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Immunity to Cryptosporidium: insights into principles of enteric responses to infection

Nature Reviews Immunology volume 24, pages 142–155 (2024)Cite this article

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Abstract

Cryptosporidium parasites replicate within intestinal epithelial cells and are an important cause of diarrhoeal disease in young children and in patients with primary and acquired defects in T cell function. This Review of immune-mediated control of Cryptosporidium highlights advances in understanding how intestinal epithelial cells detect this infection, the induction of innate resistance and the processes required for activation of T cell responses that promote parasite control. The development of a genetic tool set to modify Cryptosporidium combined with tractable mouse models provide new opportunities to understand the principles that govern the interface between intestinal epithelial cells and the immune system that mediate resistance to enteric pathogens.

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Fig. 1: Cryptosporidium life cycle.
Fig. 2: Pathological changes during Cryptosporidium infection.
Fig. 3: Sensing of infection by intestinal epithelial cells.
Fig. 4: Innate responses to Cryptosporidium infection.
Fig. 5: Adaptive responses to Cryptosporidium infection.

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References

  1. Pohlenz, J., Bemrick, W. J., Moon, H. W. & Cheville, N. F. Bovine cryptosporidiosis: a transmission and scanning electron microscopic study of some stages in the life cycle and of the host–parasite relationship. Vet. Pathol. 15, 417–427 (1978).

    Article  CAS  PubMed  Google Scholar 

  2. Checkley, W. et al. A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for Cryptosporidium. Lancet Infect. Dis. 15, 85–94 (2015).

    Article  PubMed  Google Scholar 

  3. Striepen, B. Parasitic infections: time to tackle cryptosporidiosis. Nature 503, 189–191 (2013).

    Article  PubMed  Google Scholar 

  4. Kotloff, K. L. et al. The incidence, aetiology, and adverse clinical consequences of less severe diarrhoeal episodes among infants and children residing in low-income and middle-income countries: a 12-month case-control study as a follow-on to the Global Enteric Multicenter Study (GEMS). Lancet Glob. Health 7, e568–e584 (2019). A landmark clinical study that identified Cryptosporidium as second only to rotavirus as a cause of severe diarrhoea in infants and toddlers.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Perin, J. et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child. Adolesc. Health 6, 106–115 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Macfarlane, D. E. & Horner-Bryce, J. Cryptosporidiosis in well-nourished and malnourished children. Acta Paediatr. Scand. 76, 474–477 (1987).

    Article  CAS  PubMed  Google Scholar 

  7. Bourke, C. D., Berkley, J. A. & Prendergast, A. J. Immune dysfunction as a cause and consequence of malnutrition. Trends Immunol. 37, 386–398 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mondal, D. et al. Contribution of enteric infection, altered intestinal barrier function, and maternal malnutrition to infant malnutrition in Bangladesh. Clin. Infect. Dis. 54, 185–192 (2012).

    Article  PubMed  Google Scholar 

  9. Khalil, I. A. 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 6, e758–e768 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kabir, M. et al. Nonsterile immunity to cryptosporidiosis in infants is associated with mucosal IgA against the sporozoite and protection from malnutrition. PLoS Pathog. 17, e1009445 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jenkins, M., Higgins, J., Kniel, K., Trout, J. & Fayer, R. Protection of calves against cryptosporiosis by oral inoculation with gamma-irradiated Cryptosporidium parvum oocysts. J. Parasitol. 90, 1178–1180 (2004).

    Article  PubMed  Google Scholar 

  12. McDonald, V., Deer, R., Uni, S., Iseki, M. & Bancroft, G. J. Immune responses to Cryptosporidium muris and Cryptosporidium parvum in adult immunocompetent or immunocompromised (nude and SCID) mice. Infect. Immun. 60, 3325–3331 (1992). An early demonstration of the key role of T cells and IFNγ in resistance to Cryptosporidium.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chappell, C. L., Okhuysen, P. C., Sterling, C. R. & DuPont, H. L. Cryptosporidium parvum: intensity of infection and oocyst excretion patterns in healthy volunteers. J. Infect. Dis. 173, 232–236 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. DuPont, H. L. et al. The infectivity of Cryptosporidium parvum in healthy volunteers. N. Engl. J. Med. 332, 855–859 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Clifford, C. P. et al. Impact of waterborne outbreak of cryptosporidiosis on AIDS and renal transplant patients. Lancet 335, 1455–1456 (1990).

