetiew et al. 2015). Clinical anaplasmosis mostly occurs in cattle but other ruminants usually develop persistent infection. However, natural or experimental infection has been reported in buffaloes (Bubalus bubalis), African buffalo (Syncerus caffer), black-tailed deer (Odocoileus hemionus columbianus), white-tailed deer (Odocoileus virginianus), marsh deer (Blastocerus dichotomus), Brazilian brown brocket deer (Mazama gouazoubira), mule deer (Odocoileus hemionus), bighorn sheep (Ovis canadensis), pronghorn antelope (Antelocapra americana), elk (Cervus elaphus nannodes), rocky mountain elk (Cervus elaphus nelson), giraffes (Giraffa camelopardalis) and bison (Bison bison), (Stiller et al. 1981; Kuttler, 1984; Davidson and Goff, 2001; Lobanov et al. 2012; Silveira et al. 2012; Eygelaar et al. 2015; Table 7). Most of the earlier reports on wildlife were based on serology. There is a need for advanced studies using molecular techniques. Risk factors vary from region to region and various epidemiological and managemental factors contribute for occurrence of the disease in an area. During a risk factors study, it was revealed that heavy tick-infested crossbred cattle of more than 4 year of age was significantly at higher risk as compared to low tick infested indigenous cattle. On the contrary, sex and health status of the animals had no effect on the occurrence of A. marginale infection (Atif et al. 2013). Other farm management factors associated with BA include stall feeding, moderate acaricide frequency, use of ivermectin and unhygienic needles. Animals receiving avermectin (ivermectin) were found at higher risk compared to pyrethroid and organophosphate class of acaricide. Farm type (beef, dairy, mix), herd size, livestock



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Table 5. Detection of Anaplasma ovis among vertebrate hosts from different countriesa Country

Animalsb

Prevalence

Methodc

References

Hungary Greece Italy Spain

Sheep Cattle Sheep European roe deer (Capreolus capreolus) Sheep/goat Bighorn sheep (ovis canadensis)

99·4% 35·9% 37·0% 53·0%

cELISA cELISA PCR (msp4) PCR (msp4)

Hornok et al. (2007) Giadinis et al. (2015) Torina et al. (2010) de la Fuente et al. (2008)

82·5% 14·0%, 39·0%

PCR (msp4) cELISA kit, PCR (msp4) PCR (msp4) PCR (msp4) PCR (msp4) Blood smear

Renneker et al. (2013) de la Fuente et al. (2006a, b, c) Renneker et al. (2013) Öter et al. (2015) Öter et al. (2015) Yasini et al. (2012)

PCR (msp4)

Portugal USA (Montana) Turkey Turkey Turkey Iran

Sheep/goat Sheep Goat Sheep

Iran

Goat

Iraq Tunisia Sudan Kenya Pakistan Pakistan Pakistan India China China China China

Sheep/goat Sheep Sheep/goat Goats Sheep Goats Sheep Sheep Sheep Red deer (Cervus elaphus) Sika deer Mongolian gazelle (Procapra gutturosa) Mongolian reindeer (Rangifer Tarandus) Native Korean goats (Capra hircus coreanae)

China Korea

a b c d e

31·4% 58·8% 42·5% Clinical study 63·7% 66·6% 11·6% 41·7% 22–87% 55·3% 30·7% 28·0% 9·2% 40·5% 32·0% 20·0% 52·2%

PCR (msp4) Blood smear PCR (msp4) DNA prob Blood smear Blood smear Blood smear/PCR Blood smear nPCRd (msp4) PCR (msp4) PCR (msp4) PCR (msp4)

Ahmadi-hamedani et al. (2012) Renneker et al. (2013) Gharbi et al. (2015) Renneker et al. (2013) Shompole et al. (1989) Ali et al. (2014) Ali et al. (2014) Khan et al. (2015) Arunkumar (2014) Yang et al. (2015a) Li et al. (2015a) Li et al. (2015a) Li et al. (2014)

80·0%

PCR (cpn60)

Haigh et al. (2008)

6·6%

cELISAe

Lee et al. (2015)

Detection of A. ovis from 1989 to 2015 including a clinical study. Organism detected in tissue or blood specimen. In parenthesis target gene has been mentioned. Nested PCR. Detected Anaplasma species.

Table 6. Detection of Anaplasma ovis in different tick/vector species Country

Tick/vector species

Hungary

Ixodes ricinus

Hungary Hungary

Melophagus ovinus Lipoptena cervi

USA Asia, Europe, Africa

Dermacentor spp. Rhipicephalus bursa

References Hornok et al. (2012) Hornok et al. (2011) Hornok et al. (2012) Friedhoff (1997) de la Fuente et al. (2007)

species at farm, sources of animals and farm instruments were not significantly involved. Moderate climatic regions are at higher risk as compared with arid and cooler regions for the occurrence of A. marginale infection in cattle (Tembue et al. 2011; Ashraf et al. 2013; Atif et al. 2013). Da Silva and da Fonseca (2014) reported Bos indicus, primiparous tick

infested, high milk producing female cattle with high-density grazing are at higher risk for A. marginale infection (da Silva and da Fonseca, 2014). There are six major surface proteins (MSPs), while MSP2 and MSP3 play a vital role in the aetiology of disease because they undergo antigenic variation (Palmer et al. 2006). The MSP1a, MSP4 and MSP5 are antigenically similar within strains because they are encoded by single gene while MSP1b, MSP2 and MSP3 belong to multigene families and hence antigenically different (Kocan et al. 2003). The msp1a and msp4 genes have been used as constant genetic marker for the differentiation of A. marginale strains (de la Fuente et al. 2001; Kocan et al. 2010b). The Msp1a genes do not provide phylogenetic information, whereas msp4 provide information (Kocan et al. 2010a; CabezasCruz and de la Fuente, 2015). Major surface protein 5 is highly conserved in Anaplasma species and is being effectively used as diagnostic antigen for serodiagnosis in competitive ELISA (cELISA; Torioni de Echaide et al. 1998).


