Cryptosporidium
5.9 Immunopathology in the gut and intestinal tract
Cryptosporidium parvum is a minimally invasive pathogen in immunocom- petent hosts, but does result in villus atrophy and reduced epithelial bar- rier function. In immunodeficient hosts, where infections can be more severe and chronic, greater influx in the number of inflammatory cells (including macrophages, dendritic cells, and lymphocytes) has been observed.
The parasite has been reported to cause flare-ups in patients with inflamma- tory bowel disease or to cause severe infections in individuals with Crohn’s disease. However, the immune cells responsible for this are currently unde- termined. Hypersensitivity with mast cell accumulation in the gut wall after infection has been noted with certain isolates ofC. parvumin an un-weaned rat model. On the other hand, neutrophils in human and animal cryptosporid- iosis may play a role in enhancing the epithelial cell barrier function, rather than in mediating the pathological sequelae of C. parvum infection. They do not appear to contribute to the pathology of disease during infection, as they do not contribute to peroxynitrite formation or have any impact on the severity of epithelial infection, villus atrophy or diarrhoea in a pig model of cryptosporidiosis.
REFERENCES FOR FURTHER READING Life cycle
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Clinical presentation
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General immune responses in cryptosporidiosis
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Gookin, JLet al. (2004).Nitric oxide synthase stimulates prostaglandin synthesis and barrier function inC. parvum-infected porcine ileum.American Journal of Physiology. Gastrointestinal and Liver Physiology287(3), G571–581.
Griffiths, JKet al. (1994).Cryptosporidium parvuminfection of Caco-2 cell monolayers induces an apical monolayer defect, selectively increases transmonolayer permeability, and causes epithelial cell death.Infection and Immunity62(10), 4506–4514.
Innate effector mechanisms
Toll-like receptors
Barrier, Met al. (2006).Oral and intraperitoneal administration of phosphorothioate oligodeoxynucleotides leads to control of Cryptosporidium parvuminfection in neonatal mice.Journal of Infectious Diseases193(10), 1400–1407.
Chen, XMet al. (2005).Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvumvia activation of NF-B.Journal of Immunology175(11), 7447–7456.
Chen, XMet al. (2007).A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses againstCryptosporidium parvuminfection.
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Chemokines and chemokine receptors
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Lacroix-Lamande, Set al. (2002).Role of␥-interferon in chemokine expression in the ileum of mice and in a murine intestinal epithelial cell line afterCryptosporidium parvuminfection.Infection and Immunity70(4), 2090–2099.
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Wang, HCet al. (2007).High levels of CXCL10 are produced by intestinal epithelial cells in AIDS patients with active
cryptosporidiosis but not after reconstitution of immunity.Infection and Immunity75(1), 481–487.
Mannose-binding lectin
Carmolli, Met al. (2009).Deficient serum mannose-binding lectin levels and MBL2 polymorphisms increase the risk of single and recurrentCryptosporidiuminfections in young children.Journal of Infectious Diseases200(10), 1540–1547.
Kelly, Pet al. (2000).Mannose-binding lectin is a component of innate mucosal defense againstCryptosporidium parvumin AIDS.
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Petry, Fet al. (2008).Binding and activation of human and mouse complement byCryptosporidium parvum(Apicomplexa) and susceptibility of C1q- and MBL-deficient mice to infection.Molecular Immunology45(12), 3392–3400.
Type 1 interferons
Barakat, FMet al. (2009).Cryptosporidium parvuminfection rapidly induces a protective innate immune response involving type I interferon.Journal of Infectious Diseases200(10), 1548–1555.
Anti-microbial peptides
Arrowood, MJet al. (1991).In vitro activities of lytic peptides against the sporozoites ofCryptosporidium parvum.Antimicrobial Agents and Chemotherapy35, 224–227.
Giacometti, Aet al. (2003).In vitroeffect onCryptosporidium parvumof short-term exposure to cathelicidin peptides.Journal of Antimicrobial Chemotherapy51(4), 843–847.
