BACKGROUND: Microsporidia of the genus Encephalitozoon are usually associated with severe infections in immunodeficient hosts while, in immunocompetent ones, microsporidiosis produces minimal clinically apparent disease. Despite their microscopic size, microsporidia are capable of causing systemic infection within a few days. However, the mechanisms by which microsporidia reach target tissues during acute infection remain unclear. Out of four genotypes of Encephalitozoon cuniculi, only three are available for experimental studies, with E. cuniculi genotype II being the best characterized. METHODS: In the present study, we tested the association between inflammation induction in immunocompetent and immunodeficient mice and the presence of spores of E. cuniculi genotypes I and III in selected organs using molecular methods and compared the results with previously published data on E. cuniculi genotype II. RESULTS: We reported the positive connection between inflammation induction and the significant increase of E. cuniculi genotypes I and III occurrence in inflammatory foci in both immunocompetent BALB/c and immunodeficient severe combined immunodeficient (SCID) mice in the acute phase of infection. The induction of inflammation resulted in increased concentration of E. cuniculi of both genotypes in the site of inflammation, as previously reported for E. cuniculi genotype II. Moreover, our study extended the spectrum of differences among E. cuniculi genotypes by the variations in dispersal rate within host bodies after experimentally induced inflammation. CONCLUSION: The results imply possible involvement of immune cells serving as vehicles transporting E. cuniculi towards inflammation foci. The elucidation of possible connection with pro-inflammatory immune responses represents an important challenge with implications for human health and the development of therapeutic strategies.

Department of Biology and Medical Parasitology Wroclaw Medical University Wroclaw Poland

Faculty of Agriculture University of South Bohemia in České Budějovice České Budějovice Czech Republic

Faculty of Science University of South Bohemia in České Budějovice České Budějovice Czech Republic

Institute of Parasitology Biology Centre Czech Academy of Science České Budějovice Czech Republic

Zobrazit více v PubMed

Canning EU, Lom J, Dyková I. The Microsporidia of Vertebrates. London: Academic Press; 1986:289.

Didier ES, Vossbrinck CR, Baker MD, et al. Identification and characterization of three Encephalitozoon cuniculi strains. Parasitology. 1995;111:411–421. doi:10.1017/S0031182000065914 PubMed DOI

Talabani H, Sarfati C, Pillebout E, et al. Disseminated infection with a new genovar of Encephalitozoon cuniculi in a renal transplant recipient. J Clin Microbiol. 2010;48:2651–2653. doi:10.1128/JCM.02539-09 PubMed DOI PMC

Kašičková D, Sak B, Kváč M, et al. Sources of potentially infectious human microsporidia: molecular characterisation of microsporidia isolates from exotic birds in the Czech Republic, prevalence study and importance of birds in epidemiology of the human microsporidial infections. Vet Parasitol. 2009;165:125–130. doi:10.1016/j.vetpar.2009.06.033 PubMed DOI

Engelhardt S, Buder A, Pfeil K, et al. Nephritis in a Staffordshire Terrier puppy caused by Encephalitozoon cuniculi genotype I. Tierarztl Prax Ausg K Kleintiere Heimtiere. 2017;45(6). doi:10.15654/TPK-161123 PubMed DOI

Sak B, Kváč M, Petrželková K, et al. Diversity of microsporidia (Fungi: microsporidia) among captive great apes in European zoos and African sanctuaries: evidence for zoonotic transmission? Folia Parasitol. 2011;58:81–86. doi:10.14411/fp.2011.008 PubMed DOI

Sak B, Petrželková KJ, Květoňová D, et al. Long-term monitoring of microsporidia, Cryptosporidium and Giardia infections in western Lowland Gorillas (Gorilla gorilla gorilla) at different stages of habituation in Dzanga Sangha Protected Areas, Central African Republic. PLoS One. 2013;8:e71840. doi:10.1371/journal.pone.0071840 PubMed DOI PMC

Sak B, Petrželková KJ, Květoňová D, et al. Diversity of microsporidia, Cryptosporidium and Giardia in mountain gorillas (Gorilla beringei beringei) in Volcanoes National Park, Rwanda. PLoS One. 2014;9:e109751. doi:10.1371/journal.pone.0109751 PubMed DOI PMC