Farhan Ahmad Atif

Fig. 2. Anaplasma ovis in sheep’s erythrocyte (Jalali et al. 2013); magnification 100×.

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Experimental and clinical studies have proved that infected erythrocytes move from infected cows to their offspring through placenta (Zaugg, 1985; Potgieter and Van Rensburg, 1987; Salabarria and Pino, 1988; Costa et al. 2015; Silvestre et al. 2016). Barbosa Da Silva reported transplacental transmission using indirect enzyme-linked immunosorbent assay (ELISA) and nested PCR in calves (Barbosa da Silva et al. 2014a). Blood-contaminated needles, ear tagging devices, castration, dehorning equipments and nose tongs contribute in mechanical transmission within the herd (Kocan et al. 2003; The Merck Veterinary Manual, 2014). Biting flies were not able to experimentally transmit infection (Scoles et al. 2005, 2008). Recently Haematopinus tuberculatus, sucking lice have been reported as the potential vector of A. marginale in buffaloes (da Silva et al. 2013). The transplacental and mechanical routes do not contribute much in the transmission of A. marginale infection. Diagnosis

The lifecycle starts with the ingestion of blood by vector ticks. The initial replication of A. marginale takes place in gut cells; bacterium infects the salivary glands of ticks and transmits disease to cattle during blood meal (Kocan et al. 2003). After gaining entry in the host cells A. marginale multiply in erythrocytes; they divide up to eight initial bodies within its outer membrane. Along with rupture of infected erythrocytes, the parasite membrane also ruptures releasing the initial bodies into blood stream to invade other erythrocytes (Stewart et al. 1981). Later the infected erythrocytes are phagocytized by bovine spleen and reticuloendothelial cells leading to hemolytic anaemia and icterus (Kocan et al. 2003; Fig. 3). Transmission: Rhipicephalus, Ixodes, Dermacentor and Amblyomma genera of ticks are the important vectors of Anaplasma species (Table 8). A total of 17 species of ticks have been experimentally proved to transmit A. marginale (The Merck Veterinary Manual, 2014). Rhipicephalus microplus is the major vector of A. marginale in various countries including India, South Africa, Brazil, Malaysia and Australia (Guglielmone et al. 1995; Potgieter, 1996; Mirwan, 2003; Ghosh et al. 2007; Table 8). Ixodes ricinus is the main vector in Europe; Dermacentor (D.) andesrsoni, D. variabilis and D. albipictus in North America (Table 8). Some tick species or genotypes are selective for the transmission of specific A. marginale strains (Scoles et al. 2005). Intrastadial and interstadial (one stage to another stage) transmission is reported while transovarial transmission does not occur (Kocan et al. 1992a, b). In endemic region, animal-toanimal transmission usually results from infested mother to suckling calves (Kocan, 1994).

Anaemia, pale to yellow mucous membranes, brown lymph nodes, jaundice, enlarged spleen and distended gall bladder are important clinical findings of BA (The Merck Veterinary Manual, 2014). Diagnosis is based on giemsa stained blood smear (Fig. 4), serology, nucleic acid detection and sub-inoculation of blood into splenectomized calf. Giemsa stained blood smear examination is inexpensive, rapid and most widely used method for the diagnosis of tick-borne diseases (Salih et al. 2007), but this technique is not suitable in persistently infected carrier animals with low levels of parasitaemia (Kocan et al. 2010b). There are problems of sensitivity, reproducibility, interpretation and non-specific reactions associated with these serological tests (OIE, 2015). The results of serological assays should be interpreted with caution because of possible cross-reactivity implications. Sub-inoculation of blood from suspected into splenectomized calf is a gold standard for the demonstration of Anaplasma-free status (Coetzee et al. 2006). But this method is expensive, time consuming and may not be good for validation of assays. World animal health organization recommended cELISA for serodiagnosis of anaplasmosis in cattle. The cELISA is cost effective test and also commercially available as diagnostic kit “Anaplasma Antibody Test Kit” (cELISA); VMRD Inc., Pullman, WA, USA for the detection of early and persistent Anaplasma infection. Recently improved cELISA, uses monoclonal antibody with 100% sensitivity and 99·7% specificity at 30% cutoff (Chung et al. 2014). Card agglutination test is sensitive, may be performed in laboratory as well as under field conditions and results can be obtained within few minutes.