Imboden, Met al. (2010).Antibodies fused to innate immune molecules reduce initiation ofCryptosporidium parvuminfection in mice.Antimicrobial Agents and Chemotherapy54(4), 1385–1392.
Zaalouk, TKet al. (2004).Differential regulation of-defensin gene expression duringCryptosporidium parvuminfection.Infection and Immunity72(5), 2772–2779.
NK cells
Dann, SMet al. (2005).Interleukin-15 activates human natural killer cells to clear the intestinal protozoanCryptosporidium.Journal of Infectious Diseases192(7), 1294–1302.
McDonald, V & Bancroft, GJ (1994).Mechanisms of innate and acquired resistance toCryptosporidiumparvum infection in SCID mice.Parasite Immunology16(6), 315–320.
Mead, JRet al. (1991).ChronicCryptosporidium parvum infections in congenitally immunodeficient SCID and nude mice.
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Rohlman, VCet al. (1993).Cryptosporidium parvuminfection after abrogation of natural killer cell activity in normal and severe combined immunodeficiency mice.Journal of Parasitology79(2), 295–297.
Macrophages and dendritic cells
Auray, Get al. (2007).Involvement of intestinal epithelial cells in dendritic cell recruitment duringC. parvuminfection.Microbes and Infection9(5), 574–582.
Hayward, ARet al. (2001).Marrow-derived CD40-positive cells are required for mice to clearCryptosporidium parvuminfection.
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Ponnuraj, EM & Hayward, AR (2001).Intact intestinal mRNAs and intestinal epithelial cell esterase, but notCryptosporidium parvum, reach mesenteric lymph nodes of infected mice.Journal of Immunology167(9), 5321–5328.
Takeuchi, Det al. (2008).Cooperative role of macrophages and neutrophils in host antiprotozoan resistance in mice acutely infected withCryptosporidium parvum.Infection and Immunity76(8), 3657–3663.
Adaptive immunity
Pozio, Eet al. (1997).Clinical cryptosporidiosis and human immunodeficiency virus (HIV)-induced immunosuppression:
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Waters, WR & Harp, JA (1996).Cryptosporidium parvum infection in T-cell receptor (TCR)-- and TCR-␦-deficient mice.
Infection and Immunity64(5), 1854–1857.
CD4+ T cells
Aguirre, SAet al. (1994).Susceptibility of major
histocompatibility complex (MHC) class I- and MHC class II-deficient mice toCryptosporidium parvuminfection.Infection and Immunity 62(2), 697–699.
Harp, JAet al. (1994).In vitroproliferation and production of
␥-interferon by murine CD4(+) cells in response toCryptosporidium parvumantigen.Journal of Parasitology80(1), 67–72.
McDonald, Vet al. (1996).Immunity toCryptosporidium muris infection in mice is expressed through gut CD4+ intraepithelial lymphocytes.Infection and Immunity64(7), 2556–2562.
CD8+ T cells
Abrahamsen, MSet al. (1997).Localization of␣/and␥/␦T lymphocytes inCryptosporidium parvum-infected tissues in naive and immune calves.Infection and Immunity65(6), 2428–2433.
Leav, BAet al. (2005).An early intestinal mucosal source of
␥-interferon is associated with resistance to and control of Cryptosporidium parvuminfection in mice.Infection and Immunity 73(12), 8425–8428.
Pantenburg, Bet al. (2010).Human CD8(+) T cells clear Cryptosporidium parvumfrom infected intestinal epithelial cells.
American Journal of Tropical Medicine and Hygiene82(4), 600–607.
Cytokines
IFN-␥
Hayward, ARet al. (2000).Interferon-␥is required for innate immunity toCryptosporidium parvumin mice.Journal of Infectious Diseases182(3), 1001–1004.