Sak B, Kváč M, Květoňová D, et al. The first report on natural Enterocytozoon bieneusi and Encephalitozoon spp. infections in wild East-European House Mice (Mus musculus musculus) and West-European House Mice (M. m. domesticus) in a hybrid zone across the Czech Republic–Germany border. Vet Parasitol. 2011;178:246–250. doi:10.1016/j.vetpar.2010.12.044 PubMed DOI

Tsukada R, Tsuchiyama A, Sasaki M, et al. Encephalitozoon infections in Rodentia and Soricomorpha in Japan. Vet Parasitol. 2013;198:193–196. doi:10.1016/j.vetpar.2013.08.018 PubMed DOI

Wagnerová P, Sak B, Květoňová D, et al. Enterocytozoon bieneusi and Encephalitozoon cuniculi in horses kept under different management systems in the Czech Republic. Vet Parasitol. 2012;190:573–577. doi:10.1016/j.vetpar.2012.07.013 PubMed DOI

Laatamna A, Wagnerová P, Sak B, et al. Microsporidia and Cryptosporidium in horses and donkeys in Algeria: detection of a novel Cryptosporidium hominis subtype family (Ik) in a horse. Vet Parasitol. 2015;208:135–142. doi:10.1016/j.vetpar.2015.01.007 PubMed DOI

Kimura M, Aoki M, Ichikawa-Seki M, et al. Detection and genotype of Encephalitozoon cuniculi DNA from urine and feces of pet rabbits in Japan. J Vet Med Sci. 2013;75:1017–1020. doi:10.1292/jvms.12-0567 PubMed DOI

Deng L, Chai Y, Xiang L, et al. First identification and genotyping of Enterocytozoon bieneusi and Encephalitozoon spp. in pet rabbits in China. BMC Vet Res. 2020;16:212. doi:10.1186/s12917-020-02434-z PubMed DOI PMC

Němejc K, Sak B, Květoňová D, et al. Prevalence and diversity of Encephalitozoon spp. and Enterocytozoon bieneusi in wild boars (Sus scrofa) in Central Europe. Parasitol Res. 2014;113:761–767. doi:10.1007/s00436-013-3707-6 PubMed DOI

Ditrich O, Chrdle A, Sak B, et al. Encephalitozoon cuniculi genotype I as a causative agent of brain abscess in an immunocompetent patient. J Clin Microbiol. 2011;49:2769–2771. doi:10.1128/JCM.00620-11 PubMed DOI PMC

Halánová M, Valenčáková A, Malčeková B, et al. Occurrence of microsporidia as emerging pathogens in Slovak Roma children and their impact on public health. Ann Agric Environ Med. 2013;20:695–698. PubMed

Tavalla M, Mardani-Kateki M, Abdizadeh R, et al. Molecular identification of Enterocytozoon bieneusi and Encephalitozoon spp. in immunodeficient patients in Ahvaz, Southwest of Iran. Acta Trop. 2017;172:107–112. doi:10.1016/j.actatropica.2017.04.015 PubMed DOI

Botha WS, Dormehl IC, Goosen DJ. Evaluation of kidney function in dogs suffering from canine encephalitozoonosis by standard clinical pathological and radiopharmaceutical techniques. J S Afr Vet Assoc. 1986;57:79–86. PubMed

Cutlip RC, Beall CW. Encephalitozoonosis in Arctic lemmings. Lab Anim Sci. 1989;39:331–333. PubMed

van Dellen AF, Stewart CG, Botha WS. Studies of encephalitozoonosis in vervet monkeys (Cercopithecus pygerythrus) orally inoculated with spores of Encephalitozoon cuniculi isolated from dogs (Canis familiaris). Onderstepoort J Vet Res. 1989;56:1–22. PubMed

Didier ES, Varner PW, Didier PJ, et al. Experimental microsporidiosis in immunocompetent and immunodeficient mice and monkeys. Folia Parasitol. 1994;41:1–11. PubMed

Guscetti F, Mathis A, Hatt JM, et al. Overt fatal and chronic subclinical Encephalitozoon cuniculi microsporidiosis in a colony of captive emperor tamarins (Saguinus imperator). J Med Primatol. 2003;32:111–119. doi:10.1034/j.1600-0684.2003.00016.x PubMed DOI