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Table 7. Detection of Anaplasma marginale from different countriesa Country

Animalsb

Prevalence

Methodc

References

Switzerland Hungary Italy Spain USA (Texas)

Cattle Cattle Cattle Cattle Cattle

Canada

Mule deer (Odocoileus hemionus) Cattle

47% 92% 18·1% NA 82% 88% 33·3%

PCR (msp5) PCR RLBd assay PCR (msp4) qPCRe cELISA cELISA

Hofmann-Lehmann et al. (2004) Hornok et al. (2012) Ceci et al. (2014) de la Fuente et al. (2005) Hairgrove et al. (2015) Hairgrove et al. (2015) Lobanov et al. (2012)

69·75%

Rapid-card agglutination cELISA kit nPCRf (msp5) qPCRe ELISA PCR nPCRf (msp4, msp1 and 16S rRNA) nPCRf (msp4, msp1a)

Rodríguez-Vivas et al. (2004)

Mexico Puerto Rico Cuba Brazil Brazil Brazil Brazil Brazil Turkey Saudi Arabia Pakistan Bangladesh Sri Lanka Tajikistan China Malaysia Philippines Japan India India India India Kenya Tunisia Egypt Sudan Central Angola Mozambique Mozambique Botswana South Africa

Cattle Water buffalo Cattle Water buffalo Water buffalo Brazilian brown brocket deer (Mazama gouazoubira) Marsh deer (Blastocerus dichotomus) Cattle Cattle Cattle Cattle Cattle Cattle Cattle Cattle/Water buffalo cattle Cattle Cattle Cattle Water buffalo Water buffalo Cattle Cattle Cattle Cattle Cattle Cattle Cattle African buffalo (Syncerus caffer) Cattle

27·4% 90·4% 15–100% 49% 5·4% 76% 75% 37·8% 1–3·4% 31·1% 25·8% NA 14% 8·7% 77·6% 95·5% Case report

Urdaz-Rodríguez et al. (2009) Álvarez (2015) da Silva et al. (2016) Barbosa da Silva et al. (2014b) Barbosa da Silva et al. (2014b) Silveira et al. (2012) Silveira et al. (2012)

cELISA (kit) Blood smear cELISA Blood smear Card agglutination Indirect ELISA (kit) PCR (msp5) cELISA (kit) PCR PCR (16S rRNA and groEL) 16·7% PCR (msp5) 20·6% Indirect ELISA 1·25% PCR (msp 1β) 2·9% Indirect ELISA (kit) 15·8 & 2·5% nPCRf (msp5) 25·4% nPCRf (msp1b) 21·3% PCR/sequencing 50·4% Indirect ELISA 38·0% PCR

Açici et al. (2016) Al-Khalifa et al. (2009) Atif et al. (2013) Belal et al. (2014) Jorgensen et al. (1992) Gralen (2009) Ybañez et al. (2013a) Rahman et al. (2012) Ochirkhuu et al. (2015) Ooshiro et al. (2009) Nair et al. (2013) Filia et al. (2015) Ashuma et al. (2013) Filia et al. (2015) Adjou Moumouni et al. (2015) Belkahia et al. (2015a) El-Ashker et al. (2015) Kivaria et al. (2012) Kubelová et al. (2012)

76·5% 63·0% 20·0%

Indirect ELISA Card agglutination RLBd assay

Tembue et al. (2011) Alfredo et al. (2005) Eygelaar et al. (2015)

65–100%

PCR (msp1a)

Mutshembele et al. (2014)

NA = not available. a Detection of A. marginale from 1992 to 2015. b Organism detected in tissue or blood specimen. c In parenthesis target gene has been mentioned. d Reverse line blot hybridization. e Real-time PCR. f Nested PCR.

There are problems of non-specific reactions, reproducibility and interpretation of the test results as well as preparation of the antigen which is the suspension of A. marginale which differs from batch to batch and laboratory to laboratory. Card agglutination and complement fixation tests have been replaced with ELISA for regional and international movement of cattle (OIE, 2008). Newly improved, competitive ELISA has obvious advantage because

of greater sensitivity 100% and specificity 99·7% (Chung et al. 2014). Recently developed nested PCRs based on groEL, 16SrRNA (longer sequence), msp1α, msp5, groEL and gltA genes to characterize A. marginale isolates. Ybañez and associates developed nPCR which is highly specific and sensitive with a detection limit of two copies per PCR (Ybañez et al. 2013a). Furthermore, (Bilgiç et al. 2013) developed


Farhan Ahmad Atif

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Fig. 3. Life cycle of Anaplasma marginale in erythrocytes and tick gut cells (Marcelino et al. 2012).

Table 8. Detection of Anaplasma marginale in different tick species Country

Ticks

References

India, South Africa, Brazil Europe Iraq North America

Rhipicephalus microplus

Guglielmone (1995); Potgieter (1996); Ghosh et al. (2007) da Silva (2008) Ameen et al. (2012) Lankester et al. (2007); Logan et al. (1987); Ewing et al. (1997) da Silva (2008) da Silva (2008) The Merck Veterinary Manual (2014) de Waal (2000)

USA North Africa Central, Southern Africa South Africa Zambia Hungary Australia Brazil