Gomez Morales, MAet al. (1999).Cytokine profile induced by Cryptosporidiumantigen in peripheral blood mononuclear cells from immunocompetent and immunosuppressed persons with cryptosporidiosis.Journal of Infectious Diseases179(4), 967–
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Pollok, RCet al. (2001).Interferon-␥induces enterocyte resistance against infection by the intracellular pathogen Cryptosporidium parvum.Gastroenterology120(1), 99–107.
Lean, ISet al. (2002).The role of cytokines in the pathogenesis ofCryptosporidiuminfection.Current Opinion in Infectious Diseases 15(3), 229–234.
Nordone, SK & Gookin, JL (2010).Lymphocytes and not IFN-␥ mediate expression of iNOS by intestinal epithelium in murine cryptosporidiosis.Parasitology Research106(6), 1507–1511.
TNF-␣
Lacroix, Set al. (2001).Cryptosporidium parvum-specific mucosal immune response in C57BL/6 neonatal and␥ interferon-deficient mice: role of tumor necrosis factor␣in protection.Infection and Immunity69(3), 1635–1642.
Lean, ISet al. (2006).Role of tumor necrosis factor␣in development of immunity againstCryptosporidium parvum infection.Infection and Immunity74(7), 4379–4382.
Robinson, Pet al. (2001).Expression of tumor necrosis factor␣ and interleukin 1 beta in jejuna of volunteers after experimental challenge withCryptosporidium parvumcorrelates with exposure but not with symptoms.Infection and Immunity69(2), 1172–1174.
IL-12
Pasquali, Pet al. (2006).Recombinant bovine interleukin-12 stimulates a gut immune response but does not provide resistance toCryptosporidium parvuminfection in neonatal calves.Veterinary Parasitology135(3–4), 259–268.
Urban, JF, Jr.et al. (1996).IL-12 protects immunocompetent and immunodeficient neonatal mice against infection with
Cryptosporidium parvum.Journal of Immunology156(1), 263–268.
IL-18
McDonald, Vet al. (2006).A potential role for interleukin-18 in inhibition of the development ofCryptosporidium parvum.Clinical and Experimental Immunology145(3), 555–562.
Ehigiator, HNet al. (2007).Cryptosporidium parvum: the contribution of Th1-inducing pathways to the resolution of infection in mice.Experimental Parasitology115(2), 107–113.
Th2
Aguirre, SAet al. (1998).IL-4 protects adult C57BL/6 mice from prolongedCryptosporidium parvuminfection: analysis of CD4+␣+IFN-␥+ and CD4+␣+IL-4+ lymphocytes in gut-associated lymphoid tissue during resolution of infection.
Journal of Immunology161(4), 1891–1900.
McDonald, SAet al. (2004).Protection against the early acute phase ofCryptosporidium parvuminfection conferred by interleukin-4-induced expression of T helper 1 cytokines.Journal of Infectious Diseases190(5), 1019–1025.
Petry, Fet al. (2010).Host immune response toCryptosporidium parvuminfection.Experimental Parasitology126(3), 304–309.
Singh, Iet al. (2005).Kinetics ofCryptosporidium parvum-specific cytokine responses in healing and nonhealing murine models ofC.parvuminfection.Parasitology Research97(4), 309–317.
Smith, LMet al. (2000).Cytokine expression and specific lymphocyte proliferation in two strains ofCryptosporidium parvum-infected␥-interferon knockout mice.Journal of Parasitology 86(2), 300–307.
Smith, LMet al. (2001).Exogenous interleukin-12 (IL-12) exacerbatesCryptosporidium parvuminfection in␥interferon knockout mice.Experimental Parasitology98(3), 123–133.
Immunoregulatory cytokines
Kaushik, Ket al. (2009).Lymphoproliferative and cytokine responses toCryptosporidium parvumin patients coinfected withC. parvumand human immunodeficiency virus.Clinical and Vaccine Immunology16(1), 116–121.
