Scientific Online Resource System

Biomedical Reviews

Immunity and resistance to cryptosporidiosis: the intricate ways of an enigmatic parasitosis

Kalina Stoyanova, Stoyan Pavlov

Abstract

Genus Cryptosporidium includes around 30 known apicomplexan parasitic species which infect the gastrointestinal tract and rarely the respiratory system of more than 300 vertebrate animals. The immune response against infection by Cryptosporidium spp. includes all strata of innate and adaptive immunity with differences in their significance. The mucosal immunity, expressed predominantly by the “sentinel” role of epitheliocytes, is fundamental to the resistance against an infection (mainly via activation of the TLR4/NF-κB signalling axis). The vast array of epithelial chemokines and cytokines initiate the local inflammatory processes, attract effector cells and may directly suppress the parasite adhesion. The second line of defence includes IFN-γ-production by the NK cells in combination with their innate cytotoxicity against the parasite and the infected epitheliocytes. The adaptive immunity against the parasite depends predominantly on cytotoxic CD4+ Th1-lymphocytes, which makes IFN-γ central to the acquired response too. CD8+ cells aid to some extent the activity of Th1-cells but their involvement is not decisive. While Cryptosporidium infection elicits the synthesis of specific serum and mucosal antibodies, the humoral immunity is of minor importance. In immunocompromised hosts, infants and malnourished children, the mild and usually self-limiting infection can become life-threatening or take a chronic course. It is the second leading cause of fatal diarrhoea in children and one of the major opportunistic pathogens in the continually expanding group of patients with immunodeficiencies and systemic chronic diseases. Unravelling the mechanisms of resistance against Cryptosporidium infection is fundamental for the successful prevention of the disease.

Keywords

Cryptosporidium spp., CD4+, intestinal protozoa, IFN-γ, mucosal immunity, Th1-response

Full Text


References

Stoyanova K. Cryptosporidiosis - Current Aspects of Taxonomy, Clinical Course, Diagnostics and Treatment. 1st ed. Varna: Medical University, Varna. 2020.

Troeger C, Forouzanfar M, Rao P, Khalil I, Brown A, Reiner R, et al. Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Infect Dis. 2017;0(0). DOI:10.1016/S1473-3099(17)30276-1

Fayer R. General Bology. In: Fayer R, Xiao L, eds. Crypto-sporidium and Cryptosporidiosis. CRC Press; 2007:1-43.

McDonald V, Korbel D, Barakat F, Choudhry N, Petry F. Innate immune responses against Cryptosporidium parvum infection. Parasite Immunol 2013;35(2):55-64. DOI:10.1111/pim.12020

Hu G, Feng Y, O’Hara S, Chen X. Immunology of Cryptosporidiosis. In: Caccio S, Widmer G, eds. Cryptosporidium: Parasite and Disease. Wien: Springer-Verlag; 2014:423-454.

McDonald V. Immune responses. In: Fayer R, ed. Cryptosporidium and Cryptosporidiosis. CRC Press; 2007:1-43.

Pantenburg B, Dann S, Wang H, Robinson P, Castellanos-Gonzalez A, Lewis D, et al. Intestinal immune response to human Cryptosporidium sp. infection. Infect Immun 2008;76(1):23-29. DOI:10.1128/IAI.00960-07

McDonald S, O’Grady J, Bajaj-Elliott M, Notley C, Alexander J, Brombacher F, et al. Protection against the early acute phase of Cryptosporidium parvum infec-tion conferred by interleukin-4-induced expression of T helper 1 cytokines. J Infect Dis 2004;190(5):1019-1025. DOI:10.1086/422761

Lantier L, Lacroix-Lamandé S, Potiron L, Metton C, Drouet F, Guesdon W, et al. Intestinal CD103+ dendritic cells are key players in the innate immune control of Cryptosporidium parvum infection in neonatal mice. PLoS Pathog 2013;9(12):e1003801. DOI:10.1371/journal.ppat.1003801

Laurent F, Lacroix-Lamandé S. Innate immune responses play a key role in controlling infection of the intestinal epithelium by Cryptosporidium. Int J Parasitol. 2017;47(12):711-721. DOI:10.1016/j.ijpara.2017.08.001