Ixodes ricinus Rhipicephalus annulatus Dermacentor andersoni, Dermacentor variabilis, Dermacentor albipictus Dermacentor andersoni, Dermacentor variabilis, Argas persicus Ixodes ricinus Rhipicephalus simus Rhipicephalus microplus, Rhipicephalus evertsi evertsi, Rhipicephalus simus, Rhipicephalus decoloratus, Hyalomma marginatum rufipes Amblyomma variegatum, Rhipicephalus decoloratus, Rhipicephalus evertsi Dermacentor reticulatus Rhipicephalus microplus Rhipicephalus microplus, Amblyomma cajennense, Amblyomma maculatum, Dermacentor nitens

multiplex and single PCR assays for simultaneous detection of A. marginale (166 bp), Theileria annulata (312 bp) and Babesia bovis (265 bp) in cattle. The test is effective for single or simultaneous detection of anaplasmosis, tropical theileriosis and bovine babesiosis in field samples. Previous molecular studies targeted 16S rRNA, msp1α, msp1β, msp4, msp5, gltA and heat-shock

Makala et al. (2003) Hornok et al. (2012) Bock et al. (2006) da Silva et al. (2015)

protein (groEL) genes for the detection and characterization of A. marginale isolates (Hornok et al. 2007; Bilgiç et al. 2013; Ybañez et al. 2013a, b; Belkahia et al. 2015a). Anaplasmosis is the most imperative cause of hemolytic anaemia in cattle (Hofmann-Lehmann et al. 2004). The important feature of anaplasmosis is extra vascular hemolytic anaemia, results due to



Fig. 4. Anaplasma marginale in erythrocytes of cattle (The Merck Veterinary Manual, 1998); magnification 100×.

phagocytosis of parasitized erythrocytes in spleen and bone marrow (Jain, 1993). The disease is divided into three stages i.e. prepatent phase, acute phase [41–47 days post infection (dpi)] and late phase (50–70 dpi). No change occurs in blood parameters during prepatent phase in A. marginale-infected cattle (Haider, 1991) except transitory decrease in lymphocytes (Alfonso et al. 1996). Anaplasmosis significantly affect packed cell volume (Marufu et al. 2010). Increase in concentration of monocytes and neutrophils occur in later stages of the disease (Alfonso et al. 1996). Hypochromic and macrocytic anaemia, increase in total white cell counts, reduced platelet counts, blood aspartate aminotransferase, serum bilirubin, glutamic dehydrogenase, gamma glutamyltransferase and blood urea nitrogen have been reported by Riond et al. (2007) in Swiss cattle infected with A. marginale along with co-infection of other vectorborne pathogens. There is a positive correlation with the increase of parasitaemia and mean corpuscular fragility (MCF) and lactate dehydrogenase (LDH), while superoxide dismutase (SOD) had negative correlation with parasitaemia level (Nazifi et al. 2008). Furthermore, increase of total protein, total bilirubin, alanine amino transferase has been reported during BA (Ashuma et al. 2013). Treatment Oxytetracycline has been approved for parenteral use for treatment and control. In addition, chlortetracycline is approved for use in continuous feed for the control of bovine anaplasmosis in the USA (FDA, 2009). Antimicrobial therapy is mainly focused to treat clinical disease and to minimize disease effects during vector season. Splenectomized calves experimentally infected with A. marginale were successfully treated with 1–3

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intramuscular injections of oxytetracycline administered at 10–20 mg kg−1 body weight and doxycycline at the dose rate of 100 mg kg−1 intramuscular (Kuttler and Simpson, 1978). Chloramphenicol and rolitetracycline had been proved effective in the treatment of clinical and carrier states of anaplasmosis (Sharma et al. 1977). Keeping Anaplasma free herds is one the important strategy for controlling bovine anaplasmosis. The carrier free status is required as per free trade policy for the movement of cattle between endemic and non-endemic regions of the world (Reinbold, 2009). There are conflicting reports on the chemosterilization of persistent infection. A recent study on carrier elimination, oxytetracycline (22 mg kg−1 IV once in a day for five days) and imidocarb dipropionate (5 mg kg−1 IM twice, 7 days apart) eliminated 86·67 and 73·33% of A. marginale infections, respectively; in adult naturally infected carrier cattle at 56th post-treatment day. The carrier clearance was confirmed by cELISA followed by sub-inoculation of blood in sero-negative splenectomized calves (Atif et al. 2012b). Chemosterilization of A. marginale carriers has been attained by oral chlortetracycline hydrochloride and injectable formulations of oxytetracycline antibiotics (Magonigle et al. 1975; Roby et al. 1978; Kuttler, 1983; Rogers and Dunster, 1984; Kocan et al. 2010b; Reinbold et al. 2010; Turse et al. 2014). ANAPLASMA PLATYS

Anaplasma platys, a zoonotic obligate intracellular alphaproteobacteria replicates in platelets (Harvey et al. 1978). In 1978, a clinical syndrome was first reported in a dog in Florida (USA) called as canine infectious cyclic thrombocytopenia (CICT) caused by Ehrlichia platys (now known as A. platys) (Harvey et al. 1978; Dumler et al. 2001). Anaplasma platys has been reported worldwide (Table 9). Prevalence in dogs from different European countries ranges from 0·4 to 70·5% using molecular methods (de la Fuente et al. 2006b; Santos et al. 2009; de Caprariis et al. 2011; Table 9). Clinical findings Incubation period in dog ranges from 7 to 14 days. After an experimental infection bacterium can be demonstrated in the peripheral blood after 8–15 days and develop severe thrombocytopenia. This recurs at 10 days interval. Later the cyclic pattern diminishes and thrombocytopenia level declines and completely resolves slowly. This cyclic infection includes low cyclic bacteremia and thrombocytopenia (Harvey, 2006). Usually dogs remain asymptomatic. Fever, lethargy, anorexia, weight loss, anaemia, icterus,