    Article  CAS  PubMed  Google Scholar 

  16. Gerber, D. A. et al. Cryptosporidial infections after solid organ transplantation in children. Pediatr. Transplant. 4, 50–55 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Winkelstein, J. A. et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine 82, 373–384 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Cohn, I. S., Henrickson, S. E., Striepen, B. & Hunter, C. A. Immunity to Cryptosporidium: lessons from acquired and primary immunodeficiencies. J. Immunol. 209, 2261–2268 (2022).

    Article  CAS  PubMed  Google Scholar 

  19. Amadi, B. et al. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial. Lancet 360, 1375–1380 (2002).

    Article  PubMed  Google Scholar 

  20. Rossignol, J. F., Ayoub, A. & Ayers, M. S. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of nitazoxanide. J. Infect. Dis. 184, 103–106 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Mead, J. R., Arrowood, M. J., Sidwell, R. W. & Healey, M. C. Chronic Cryptosporidium parvum infections in congenitally immunodeficient SCID and nude mice. J. Infect. Dis. 163, 1297–1304 (1991).

    Article  CAS  PubMed  Google Scholar 

  22. Griffiths, J. K., Theodos, C., Paris, M. & Tzipori, S. The gamma interferon gene knockout mouse: a highly sensitive model for evaluation of therapeutic agents against Cryptosporidium parvum. J. Clin. Microbiol. 36, 2503–2508 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sherwood, D., Angus, K. W., Snodgrass, D. R. & Tzipori, S. Experimental cryptosporidiosis in laboratory mice. Infect. Immun. 38, 471–475 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Russler-Germain, E. V. et al. Commensal Cryptosporidium colonization elicits a cDC1-dependent Th1 response that promotes intestinal homeostasis and limits other infections. Immunity 54, 2547–2564.e7 (2021). Identifies C. tyzzeri as a relevant pathobiont in animal facilities and that cDC1s are required to generate Cryptosporidium-specific CD4+ T cell responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sateriale, A. et al. The intestinal parasite Cryptosporidium is controlled by an enterocyte intrinsic inflammasome that depends on NLRP6. Proc. Natl Acad. Sci. USA 118, e2007807118 (2021). Identifies NLRP6 as an initiator of host innate immunity via the release of IL-18 from infected cells.

    Article  CAS  PubMed  Google Scholar 

  26. Sateriale, A. et al. A genetically tractable, natural mouse model of cryptosporidiosis offers insights into host protective immunity. Cell Host Microbe 26, 135–146.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gibson, A. R. et al. A genetic screen identifies a protective type III interferon response to Cryptosporidium that requires TLR3 dependent recognition. PLoS Pathog. 18, e1010003 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gullicksrud, J. A. et al. Enterocyte-innate lymphoid cell crosstalk drives early IFN-γ-mediated control of Cryptosporidium. Mucosal Immunol. 15, 362–372 (2022). Demonstrates natural killer cells and ILC1s as a source of IFNγ that signals to IECs to promote cell-intrinsic mechanisms of parasite control.

    Article  CAS  PubMed  Google Scholar 

  29. Leitch, G. J. & He, Q. Cryptosporidiosis—an overview. J. Biomed. Res. 25, 1–16 (2012).

    Article  PubMed  Google Scholar 

  30. Sponseller, J. K., Griffiths, J. K. & Tzipori, S. The evolution of respiratory cryptosporidiosis: evidence for transmission by inhalation. Clin. Microbiol. Rev. 27, 575–586 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Guerin, A. et al. Cryptosporidium rhoptry effector protein ROP1 injected during invasion targets the host cytoskeletal modulator LMO7. Cell Host Microbe 29, 1407–1420.e5 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Guerin, A. & Striepen, B. The biology of the intestinal intracellular parasite Cryptosporidium. Cell Host Microbe 28, 509–515 (2020).

    Article  CAS  PubMed  Google Scholar 

  33. Ostrovska, K. & Paperna, I. Cryptosporidium sp of the starred lizard Agama stellio: ultrastructure and life-cycle. Parasitol. Res. 76, 712–720 (1990).

    Article  Google Scholar 

  34. Vetterling, J. M., Takeuchi, A. & Madden, P. A. Ultrastructure of Cryptosporidium wrairi from the guinea pig. J. Protozool. 18, 248–260 (1971).