Gong A, Hu G, Zhou R, Liu J, Feng Y, Soukup G, et al. MicroRNA-221 controls expression of intercellular adhesion molecule-1 in epithelial cells in response to Cryptosporidium parvum infection. Int J Parasitol. 2011;41(3-4):397-403. DOI:10.1016/j.ijpara.2010.11.011

Lacroix-Lamandé S, Mancassola R, Naciri M, Laurent

F. Role of gamma interferon in chemokine expression in the ileum of mice and in a murine intestinal epithelial cell line after Cryptosporidium parvum infection. Infect Immun 2002;70(4):2090-2099. DOI:10.1128/iai.70.4.2090-2099.2002

Chen X, Levine S, Splinter P, Tietz P, Ganong A, Jobin C, et al. Cryptosporidium parvum activates nuclear factor kappaB in biliary epithelia preventing epithelial cell apoptosis. Gastroenterology 2001;120(7):1774-1783. DOI:10.1053/gast.2001.24850

Chen X, O’Hara S, Nelson J, Splinter P, Small A, Tietz PS, et al. Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvum via activation of NF-kappaB. J Immunol Baltim Md 1950. 2005;175(11):7447-7456. DOI:10.4049/jimmunol.175.11.7447

Zhou R, Hu G, Liu J, Gong A-Y, Drescher KM, Chen X-M. NF-kappaB p65-Dependent Transactivation of miRNA Genes following Cryptosporidium parvum Infection Stimulates Epithelial Cell Immune Responses. PLOS Pathog. 2009;5(12):e1000681. DOI:10.1371/journal. ppat.1000681

Abel AM, Yang C, Thakar MS, Malarkannan S. Natural Killer Cells: Development, Maturation, and Clinical Utilization. Front Immunol. 2018;9. DOI:10.3389/fimmu.2018.01869

Ungar BL, Kao TC, Burris JA, Finkelman FD. Crypto-sporidium infection in an adult mouse model. Independ-ent roles for IFN-gamma and CD4+ T lymphocytes in protective immunity. J Immunol. 1991;147(3):1014-1022. https://www.jimmunol.org/content/147/3/1014.

Chen W, Harp J, Harmsen A. Requirements for CD4+ cells and gamma interferon in resolution of established Cryptosporidium parvum infection in mice. Infect Immun. 1993;61(9):3928-3932. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC281096/.

Mead J, You X, Pharr J, Belenkaya Y, Arrowood M, Fallon M, et al. Evaluation of maduramicin and alborixin in a SCID mouse model of chronic cryptosporidiosis. Antimicrob Agents Chemother. 1995;39(4):854-858. DOI:10.1128/AAC.39.4.854

Barakat F, McDonald V, Foster G, Tovey M, Korbel D. Cryptosporidium parvum infection rapidly induces a protective innate immune response involving type I interferon. J Infect Dis. 2009;200(10):1548-1555. DOI:10.1086/644601

Marcial M, Madara J. Cryptosporidium: cellular lo-calization, structural analysis of absorptive cell-parasite membrane-membrane interactions in guinea pigs, and suggestion of protozoan transport by M cells. Gastro-enterology. 1986;90(3):583-594. DOI:10.1016/0016-5085(86)91112-1

Lumadue J, Manabe Y, Moore R, Belitsos P, Sears C, Clark D. A clinicopathologic analysis of AIDS-related cryptosporidiosis. AIDS Lond Engl. 1998;12(18):2459-2466. DOI:10.1097/00002030-199818000-00015

Perez-Cordon G, Yang G, Zhou B, Nie W, Li S, Shi L, et al. Interaction of Cryptosporidium parvum with mouse dendritic cells leads to their activation and parasite transportation to mesenteric lymph nodes. Pathog Dis. 2014;70(1):17-27. DOI:10.1111/2049-632X.12078

Tzipori S, Widmer G. The biology of Cryptosporidium. Contrib Microbiol. 2000;6:1-32. DOI:10.1159/000060370

Schmidt W, Wahnschaffe U, Schäfer M, Zippel T, Arvand M, Meyerhans A, et al. Rapid increase of mucosal CD4 T cells followed by clearance of intestinal cryptosporidiosis in an AIDS patient receiving highly active antiretroviral therapy. Gastroenterology. 2001;120(4):984-987. DOI:10.1053/gast.2001.22557

Todorov I, Gospodinova M. Serum amyloid A protein in acute infectious diseases. Infect Dis Child. 2018;X(1):25-36.