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Table 9. Detection of Anaplasma platys in vertebrate hosts from different countriesa Country

Animalsb

Prevalence

Methodc

References

Croatia Romania Greece Italy

Dog Dog Dog Dog

Case report Case report Case report 70·5%

qPCRd (groEL) PCR Blood smear/serology PCR

Italy Portugal Portugal Portugal Spain Canada USA (South) USA (Mid Atlantic) USA (Northeast) USA (Midwest) USA (West) Maxico Caribbean Dominican republic Nicaragua Brazil Australia Australia Australia China China China Turkey Tunisia

Cat Red fox (Vulpes vulpes) Dog Dog Dog Dog Dog Dog

31·1% 14·5% 55·0% 0·4% Case report 1·8% 2·0% 1·1%

Heminested PCR (GroEL) qPCRd (16S rRNA) IFATe/PCR (16S rRNA) PCR PCR (16S rRNA) ELISA kit ELISA kit ELISA kit

Dyachenko et al. (2012) Andersson et al. (2013) Kontos et al. (1991) de Caprariis et al. (2011) Zobba et al. (2015) Cardoso et al. (2015) Santos et al. (2009) Santos et al. (2009) Aguirre et al. (2006) Qurollo et al. (2014) Qurollo et al. (2014) Qurollo et al. (2014)

Dog Dog Dog Dog Dog Dog

1·5% 0·6% 1·0% 31·0% 10·3% 11.0%

ELISA kit ELISA kit ELISA kit PCR (16S rRNA) ELISA kit qPCRd (16S/18S rRNA)

Qurollo et al. (2014) Qurollo et al. (2014) Qurollo et al. (2014) Almazán et al. (2015) Qurollo et al. (2014) Kelly et al. (2013)

Dog Dog Dog Dog Dog Red deer (Cervus elaphus) Sika deer Camel (Camelus bactrianus) Dog Camel (Camelus dromedaries) Cattle Dog

13.0% 7·19% 3·8% 51·3% 51·3% 9.0% 15.0% 7·2% 0·5% 17·7%

qPCRd (16S/18S rRNA) PCR Blood smear/ELISA/PCR qPCRd (16 S rRNA) ELISA kit PCR (16S rRNA) PCR (16S rRNA) PCR (16S rRNA) PCR based RLBf assays qPCRd, nPCRg (16S rRNA)

Wei et al. (2014) Melo et al. (2015) Hii et al. (2015) Barker et al. (2012) Barker et al. (2012) Li et al. (2015a) Li et al. (2015a) Li et al. (2015b) Aktas et al. (2015) Belkahia et al. (2015b)

4·8% 7·7%

PCR (23S rRNA) PCR

Dahmani et al. (2015) Götsch et al. (2009)

Algeria Cape Verde a b c d e f g

Detection of Anaplasma platys from 1991 to 2015. Organism detected in tissue or blood specimen. In parenthesis target gene has been mentioned. Real-time PCR. Immunofluorescence Antibody Test. Reverse line blot hybridization. Nested PCR.

Table 10. Molecular detection of Anaplasma platys in different tick species Country

Ticks

References

Italy

Rhipicephalus sanguineus Dermacentor auratus Rhipicephalus sanguineus Rhipicephalus sanguineus

Ramos et al. (2014)

Thailand Thailand Congo

Parola et al. (2003) Foongladda et al. (2011) Sanogo et al. (2003)

petechiae, nasal discharge, lymphadenopathy and lymphadenomegaly are important clinical signs of CICT. However, highly pathogenic strains of A. platys cause serious uveitis and pancytopenia after direct or autoimmune damage to platelets

(Harvey et al. 1978; Glaze et al. 1986; Huang et al. 2005; Aguirre et al. 2006). Single-case clinical study showed bilateral uveitis and epistaxis in a dog. The clinical findings mentioned in earlier studies did not rule out concurrent infections using molecular tools (Harrus et al. 1997; Sainz et al. 1999; Alleman and Heather, 2008; de Caprariis et al. 2011; Dyachenko et al. 2012). Concurrent infections with E. canis have been reported because R. sanguineus ticks transmit both the pathogens (The Merck Veterinary Manual, 2014). Mostly A. platys and Babesia vogeli concurrent infections have been reported (Otranto et al. 2010). Epidemiology Anaplasma platys has been detected in dog, cat, cattle, camel and wild ruminants (Lima et al. 2010;