    Article  CAS  PubMed  Google Scholar 

  35. Kaper, J. B., Nataro, J. P. & Mobley, H. L. Pathogenic Escherichia coli. Nat. Rev. Microbiol. 2, 123–140 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Francia, M. E. & Striepen, B. Cell division in apicomplexan parasites. Nat. Rev. Microbiol. 12, 125–136 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Tandel, J. et al. Life cycle progression and sexual development of the apicomplexan parasite Cryptosporidium parvum. Nat. Microbiol. 4, 2226–2236 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  38. English, E. D., Guerin, A., Tandel, J. & Striepen, B. Live imaging of the Cryptosporidium parvum life cycle reveals direct development of male and female gametes from type I meronts. PLoS Biol. 20, e3001604 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fayer, R., Trout, J. M. & Jenkins, M. C. Infectivity of Cryptosporidium parvum oocysts stored in water at environmental temperatures. J. Parasitol. 84, 1165–1169 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Artis, D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat. Rev. Immunol. 8, 411–420 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Nagler-Anderson, C. Tolerance and immunity in the intestinal immune system. Crit. Rev. Immunol. 20, 103–120 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Charania, R., Wade, B. E., McNair, N. N. & Mead, J. R. Changes in the microbiome of Cryptosporidium-infected mice correlate to differences in susceptibility and infection levels. Microorganisms 8, 879 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shan, M. et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342, 447–453 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. McGuckin, M. A., Linden, S. K., Sutton, P. & Florin, T. H. Mucin dynamics and enteric pathogens. Nat. Rev. Microbiol. 9, 265–278 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Marcial, M. A. & Madara, J. L. Cryptosporidium: cellular localization, structural analysis of absorptive cell-parasite membrane–membrane interactions in guinea pigs, and suggestion of protozoan transport by M cells. Gastroenterology 90, 583–594 (1986).

    Article  CAS  PubMed  Google Scholar 

  47. Noah, T. K., Donahue, B. & Shroyer, N. F. Intestinal development and differentiation. Exp. Cell Res. 317, 2702–2710 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Carryn, S. et al. Phospholipases and cationic peptides inhibit Cryptosporidium parvum sporozoite infectivity by parasiticidal and non-parasiticidal mechanisms. J. Parasitol. 98, 199–204 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Zaalouk, T. K., Bajaj-Elliott, M., George, J. T. & McDonald, V. Differential regulation of β-defensin gene expression during Cryptosporidium parvum infection. Infect. Immun. 72, 2772–2779 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Guesdon, W. et al. CCL20 displays antimicrobial activity against Cryptosporidium parvum, but its expression is reduced during infection in the intestine of neonatal mice. J. Infect. Dis. 212, 1332–1340 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Kapel, N., Huneau, J. F., Magne, D., Tome, D. & Gobert, J. G. Cryptosporidiosis-induced impairment of ion transport and Na+-glucose absorption in adult immunocompromised mice. J. Infect. Dis. 176, 834–837 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Kumar, A. et al. Cryptosporidium parvum disrupts intestinal epithelial barrier function via altering expression of key tight junction and adherens junction proteins. Cell Microbiol. 20, e12830 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Goodgame, R. W. et al. Intestinal function and injury in acquired immunodeficiency syndrome-related cryptosporidiosis. Gastroenterology 108, 1075–1082 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Hernandez, J. et al. Substance P is responsible for physiological alterations such as increased chloride ion secretion and glucose malabsorption in cryptosporidiosis. Infect. Immun. 75, 1137–1143 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Guarino, A. et al. Enteric cryptosporidiosis in pediatric HIV infection. J. Pediatr. Gastroenterol. Nutr. 25, 182–187 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Phillips, A. D., Thomas, A. G. & Walker-Smith, J. A. Cryptosporidium, chronic diarrhoea and the proximal small intestinal mucosa. Gut 33, 1057–1061 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Watson, A. J., Duckworth, C. A., Guan, Y. & Montrose, M. H. Mechanisms of epithelial cell shedding in the mammalian intestine and maintenance of barrier function. Ann. N. Y. Acad. Sci. 1165, 135–142 (2009).