Pollok R, Farthing M, Bajaj-Elliott M, Sanderson I, McDonald V. Interferon gamma induces enterocyte resistance against infection by the intracellular pathogen Crypto-sporidium parvum. Gastroenterology. 2001;120(1):99-107. DOI:10.1053/gast.2001.20907

Sateriale A, Striepen B. Beg, Borrow and Steal: Three Aspects of Horizontal Gene Transfer in the Protozoan Parasite, Cryptosporidium parvum. PLOS Pathog. 2016;12(3):e1005429. DOI:10.1371/journal.ppat.1005429

Gomez Morales M, Ausiello C, Guarino A, Urbani F, Spagnuolo M, Pignata C, et al. Severe, protracted intestinal cryptosporidiosis associated with interferon gamma deficiency: pediatric case report. Clin Infect Dis Off Publ Infect Dis Soc Am. 1996;22(5):848-850. DOI:10.1093/clinids/22.5.848

Robinson P, Okhuysen P, Chappell C, Lewis D, Shahab I, Lahoti S, et al. Expression of IL-15 and IL-4 in IFN-gam-ma-independent control of experimental human Cryptosporidium parvum infection. Cytokine. 2001;15(1):39-46. DOI:10.1006/cyto.2001.0888

Dann S, Wang H, Gambarin K, Actor J, Robinson P, Lewis DE, et al. Interleukin-15 activates human natural killer cells to clear the intestinal protozoan cryptosporidium. J Infect Dis. 2005;192(7):1294-1302. DOI:10.1086/444393

Okhuysen P, Robinson P, Nguyen M, Nannini E, Lewis D, Janecki A, et al. Jejunal cytokine response in AIDS patients with chronic cryptosporidiosis and during immune reconstitution. AIDS Lond Engl. 2001;15(6):802-804. DOI:10.1097/00002030-200104130-00019

Urban J, Fayer R, Chen S, Gause W, Gately M, Fin-kelman F. IL-12 protects immunocompetent and immunodeficient neonatal mice against infection with Cryptosporidium parvum. J Immunol Baltim Md 1950. 1996;156(1):263-268. https://www.jimmunol.org/con-tent/156/1/263.long.

Gomez Morales M, Mele R, Ludovisi A, Bruschi F, Tosini F, Riganò R, et al. Cryptosporidium parvum-specific CD4 Th1 cells from sensitized donors responding to both fractionated and recombinant antigenic proteins. Infect Im-mun. 2004;72(3):1306-1310. DOI:10.1128/iai.72.3.1306-1310.2004

Enriquez F, Sterling C. Role of CD4+ TH1- and TH2-cell-secreted cytokines in cryptosporidiosis. Folia Parasitol (Praha). 1993;40(4):307-311. https://folia.paru.cas.cz/artkey/fol-199304-0014_role_of_cd4_th1-_and_th2-cell-secreted_cytokines_and_cryptosporidiosis.php.

Lacroix S, Mancassola R, Naciri M, Laurent F. Cryptosporidium parvum-specific mucosal immune response in C57BL/6 neonatal and gamma interferon-deficient mice: role of tumor necrosis factor alpha in protection. Infect Immun. 2001;69(3):1635-1642. DOI:10.1128/IAI.69.3.1635-1642.2001

Lean I, McDonald S, Bajaj-Elliott M, Pollok R, Farthing M, McDonald V. Interleukin-4 and transforming growth factor beta have opposing regulatory effects on gamma interferon-mediated inhibition of Cryptosporidium parvum reproduction. Infect Immun. 2003;71(8):4580-4585. DOI:10.1128/iai.71.8.4580-4585.2003

Leitch G, He Q. Reactive nitrogen and oxygen species ameliorate experimental cryptosporidiosis in the neonatal BALB/c mouse model. Infect Immun. 1999;67(11):5885-5891. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC96970/.