Qurollo et al. 2014; Dahmani et al. 2015; Table 9). The organism has not been detected in wild carnivores i.e. foxes, jackals and wolves (Sainz et al. 2015). Age, sex or breed is not the important determinants for CICT (Sainz et al. 2015). Anaplasma platys infection has been reported in two human families in the USA and two individuals in Venezuela (Maggi et al. 2013; Arraga-Alvarado et al. 2014). Transmission: The R. sanguineus is the principal vector in Europe and all around the world (Sainz et al. 2015; Table 10). However, the experimental transmission has not yet been proven (Simpson et al. 1991). Other likely route of transmission is blood transfusion (Gaunt et al. 2010; Table 11). Screening of donor blood before transfusion is warranted because of associated zoonotic potential. Diagnosis Anaplasma platys morulae in platelets can be detected in stained blood smear but this method is less sensitive at persistent or low level of infection (Shaw et al. 2005; Fig. 5). This bacterium can also be found in megakaryocytes (de Tommasi et al. 2014), but the usefulness of bone marrow cytology needs to be evaluated. The serological test should be interpreted with caution. Positive serological tests do not mean active infection but there might be the case in which infection has been resolved. Usually serological test followed by molecular diagnosis (PCR/DNA sequencing) is recommended that indicate active infection. The PCR is not a definite diagnosis for persistently infected dogs with low level of bacteremia because of the cyclic peaks and lowering of the organism (Alleman and Heather, 2008). Spleen or peripheral blood with EDTA is required for PCR. Moreover, concurrent infections with other vector-borne infectious agents such as E. canis, Rickettsia conorii or B. vogeli may aggravate the clinical disease along with abnormal laboratory findings (Santos et al. 2009; Gaunt et al. 2010; de Caprariis et al. 2011). Consequently, when an infection of one specific pathogen is diagnosed, a complete work-up is required to rule out concurrent infections with other vector-transmitted pathogens (Sainz, 2011). Fifty percent of Ehrlichia canis infected dogs show a titre of A. platys infection during concurrent infection but no cross-reactivity exist between these pathogens (Stillman et al. 2014; The Merck Veterinary Manual, 2014). However, a cross-reactivity has been reported between A. phagocytophilum and A. platys (Solano-Gallego et al. 2006; Chandrashekar et al. 2010; Zobba et al. 2014, 2015). Treatment Anaplasma Platys infections can be treated with doxycycline at the dose rate of 5–10 mg kg−1 q for

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8–10 days (Sainz et al. 2015). Steroids are only indicated particularly when immune-mediated complications encounter. In these conditions, prednisolone/prednisolone should be given at the dose rate of 0·5–2 mg kg−1 day−1. Usually, most of dogs recover after acute infection with effective treatment (Wen et al. 1997; Harrus et al. 1998; Breitschwerdt et al. 1998). Thrombocytopenia characteristically disappears about 1 week after the initiation of therapy (Chang et al. 1997). Control Currently, no commercial vaccines are available for A. platys. Ticks control plays a key role in infection prevention. The R. sanguineus ticks are mainly located indoors in cooler regions and found outdoor in warmer areas. Outdoor populations of R. sanguineus are active at 10–12 °C. Collar, pouron, or spot-on acaricidal products can be selected based upon preference and therapeutic needs. Immediate response is the elimination of attached ticks responsible for pathogen transmission. To maximize the effectiveness, the acaricide must be applied at the recommended dosage according to manufacturer’s instructions (Sainz et al. 2015). Tick control methods should be implemented according to local and environmental conditions. For appropriately control knowledge of tick seasonality, ecology, stages and status of multiple tick infestations is necessary. PREVENTION AND CONTROL OF ANAPLASMOSIS

Acaricides are mostly used for the control of ticks. Drug resistance and residues are the problems associated with the use of acaricides. Housing should not favourable the growth and multiplication of vector ticks. Establishment of buffer zone between domestic animal housings and vegetations can help to control vectors (Jonsson et al. 1998). Anti-tick vaccines would be a good alternative to control infection. These vaccines are environment friendly; decrease the occurrence of tick-borne diseases by reducing tick infestation, and limit acaricide use (Graf et al. 2004; de la Fuente et al. 2006c, 2011). Understanding vector pathogen interactions can play an important role for the control of vectorborne diseases. Tick vaccines based on tick proteins Q38, SUB, SILK, TROSPA, BM86/BM95, 64P interfere with tick vector competence resulting in lower tick infection and tick-borne diseases (Labuda et al. 2006; Willadsen, 2006; Zivkovic et al. 2010; Antunes et al. 2012; Hajduˇsek et al. 2013; Merino et al. 2013). Similarly, Akirin and Subolesin proteins have the potential candidate for universal anti-tick vaccine against major vector species and vector-borne diseases (de la Fuente et al. 2013). Recently, vector-pathogen vaccine


Organism

Disease

Host

Infecting cell

Clinical findings

Diagnosis

Treatment

Control

Vectors

Anaplasma marginale

Bovine anaplasmosis

Cattle, buffalo and ruminants

Erythrocytes

Stained blood smear, hematology (anemia), serology, PCR, sub-inoculation of blood into splenectomized calf

Oxytetracycline (injection), chlortetracycline hydrochloride (feed) for elimination of carrier infection as well.

Bovine anaplasmosis

Cattle, buffalo and ruminants

Erythrocytes

Stained blood smear, hematology (anemia) serology, PCR, sub-inoculation of blood into splenectomized calf

Usually not required

Anaplasma bovis

Bovine anaplasmosis

Wide host range: cattle, sheep, goat, dog, cat, deer, wild mammals

Monocytes

Stained blood smear, hematology serology, PCR, subinoculation of blood into splenectomized calf

Oxytetracycline @ 20 mg kg−1 IV along with 500 ml normal saline.

Identification of vectors & control, oxytetracycline, tick & or anaplasma vaccine, prevent iatrogenic or mechanical transmission, endemic stability Identification of vectors & control, oxytetracycline, tick & or anaplasma vaccine, prevent iatrogenic or mechanical transmission Identification of vectors, bio/chemical control, tetracyclines, tick vaccine

Rhipicephalus, Ixodes, Dermacentor, Amblyomma spp.