    Article  PubMed  Google Scholar 

  58. Delgado, M. E., Grabinger, T. & Brunner, T. Cell death at the intestinal epithelial front line. FEBS J. 283, 2701–2719 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Cliffe, L. J. et al. Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 308, 1463–1465 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Rauch, I. et al. NAIP-NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with eicosanoid and IL-18 release via activation of caspase-1 and -8. Immunity 46, 649–659 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nusse, Y. M. et al. Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559, 109–113 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lee, K. Z. et al. Enterocyte purge and rapid recovery is a resilience reaction of the gut epithelium to pore-forming toxin attack. Cell Host Microbe 20, 716–730 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Zhang, Z. et al. IL-22-induced cell extrusion and IL-18-induced cell death prevent and cure rotavirus infection. Sci. Immunol. 5, eabd2876 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Knodler, L. A. et al. Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia. Proc. Natl Acad. Sci. USA 107, 17733–17738 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fitzgerald, K. A. & Kagan, J. C. Toll-like receptors and the control of immunity. Cell 180, 1044–1066 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Philpott, D. J. & Girardin, S. E. The role of Toll-like receptors and Nod proteins in bacterial infection. Mol. Immunol. 41, 1099–1108 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. McDonald, V. et al. A potential role for interleukin-18 in inhibition of the development of Cryptosporidium parvum. Clin. Exp. Immunol. 145, 555–562 (2006). Identifies that IL-18 is released by IECs infected with Cryptosporidium in vitro and contributes to parasite control in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ferguson, S. H. et al. Interferon-λ3 promotes epithelial defense and barrier function against Cryptosporidium parvum infection. Cell. Mol. Gastroenterol. Hepatol. 8, 1–20 (2019). Identifies the protective effect of IFNλ during Cryptosporidium infection.

    Article  PubMed  PubMed Central  Google Scholar 

  69. McNair, N. N. & Mead, J. R. CD4+ effector and memory cell populations protect against Cryptosporidium parvum infection. Microbes Infect. 15, 599–606 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Barakat, F. M., McDonald, V., Foster, G. R., Tovey, M. G. & Korbel, D. S. Cryptosporidium parvum infection rapidly induces a protective innate immune response involving type I interferon. J. Infect. Dis. 200, 1548–1555 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Deng, S. et al. Cryptosporidium uses CSpV1 to activate host type I interferon and attenuate antiparasitic defenses. Nat. Commun. 14, 1456 (2023). Demonstrates that the viral symbiont CSpV1 present in Cryptosporidium contributes to the induction of type I interferon.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chen, X. M. et al. Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvum via activation of NF-κB. J. Immunol. 175, 7447–7456 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Zhang, G. et al. Cryptosporidium parvum upregulates miR-942-5p expression in HCT-8 cells via TLR2/TLR4-NF-κB signaling. Parasit. Vectors 13, 435 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. O’Hara, S. P., Bogert, P. S., Trussoni, C. E., Chen, X. & LaRusso, N. F. TLR4 promotes Cryptosporidium parvum clearance in a mouse model of biliary cryptosporidiosis. J. Parasitol. 97, 813–821 (2011).

    Article  PubMed  Google Scholar 

  75. Lantier, L. et al. Poly(I:C)-induced protection of neonatal mice against intestinal Cryptosporidium parvum infection requires an additional TLR5 signal provided by the gut flora. J. Infect. Dis. 209, 457–467 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Pott, J. et al. Age-dependent TLR3 expression of the intestinal epithelium contributes to rotavirus susceptibility. PLoS Pathog. 8, e1002670 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Fritz, J. H., Ferrero, R. L., Philpott, D. J. & Girardin, S. E. Nod-like proteins in immunity, inflammation and disease. Nat. Immunol. 7, 1250–1257 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Ehigiator, H. N., McNair, N. & Mead, J. R. Cryptosporidium parvum: the contribution of Th1-inducing pathways to the resolution of infection in mice. Exp. Parasitol. 115, 107–113 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Choudhry, N., Petry, F., van Rooijen, N. & McDonald, V. A protective role for interleukin 18 in interferon γ-mediated innate immunity to Cryptosporidium parvum that is independent of natural killer cells. J. Infect. Dis. 206, 117–124 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. McNair, N. N., Bedi, C., Shayakhmetov, D. M., Arrowood, M. J. & Mead, J. R. Inflammasome components caspase-1 and adaptor protein apoptosis-associated speck-like proteins are important in resistance to Cryptosporidium parvum. Microbes Infect. 20, 369–375 (2018).