Gookin J, Duckett L, Armstrong M, Stauffer S, Finnegan C, Murtaugh M, et al. Nitric oxide synthase stimulates prostaglandin synthesis and barrier function in C. par-vum-infected porcine ileum. Am J Physiol-Gastrointest Liver Physiol. 2004;287(3):G571-G581. DOI:10.1152/ajpgi.00413.2003

Harp J, Whitmire W, Sacco R. In vitro proliferation and production of gamma interferon by murine CD4+ cells in response to Cryptosporidium parvum antigen. J Parasitol. 1994;80(1):67-72. https://www.jstor.org/stable/3283347?seq=1.

Gomez Morales M, La Rosa G, Ludovisi A, Onori A, Pozio E. Cytokine profile induced by Cryptosporidium antigen in peripheral blood mononuclear cells from immunocompetent and immunosuppressed persons with cryptosporidiosis. J Infect Dis. 1999;179(4):967-973. DOI:10.1086/314665

McDonald V, Bancroft G. Mechanisms of innate and acquired resistance to Cryptosporidium parvum infection in SCID mice. Parasite Immunol. 1994;16(6):315-320. DOI:10.1111/j.1365-3024.1994.tb00354.x

Boher Y, Perez-Schael I, Caceres-Dittmar G, Urbina G, Gonzalez R, Kraal G, et al. Enumeration of selected leukocytes in the small intestine of BALB/c mice infected with Cryptosporidium parvum. Am J Trop Med Hyg. 1994;50(2):145-151. https://pascal-francis. inist.fr/vibad/index.php?action=getRecordDetail&i dt=3937131.

Abrahamsen M, Lancto C, Walcheck B, Layton W, Jutila M. Localization of alpha/beta and gamma/delta T lymphocytes in Cryptosporidium parvum-infected tissues in naive and immune calves. Infect Immun. 1997;65(6):2428-2433. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC175336/.

Heine J, Moon H, Woodmansee D. Persistent Cryptosporidium infection in congenitally athymic (nude) mice. Infect Immun. 1984;43(3):856-859. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC264261/.

Hayward A, Levy J, Facchetti F, Notarangelo L, Ochs H, Etzioni A, et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol Baltim Md 1950. 1997;158(2):977-983. https://www.jimmunol. org/content/158/2/977.long.

Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr. 1997;131(1 Pt 1):47-54. DOI:10.1016/s0022-3476(97)70123-9

Blanshard C, Jackson A, Shanson D, Francis N, Gazzard B. Cryptosporidiosis in HIV-seropositive patients. Q J Med. 1992; 85(307-308):813-823. https://academic.oup. com/qjmed/article-abstract/85/2-3/813/1600173?redirec tedFrom=fulltext.

Manabe Y, Clark D, Moore R, Lumadue J, Dahlman H, Belitsos PC, et al. Cryptosporidiosis in patients with AIDS: correlates of disease and survival. Clin Infect Dis Off Publ Infect Dis Soc Am. 1998;27(3):536-542. DOI:10.1086/514701

Miao Y, Awad-El-Kariem F, Franzen C, Ellis D, Müller A, Counihan HM, et al. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr 1999. 2000;25(2):124-129. DOI:10.1097/00042560-200010010-00006

Aguirre S, Mason P, Perryman L. Susceptibility of major histocompatibility complex (MHC) class I- and MHC class II-deficient mice to Cryptosporidium parvum infection. Infect Immun. 1994;62(2):697-699. https://www. ncbi.nlm.nih.gov/pmc/articles/PMC186160/.

Mariotte D, Comby E, Brasseur P, Ballet J. Kinetics of spleen and Peyer’s patch lymphocyte populations during gut parasite clearing in Cryptosporidium parvum infected suckling mice. Parasite Immunol. 2004;26(1):1-6. DOI:10.1111/j.0141-9838.2004.00676.x

Korbel D, Barakat F, Di Santo J, McDonald V. CD4+ T cells are not essential for control of early acute Cryptosporidium parvum infection in neonatal mice. Infect Immun. 2011;79(4):1647-1653. DOI:10.1128/IAI.00922-10

Khalil I, Troeger C, Rao P, Blacker B, Brown A, Brewer TG, et al. Morbidity, mortality, and long-term consequences associated with diarrhoea from Cryptosporidium infection in children younger than 5 years: a meta-analyses study. Lancet Glob Health. 2018;6(7):e758-e768. DOI:10.1016/S2214-109X(18)30283-3