Anaplasma centrale

Fever, severe anemia, pale mucous membranes, jaundice, brownish urine, decreased milk production, weight loss and mortality during acute phase Non-pathogenic or mild signs

Anaplasma ovis

Ovine/caprine anaplasmosis

Small ruminants (sheep, goat)

Erythrocytes

Stained blood smear, hematology (anemia), serology, PCR

Tetracycline

Identification of vectors, bio/chemical control, tetracyclines, tick vaccine

R. bursa, Dermacentor andersoni, R. turanicus, Ornithodoros lahorensis

Anaplasma platys

Canine cyclic thrombocytopenia

Dog

Platelets

Stained blood smear, thrombocytopenia, serology, PCR/ DNA sequencing

Doxycycline @5–10 mg kg−1 q12–24 h for 8–10 days or Enrofloxacin @ 5 mg kg−1, q12 h for 14–21 days

Tick elimination, collar, pour-on, or spot-on acaricidal products for R. sanguineus ticks, knowledge of tick seasonality and ecology

R. sanguineus

Fever, weakness, obvious weight loss, pale mucous membranes, enlargement of prescapular lymph nodes and death in naïve or stressed cattle Fever, weakness, anemia, pallor mucous membrane, lower milk production, weight loss, jaundice, abortion and often death Dogs usually remain asymptomatic but fever, lethargy, anorexia, weight loss, anemia, icterus, petechiae, nasal discharge, lymphadenopathy and lymphadenomegaly may be observed

Farhan Ahmad Atif

Rhipicephalus, Ixodes, Dermacentor, Amblyomma spp. Rhipicephalus, Haemaphysalis, Amblyomma spp.

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Table 11. The characteristic of Anaplasma species (Rickettsiales, Anaplasmataceae)

(1) Tick-borne fever/pasture fever (2) Canine granulocytic anaplasmosis (3) Feline granulocytic anaplasmosis (4) Equine granulocytic anaplasmosis (5) Human granulocytic anaplasmosis

(1) Cattle, sheep, goat, wild ruminants (2) Dog, wild canids (3) Cats and wild felids (4) Equines (5) Humans

Granulocytes (especially neutrophils) Granulocytes Granulocytes Granulocytes Granulocytes

(1) Cattle & sheep: High fever, dullness, inappetence, sudden drop in milk yield, reduced weight gain, coughing, abortion, stillbirth and low fertility in sheep and reduced semen quality in rams (2) Non-specific signs, fever, anorexia, dullness (3) Non-specific signs, fever, anorexia, dullness (4) Fever, petechial hemorrhages, icterus, ataxia and distal limb edema and may have severe myopathy. (5) Fever, headache, myalgias and chills

Morulae in stained blood smear, thrombocytopenia, leucopenia, elevated liver enzymes, serology, PCR/DNA sequencing

(1) Lambs: Oxytetracycline 20 mg kg−1 & 10 mg kg−1 IM (2) Doxycycline (3) Doxycycline (4) Oxytetracycline 6·6 mg kg−1 & 10 mg kg−1 IV daily (5) Humans: Doxycycline @ 100 mg, oral, twice daily for 7–14 days OR rifampin @ 10 mg kg−1 day−1, oral

(1) Cattle, sheep, goats: Elimination of reservoirs, vector control, habitat modification, rearing tick resistant breeds, chemotherapy (2) Vector control, habitat modification, rearing tick resistant breeds, chemotherapy (3) Vector control, habitat modification, chemotherapy (4) Humans: Minimizing the high-risk tick exposure activities (hiking, gardening), blood transfusion, immunosuppression, identification of reservoirs, vectors and their control

Western USA: I. pacificus Eastern USA: I. scapularis Europe: Ixodes ricinus. Latvia, Estonia: I. persulcatus Russia: I. persulcatus China: I. persulcatus, Dermacentor silvarum

Epidemiology and characteristics of Anaplasma species related to veterinary and public health importance 675


Anaplasma phagocytophilum

Farhan Ahmad Atif

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use of live and killed vaccines. Detection, elimination and chemosterilization policy may be launched (Reinbold et al. 2010) where no endemic stability exist. However, this approach is costly and may not work for the poor livestock farmers. Testing of animals at 3 weeks interval, vector control and purchase of animals from Anaplasma-free areas is a good option to prevent the entry of infected animals. COMMON FEATURES OF ANAPLASMA SPECIES

Fig. 5. Anaplasma platys in dog’s platelet (Sainz et al. 2015); magnification 100×.