Kirkpatrick, BDet al. (2002).Cryptosporidiosis stimulates an inflammatory intestinal response in malnourished Haitian children.
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Lean, ISet al. (2003).Interleukin-4 and transforming growth factor beta have opposing regulatory effects on gamma interferon-mediated inhibition ofCryptosporidium parvum reproduction.Infection and Immunity71(8), 4580–4585.
Robinson, Pet al. (2000).Transforming growth factor1 is expressed in the jejunum after experimentalCryptosporidium parvuminfection in humans.Infection and Immunity68(9), 5405–5407.
Roche, JKet al. (2000).Transforming growth factor1 ameliorates intestinal epithelial barrier disruption by Cryptosporidium parvumin vitro in the absence of mucosal T lymphocytes.Infection and Immunity68(10), 5635–5644.
Wyatt, CRet al. (2002).Association of IL-10 expression by mucosal lymphocytes with increased expression of
Cryptosporidium parvumepitopes in infected epithelium.Journal of Parasitology88(2), 281–286.
Antibody responses
Arrowood, MJet al. (1989).Effects of immune colostrum and orally administered antisporozoite monoclonal antibodies on the outcome ofCryptosporidium parvuminfections in neonatal mice.
Infection and Immunity57, 2283–2288.
Bjorneby, JMet al. (1990).Cryptosporidium parvummerozoites share neutralization-sensitive epitopes with sporozoites.Journal of Immunology145(1), 298–304.
Chen, Wet al. (2003).Cryptosporidium parvuminfection in gene-targeted B cell-deficient mice.Journal of Parasitology89(2), 391–393.
Frost, FJet al. (2004).Analysis of serological responses to Cryptosporidiumantigen among NHANES III participants.Annals of Epidemiology14(7), 473–478.
Jenkins, MCet al. (1999).Hyperimmune bovine colostrum specific for recombinantCryptosporidium parvumantigen confers partial protection against cryptosporidiosis in immunosuppressed adult mice.Vaccine17(19), 2453–2460.
Kassa, Met al. (1991).Characterization of anti-Cryptosporidium IgA antibodies in sera from immunocompetent individuals and HIV-infected patients.Journal of Protozoology38, S179–S180.
Perryman, LEet al. (1999).Protection of calves against cryptosporidiosis with immune bovine colostrum induced by a Cryptosporidium parvumrecombinant protein.Vaccine17(17), 2142–2149.
Priest, JWet al. (2001).Enzyme immunoassay detection of antigen-specific immunoglobulin g antibodies in longitudinal serum samples from patients with cryptosporidiosis.Clinical and Diagnostic Laboratory Immunology8(2), 415–423.
Reperant, JMet al. (1994).Major antigens ofCryptosporidium parvumrecognised by serum antibodies from different infected animal species and man.Veterinary Parasitology55(1–2), 1–13.
Wolska-Kusnierz, Bet al. (2007).Cryptosporidiuminfection in patients with primary immunodeficiencies.Journal of Pediatric Gastroenterology and Nutrition45(4), 458–464.
Memory responses
Ehigiator, HNet al. (2003).IL-12 knockout C57BL/6 mice are protected from re-infection withCryptosporidium parvumafter challenge.Journal of Eukaryotic Microbiology50 Suppl, 539–541.
Surl, CG & Kim, HC (2006).Concurrent response to challenge infection withCryptosporidium parvumin immunosuppressed C57BL/6N mice.Journal of Veterinary Science7(1), 47–51.
Okhuysen, PCet al. (1998).Susceptibility and serologic response of healthy adults to reinfection withCryptosporidium parvum.Infection and Immunity66(2), 441–443.
Gomez Morales, MAet al. (2004).Cryptosporidium
parvum-specific CD4 Th1 cells from sensitized donors responding to both fractionated and recombinant antigenic proteins.Infection and Immunity72(3), 1306–1310.