Reetz J, Wiedemann M, Aue A, et al. Disseminated lethal Encephalitozoon cuniculi (genotype III) infections in cotton-top tamarins (Oedipomidas oedipus)-a case report. Parasitol Int. 2004;53:29–34. doi:10.1016/j.parint.2003.10.003 PubMed DOI

Reetz J, Nöckler K, Reckinger S, et al. Identification of Encephalitozoon cuniculi genotype III and two novel genotypes of Enterocytozoon bieneusi in swine. Parasitol Int. 2009;58:285–292. doi:10.1016/j.parint.2009.03.002 PubMed DOI

Mathis A, Weber R, Deplazes P. Zoonotic potential of the microsporidia. Clin Microbiol Rev. 2005;18:423–445. doi:10.1128/CMR.18.3.423-445.2005 PubMed DOI PMC

Asakura T, Nakamura S, Ohta M, et al. Genetically unique microsporidian Encephalitozoon cuniculi strain type III isolated from squirrel monkeys. Parasitol Int. 2006;55:159–162. doi:10.1016/j.parint.2006.02.002 PubMed DOI

Juan-Sallés C, Garner MM, Didier ES, et al. Disseminated encephalitozoonosis in captive, juvenile, cotton-top (Saguinus oedipus) and neonatal emperor (Saguinus imperator) tamarins in North America. Vet Pathol. 2006;43:438–446. doi:10.1354/vp.43-4-438 PubMed DOI

Snowden KF, Lewis BC, Hoffman J, et al. Encephalitozoon cuniculi infections in dogs: a case series. J Am Anim Hosp Assoc. 2009;45:225–231. doi:10.5326/0450225 PubMed DOI

Valencakova A, Balent P, Ravaszova P, et al. Molecular identification and genotyping of Microsporidia in selected hosts. Parasitol Res. 2011;110:689–693. doi:10.1007/s00436-011-2543-9 PubMed DOI

Hocevar SN, Paddock CD, Spak CW, et al. Microsporidiosis acquired through solid organ transplantation: a public health investigation. Ann Intern Med. 2014;160:213–220. doi:10.7326/M13-2226 PubMed DOI PMC

Hofmannová L, Sak B, Jekl V, et al. Lethal Encephalitozoon cuniculi genotype III infection in Steppe lemmings (Lagurus lagurus). Vet Parasitol. 2014;205:357–360. doi:10.1016/j.vetpar.2014.07.008 PubMed DOI

Meng X, Zheng J, He X, et al. First characterization in China of Encephalitozoon cuniculi in the blue fox (Alopex lagopus). J Eukaryot Microbiol. 2014;61:580–585. doi:10.1111/jeu.12135 PubMed DOI

Scurrell EJ, Holding E, Hopper J, et al. Bilateral lenticular Encephalitozoon cuniculi infection in a snow leopard (Panthera uncia). Vet Ophthalmol. 2015;18:143–147. doi:10.1111/vop.12218 PubMed DOI

Weber R, Bryan RT. Microsporidial infections in immunodeficient and immunocompetent patients. Clin Infect Dis. 1994;19:517–521. doi:10.1093/clinids/19.3.517 PubMed DOI

Weber R, Bryan RT, Schwartz DA, et al. Human microsporidial infections. Clin Microbiol Rev. 1994;7:426–461. doi:10.1128/CMR.7.4.426 PubMed DOI PMC

Mertens RB, Didier ES, Fishbein MC, et al. Encephalitozoon cuniculi microsporidiosis: infection of the brain, heart, kidneys, trachea, adrenal glands, and urinary bladder in a patient with AIDS. Mod Pathol. 1997;10:68–77. PubMed

Didier ES, Snowden KF, Shadduck JA. Biology of microsporidian species infecting mammals. Adv Parasitol. 1998;40:283–320. doi:10.1016/S0065-308X(08)60125-6 PubMed DOI

Didier ES. Microsporidiosis: an emerging and opportunistic infection in humans and animals. Acta Trop. 2005;94:61–76. doi:10.1016/j.actatropica.2005.01.010 PubMed DOI

Perec-Matysiak A, Leśniańska K, Buńkowska-Gawlik K, et al. The opportunistic pathogen Encephalitozoon cuniculi in wild living Murinae and Arvicolinae in Central Europe. Eur J Protistol. 2019;69:14–19. doi:10.1016/j.ejop.2019.02.004 PubMed DOI

Nell B, Fuchs-Baumgartinger A, Fritsche J, et al. Distribution of Encephalitozoon cuniculi infections in the cat resulting in ophthalmological symptoms in Europe. Vet Ophthalmol. 2014;17:E24.