Chen W, Harp J, Harmsen A. Cryptosporidium par-vum infection in gene-targeted B cell-deficient mice. J Parasitol. 2003;89(2):391-393. DOI:10.1645/0022-3395(2003)089[0391:CPIIGB]2.0.CO;2

Priest J, Kwon J, Moss D, Roberts J, Arrowood M, Dworkin M, et al. Detection by enzyme immunoassay of serum immunoglobulin G antibodies that recognize specific Cryptosporidium parvum antigens. J Clin Microbiol. 1999;37(5):1385-1392. https://jcm.asm.org/content/37/5/1385.long.

Priest J, Bern C, Xiao L, Roberts J, Kwon JP, Lescano A, et al. Longitudinal analysis of cryptosporidium species-specific immunoglobulin G antibody responses in Peruvian children. Clin Vaccine Immunol CVI. 2006;13(1):123-131. DOI:10.1128/CVI.13.1.123-131.2006

Frost F, Roberts M, Kunde T, Craun G, Tollestrup K, Harter L, et al. How clean must our drinking water be:the importance of protective immunity. J Infect Dis. 2005;191(5):809-814. DOI:10.1086/427561

Frost F, Tollestrup K, Craun G, Fairley C, Sinclair M, Kunde T. Protective immunity associated with a strong serological response to a Cryptosporidium-specific antigen group, in HIV-infected individuals. J Infect Dis. 2005;192(4):618-621. DOI:10.1086/431681

Kozisek F, Craun G, Cerovska L, Pumann P, Frost F, Muller T. Serological responses to Cryptosporidium-specific antigens in Czech populations with different water sources. Epidemiol Infect. 2008;136(2):279-286. DOI:10.1017/S0950268807008370

Albert M, Rusnak J, Luther M, Graybill J. Treatment of murine cryptosporidiosis with anticryptosporidial immune rat bile. Am J Trop Med Hyg. 1994;50(1):112-119. DOI:10.4269/ajtmh.1994.50.112

Enriquez F, Riggs M. Role of immunoglobulin A monoclonal antibodies against P23 in controlling murine Cryptosporidium parvum infection. Infect Im-mun 1998;66(9):4469-4473. https://iai.asm.org/con-tent/66/9/4469.long.

Jacyna M, Parkin J, Goldin R, Baron J. Protracted enteric cryptosporidial infection in selective immunoglobulin A and saccharomyces opsonin deficiencies. Gut 1990;31(6):714-716. DOI:10.1136/gut.31.6.714

Hunter P, Nichols G. Epidemiology and clinical features of Cryptosporidium infection in immunocompromised patients. Clin Microbiol Rev 2002;15(1):145-154. DOI:10.1128/cmr.15.1.145-154.2002

Motta I, Gissot M, Kanellopoulos J, Ojcius D. Absence of weight loss during Cryptosporidium infection in susceptible mice deficient in Fas-mediated apoptosis. Microbes Infect 2002;4(8):821-827. DOI:10.1016/s1286-4579(02)01602-7

Javier Enriquez F, Avila C, Ignacio Santos J, Tanaka-Kido J, Vallejo O, Sterling C. Cryptosporidium infections in Mexican children: clinical, nutritional, enteropathogenic, and diagnostic evaluations. Am J Trop Med Hyg 1997;56(3):254-257. DOI:10.4269/ajtmh.1997.56.254

Nchito M, Kelly P, Sianongo S, Farthing M, Baboo K. Cryptosporidiosis in urban Zambian children: an analysis of risk factors. Am J Trop Med Hyg 1998;59(3):435-437. DOI:10.4269/ajtmh.1998.59.435




DOI: http://dx.doi.org/10.14748/bmr.v30.6386

Refbacks

Article Tools
Email this article (Login required)
About The Authors

Kalina Stoyanova
Medical University of Varna
Bulgaria

Department of Infectious Diseases, Parasitology and Dermatovenerеology, Faculty of Medicine

Stoyan Pavlov
Medical University of Varna
Bulgaria

Department of Anatomy and Cell Biology, Faculty of Medicine

Font Size


|