Jakobi, V & Petry, F (2008).Humoral immune response in IL-12 and IFN-gamma deficient mice after infection withCryptosporidium parvum.Parasite Immunology30(3), 151–161.
Chappell, CLet al. (1999).Infectivity ofCryptosporidium parvum in healthy adults with pre-existing anti-C.parvumserum
immunoglobulin G.American Journal of Tropical Medicine and Hygiene 60(1), 157–164.
Antigens eliciting the immune response
Bonnin, Aet al. (1991).Characterization of microneme antigens ofCryptosporidium parvum(Protozoa, Apicomplexa).Infection and Immunity59, 1703–1708.
Enriquez, FJ & Riggs, MW (1998).Role of immunoglobulin A monoclonal antibodies against P23 in controlling murine Cryptosporidium parvuminfection.Infection and Immunity66(9), 4469–4473.
Mead, JRet al. (1988).Antigens ofCryptosporidium sporozoites recognized by immune sera of infected animals and humans.Journal of Parasitology74, 135–143.
Moss, DMet al. (1994).Kinetic and isotypic analysis of specific immunoglobulins from crew members with cryptosporidiosis on a U.S. Coast Guard cutter.Journal of Eukaryotic Microbiology41(5), 52S–55S.
O’Connor, RMet al. (2007).Cryptosporidium parvum
glycoprotein gp40 localizes to the sporozoite surface by association with gp15.Molecular and Biochemical Parasitology156(1), 80–83.
Peeters, JEet al. (1992).Cryptosporidium parvumin calves:
kinetics and immunoblot analysis of specific serum and local antibody responses (immunoglobulin A [IgA], IgG, and IgM) after natural and experimental infections.Infection and Immunity60, 2309–2316.
Priest, JWet al. (2001).The immunodominant 17-kDa antigen fromCryptosporidium parvumis
glycosylphosphatidylinositol-anchored.Molecular and Biochemical Parasitology113(1), 117–126.
Priest, JWet al. (2003).Characterization of a low molecular weight glycolipid antigen fromCryptosporidium parvum.Journal of Biological Chemistry278(52), 52212–52222.
Immune evasion
Ceponis, PJet al. (2003).EnterohemorrhagicEscherichia coli O157:H7 disrupts Stat1-mediated gamma interferon signal transduction in epithelial cells.Infection and Immunity71(3), 1396–1404.
Choudhry, Net al. (2009).Dysregulation of
interferon-gamma-mediated signalling pathway in intestinal epithelial cells byCryptosporidium parvuminfection.Cellular Microbiology11(9), 1354–1364.
Gong, AYet al. (2010).Cryptosporidium parvuminduces B7-H1 expression in cholangiocytes by down-regulating microRNA-513.
Journal of Infectious Diseases201(1), 160–169.
Liu, Jet al. (2009).Biphasic modulation of apoptotic pathways inCryptosporidium parvum-infected human intestinal epithelial cells.Infection and Immunity77(2), 837–849.
Immunopathology
Khaldi, Set al. (2009).Cryptosporidium parvum
isolate-dependent postinfectious jejunal hypersensitivity and mast cell accumulation in an immunocompetent rat model.Infection and Immunity77(11), 5163–5169.
Lumadue, JAet al. (1998).A clinicopathologic analysis of AIDS-related cryptosporidiosis.Acquired Immune Deficiency Syndrome12(18), 2459–2466.
Colussi, Oet al. (2010).Acute cryptosporidiosis as a cause of sudden recurrence of digestive symptoms in patients with Crohn’s disease.Journal of Crohn’s & Colitis4(6), 669–670.
Manthey, MWet al. (1997).Cryptosporidiosis and inflammatory bowel disease. Experience from the Milwaukee outbreak.Digestive Diseases and Sciences42(8), 1580–1586.
Zadrozny, LMet al. (2006).Neutrophils do not mediate the pathophysiological sequelae ofCryptosporidium parvuminfection in neonatal piglets.Infection and Immunity74(10), 5497–5505.