Milnes E, Delnatte P, Cai HY, et al. Systemic Encephalitozoonosis due to Encephalitozoon cuniculi strain IV in a Vancouver Island Marmot (Marmota Vancouverensis). J Zoo Wildl Med. 2018;49:484–488. doi:10.1638/2017-0175.1 PubMed DOI

Didier ES, Stovall ME, Green LC, et al. Epidemiology of microsporidiosis: sources and modes of transmission. Vet Parasitol. 2004;126:145–166. doi:10.1016/j.vetpar.2004.09.006 PubMed DOI

Weiss LM. and now microsporidiosis. Ann Intern Med. 1995;123:954–956. doi:10.7326/0003-4819-123-12-199512150-00012 PubMed DOI

Weiss LM, Keohane EM. Microsporidia at the turn of the millenium: Raleigh 1999. J Eukaryot Microbiol. 1999;46:3S–5S. doi:10.1111/j.1550-7408.1999.tb06055.x PubMed DOI

Wittner M, Weiss L. The Microsporidia and Microsporidiosis. Washington DC: ASM Press; 1995.

Kicia M, Weselowska M, Kopacz Z, et al. Disseminated infection of Encephalitozoon cuniculi associated with osteolysis of hip periprosthetic tissue. Clin Infect Dis. 2018;67:1228–1234. doi:10.1093/cid/ciy256 PubMed DOI

Brdíčková K, Sak B, Holubová N, et al. Encephalitozoon cuniculi genotype II concentrates in inflammation foci. J Inflamm Res. 2020;13:583–593. doi:10.2147/JIR.S271628 PubMed DOI PMC

Kotková M, Sak B, Květoňová D, et al. Latent microsporidiosis caused by Encephalitozoon cuniculi in immunocompetent hosts: a murine model demonstrating the ineffectiveness of the immune system and treatment with albendazole. PLoS One. 2013;8:e60941. doi:10.1371/journal.pone.0060941 PubMed DOI PMC

De Bosscuere H, Wang Z, Orlandi PA. First diagnosis of Encephalitozoon intestinalis and E. hellem in a European brown hare (Lepus europaeus) with kidney lesions. Zoonoses Public Health. 2007;54:131–134. doi:10.1111/j.1863-2378.2007.01034.x PubMed DOI

Katzwinkel-Wladarsch S, Lieb M, Helse W, et al. Direct amplification and species determination of microsporidian DNA from stool specimens. Trop Med Int Health. 1996;1:373–378. doi:10.1046/j.1365-3156.1996.d01-51.x PubMed DOI

Wolk DM, Schneider SK, Wengenack NL, et al. Real-time PCR method for detection of Encephalitozoon intestinalis from stool specimens. J Clin Microbiol. 2002;40:3922–3928. doi:10.1128/JCM.40.11.3922-3928.2002 PubMed DOI PMC

Dai J, Wang P, Adusumilli S, et al. Antibodies against a tick protein, Salp15, protect mice from the Lyme disease agent. Cell Host Microbe. 2009;6:482–492. doi:10.1016/j.chom.2009.10.006 PubMed DOI PMC

Sak B, Jandová A, Doležal K, et al. Effects of selected Indonesian plant extracts on E. cuniculi infection in vivo. Exp Parasitol. 2017;181:94–101. doi:10.1016/j.exppara.2017.07.014 PubMed DOI

Sak B, Kotková M, Hlásková L, et al. Limited effect of adaptive immune response to control encephalitozoonosis. Parasite Immunol. 2017;39:e12496. doi:10.1111/pim.12496 PubMed DOI

Gannon J. A survey of Encephalitozoon cuniculi in laboratory animal colonies in the United Kingdom. Lab Anim. 1980;14:91–94. doi:10.1258/002367780780942917 PubMed DOI

Kotková M, Sak B, Kváč M. Differences in the intensity of infection caused by Encephalitozoon cuniculi genotype II and III – comparison using quantitative real-time PCR. Exp Parasitol. 2018;192:93–97. doi:10.1016/j.exppara.2018.07.019 PubMed DOI