comprising A. marginale MSP1a and tick Subolesin proteins showed efficacy in lowering tick infestation, lower weight of female ticks (Boophilus microplus) and reduced A. marginale infection in cattle (Torina et al. 2014). Immunization of high-risk human population and animal reservoirs would help in the control of anaplasmosis. The universal vaccine for any Anaplasma specie is not yet available which is effective against diverse strains. Blood based A. marginale subsp. centrale has been used as live vaccine in South Africa, Australia, Israel and several other South American countries for more than three decades against bovine anaplasmosis (Kocan et al. 2010a, b). Anaplasma marginale subsp. centrale vaccine has proved effective in preventing clinical disease against field strains. This blood-based vaccine had the potential to transmit other blood-borne pathogens during inoculation (Rogers et al. 1988). Because of inherent danger this vaccine has not been permitted by the European Union and USA (Rogers et al. 1988). Studies have shown that vaccination caused mild clinical signs after vaccination and protect severe disease, whereas some studies have suggested that A. centrale strain provided slight to no protection (Abdala et al. 1990). Recently, A. centrale has been cultured in vitro in tick cell lines with the possibility of safer vaccine for bovine anaplasmosis (Bell-Sakyi et al. 2015). Various proteins have been recommended as vaccine candidates but the main issue associated with development of successful vaccine is the selection of suitable conserved antigen, existence of different variants, antigenic variations and lack of cross protection studies (Stuen et al. 2013b). Control measures vary from region to region. Prevention and control mainly focus on vector control, use of antibiotics, breeding Anaplasmafree herds, prevention of mechanical transmission,

(1) Persistent infection is the common sequel after acute disease. (2) Serologic cross reactivity; because MSP5 proteins is conserved among all Anaplasma species. (3) Breed resistance, biological, mechanical and transplacental transmission potentials. (4) The 16SrRNA gene based classification and similarity in family Anaplasmataceae. (5) A. phagocytophilum and A. platys have blood associated zoonotic potential. (6) Major common prevention and control strategies [References are mentioned in the text above. Comparative features of Anaplasma species are mentioned in Table 11]. CONCLUSION

All age groups are susceptible but prevalence increases with age. Movement of young animals from tick-free area to tick-infested areas is the major risk for anaplasmosis in animals. High-risk outdoor tick exposure activities and blood transfusion are important risk factor for HGA. These organisms attribute a reasonable degree of similarity. No successful vaccine is available for any Anaplasma specie, effective against ecologically diverse strains. Identification of novel antigenic parts had been the major effort for the development of a universal Anaplasma vaccine. Major problem associated with development of a successful vaccine is the selection of suitable conserved antigen, existence of different variants, antigenic variations and lack of cross-protection studies (Stuen et al. 2013b). The advances in epidemiology, biotechnology, genetic engineering, vector ecology, immunology, cell culture, clinical, experimental and longitudinal studies should be utilized to reveal ecology and infection biology for effective prevention and control of anaplasmosis in humans, domestic and wild animals. ACKNOWLEDGEMENTS

I am grateful to Dr Georg Gerhard Duscher from Institute of Parasitology, Department of Pathobiology, University of Veterinary Medicine, Vienna, Austria for valuable comments on anaplasmosis. FINANCIAL SUPPORT

This review paper received no financial support from any funding agency.


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Persistence of Anaplasma marginale (Rickettsiales: Anaplasmataceae) in male Dermacentor andersoni (Acari: Ixodidae) transferred successively from infected to susceptible calves.

Development of a new PCR-based assay to detect Anaplasmataceae and the first report of Anaplasma phagocytophilum and Anaplasma platys in cattle from Algeria.

Detection of tick-borne Anaplasma bovis, Anaplasma phagocytophilum and Anaplasma centrale in Spain.

An Anaplasma centrale DNA probe that differentiates between Anaplasma ovis and Anaplasma marginale DNA.

The Anaplasma marginale msp5 gene encodes a 19-kilodalton protein conserved in all recognized Anaplasma species.

Echinococcosis in wild carnivorous species: epidemiology, genotypic diversity, and implications for veterinary public health.

Identification of immunodominant polypeptides common between Anaplasma centrale and Anaplasma marginale.

Molecular Identification of Mycobacterium Species of Public Health and Veterinary Importance from Cattle in the South State of México.

The prevalence of Anaplasma platys and a potential novel Anaplasma species exceed that of Ehrlichia canis in asymptomatic dogs and Rhipicephalus sanguineus in Taiwan.

An enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies to Anaplasma centrale and Anaplasma marginale.

Epidemiology and Genetic Diversity of Anaplasma phagocytophilum in the San Francisco Bay Area, California.

Cell tropism and molecular epidemiology of Anaplasma platys-like strains in cats.

Molecular study on infection rates of Anaplasma ovis and Anaplasma marginale in sheep and cattle in West-Azerbaijan province, Iran.

Collective contributions to veterinary public health.

Prevalence of Anaplasma, Bartonella and Borrelia Species in Haemaphysalis longicornis collected from goats in North Korea.

Coinfection of sheep with Anaplasma, Theileria and Babesia species in the Kurdistan Region, Iraq.

Molecular detection of Anaplasma platys, Anaplasma phagocytophilum and Wolbachia sp. but not Ehrlichia canis in Croatian dogs.

Dendrimer-enabled transformation of Anaplasma phagocytophilum.

Improved molecular detection of Ehrlichia and Anaplasma species applied to Amblyomma ticks collected from cattle and sheep in Ethiopia.

Co-infections with Borrelia species, Anaplasma phagocytophilum and Babesia spp. in patients with tick-borne encephalitis.

Bacterial Profiling Reveals Novel "Ca. Neoehrlichia", Ehrlichia, and Anaplasma Species in Australian Human-Biting Ticks.

Epidemiology and public health aspects of malocclusion.

Anaplasma marginale and A. phagocytophilum in cattle in Tunisia.

Anaplasma spp. in dogs and owners in north-western Morocco.