Sak B, Brdíčková K, Holubová N, et al. Encephalitozoon cuniculi genotype III evinces a resistance to albendazole treatment in both immunodeficient and immunocompetent Mice. Antimicrob Agents Chemother. 2020;64:e00058–20. doi:10.1128/AAC.00058-20 PubMed DOI PMC

Couzinet S, Cejas E, Schittny J, et al. Phagocytic uptake of Encephalitozoon cuniculi by nonprofessional phagocytes. Infect Immun. 2000;68:6939–6945. doi:10.1128/IAI.68.12.6939-6945.2000 PubMed DOI PMC

Nassonova E, Tokarev YS, Trammer T, et al. Phagocytosis of Nosema grylli (Microsporidia, Nosematidae) spores in vivo and in vitro. J Eukar Microbiol. 2001;48:83–84. doi:10.1111/j.1550-7408.2001.tb00462.x PubMed DOI

Fischer J, Tran D, Juneau R, et al. Kinetics of Encephalitozoon spp. infection of human macrophages. J Parasitol. 2008;94:169–175. doi:10.1645/GE-1303.1 PubMed DOI

Niederkorn JY, Shadduck JA. Role of antibody and complement in the control of Encephalitozoon cuniculi infections by rabbit macrophages. Infect Immun. 1980;27:995–1002. doi:10.1128/iai.27.3.995-1002.1980 PubMed DOI PMC

Weidner E. Interactions between Encephalitozoon cuniculi and macrophages. Parasitophorous vacuole growth and the absence of lysosomal fusion. Z Parasitenkd. 1975;47:1–9. doi:10.1007/BF00418060 PubMed DOI

Didier ES, Weiss LM. Microsporidiosis: not just in AIDS patients. Curr Opin Infect Dis. 2011;24:490–495. doi:10.1097/QCO.0b013e32834aa152 PubMed DOI PMC

Zender HO, Arrigoni E, Eckert J, et al. A case of Encephalitozoon cuniculi peritonitis in a patient with AIDS. Am J Clin Pathol. 1989;92:352–356. doi:10.1093/ajcp/92.3.352 PubMed DOI

Tosoni A, Nebuloni M, Ferri A, et al. Disseminated microsporidiosis caused by Encephalitozoon cuniculi III (dog type) in an Italian AIDS patient: a retrospective study. Mod Pathol. 2002;15:577–583. doi:10.1038/modpathol.3880566 PubMed DOI

Torres G, Izquierdo F, Capo V, et al. Genital microsporidiosis in women with AIDS: a post-mortem study. Rev Iberoam Micol. 2013;30:47–50. doi:10.1016/j.riam.2012.04.001 PubMed DOI

Kicia M, Wesolowska M, Jakuszko K, et al. Concurrent infection of the urinary tract with Encephalitozoon cuniculi and Enterocytozoon bieneusi in a renal transplant recipient. J Clin Microbiol. 2014;52:1780–1782. doi:10.1128/JCM.03328-13 PubMed DOI PMC

Ladapo TA, Nourse P, Pillay K, et al. Microsporidiosis in pediatric renal transplant patients in Cape Town, South Africa: two case reports. Pediatr Transplant. 2014;8:E220–226. doi:10.1111/petr.12327 PubMed DOI

Neumayerová H, Juránková J, Jeklová E, et al. Seroprevalence of Toxoplasma gondii and Encephalitozoon cuniculi in rabbits from different farming systems. Vet Parasitol. 2014;204:184–190. doi:10.1016/j.vetpar.2014.04.020 PubMed DOI

Kotková M, Sak B, Hlásková L, et al. The course of infection caused by Encephalitozoon cuniculi genotype III in immunocompetent and immunodeficient mice. Exp Parasitol. 2017;182:16–21. doi:10.1016/j.exppara.2017.09.022 PubMed DOI

Sak B, Brdíčková K, Holubová N, et al. The course of infection of Encephalitozoon cuniculi genotype I in mice possess combination of features reported in genotypes II and III. Exp Parasitol. 2021;224:108101. doi:10.1016/j.exppara.2021.108101 PubMed DOI

Encephalitozoon cuniculi Microsporidia in Cerebrospinal Fluid from Immunocompetent Patients, Czech Republic

Microsporidia (Encephalitozoon cuniculi) in Patients with Degenerative Hip and Knee Disease, Czech Republic