    Article  CAS  PubMed  Google Scholar 

  81. Bedi, B. & Mead, J. R. Cryptosporidium parvum antigens induce mouse and human dendritic cells to generate Th1-enhancing cytokines. Parasite Immunol. 34, 473–485 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Kalantari, P. et al. Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria. Cell Rep. 6, 196–210 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Witola, W. H. et al. NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells. Infect. Immun. 79, 756–766 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Wang, P. et al. Nlrp6 regulates intestinal antiviral innate immunity. Science 350, 826–830 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wlodarska, M. et al. NLRP6 inflammasome orchestrates the colonic host–microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Stolzer, I. et al. STAT1 coordinates intestinal epithelial cell death during gastrointestinal infection upstream of caspase-8. Mucosal Immunol. 15, 130–142 (2022).

    Article  CAS  PubMed  Google Scholar 

  87. Dumaine, J. E. et al. The enteric pathogen Cryptosporidium parvum exports proteins into the cytosol of the infected host cell. eLife 10, e70451 (2021). Identifies a Cryptosporidium protein that is exported into the host cell and modulates its function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mostowy, S. & Shenoy, A. R. The cytoskeleton in cell-autonomous immunity: structural determinants of host defence. Nat. Rev. Immunol. 15, 559–573 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Stradal, T. E. B. & Schelhaas, M. Actin dynamics in host–pathogen interaction. FEBS Lett. 592, 3658–3669 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang, Y. et al. Delivery of parasite RNA transcripts into infected epithelial cells during Cryptosporidium infection and its potential impact on host gene transcription. J. Infect. Dis. 215, 636–643 (2017).

    CAS  PubMed  Google Scholar 

  91. Khramtsov, N. V. & Upton, S. J. Association of RNA polymerase complexes of the parasitic protozoan Cryptosporidium parvum with virus-like particles: heterogeneous system. J. Virol. 74, 5788–5795 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Perez-Cordon, G. et al. Interaction of Cryptosporidium parvum with mouse dendritic cells leads to their activation and parasite transportation to mesenteric lymph nodes. Pathog. Dis. 70, 17–27 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. MacMicking, J. D. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nat. Rev. Immunol. 12, 367–382 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Jarret, A. et al. Enteric nervous system-derived IL-18 orchestrates mucosal barrier immunity. Cell 180, 50–63.e12 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Takeuchi, D., Jones, V. C., Kobayashi, M. & Suzuki, F. Cooperative role of macrophages and neutrophils in host antiprotozoan resistance in mice acutely infected with Cryptosporidium parvum. Infect. Immun. 76, 3657–3663 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Vivier, E. et al. Innate lymphoid cells: 10 years on. Cell 174, 1054–1066 (2018).

    Article  CAS  PubMed  Google Scholar 

  97. Lee, J. S. et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43, 727–738 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Munoz, M. et al. Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity 42, 321–331 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Stange, J. et al. IL-22 mediates host defense against an intestinal intracellular parasite in the absence of IFN-γ at the cost of Th17-driven immunopathology. J. Immunol. 188, 2410–2418 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Lieberman, L. A. et al. IL-23 provides a limited mechanism of resistance to acute toxoplasmosis in the absence of IL-12. J. Immunol. 173, 1887–1893 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Schmidt, W. 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 120, 984–987 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Ma, H., Tao, W. & Zhu, S. T lymphocytes in the intestinal mucosa: defense and tolerance. Cell. Mol. Immunol. 16, 216–224 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wang, Y. et al. Structural analyses of a dominant Cryptosporidium parvum epitope presented by H-2Kb offer new options to combat cryptosporidiosis. mBio 14, e0266622 (2023). Identifies an immunodominant epitope recognized by CD8+ T cells that is associated with resistance to Cryptosporidium.

    Article  PubMed  Google Scholar 

  106. Lantier, L. et al. Intestinal CD103+ dendritic cells are key players in the innate immune control of Cryptosporidium parvum infection in neonatal mice. PLoS Pathog. 9, e1003801 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Yin, X., Chen, S. & Eisenbarth, S. C. Dendritic cell regulation of T helper cells. Annu. Rev. Immunol. 39, 759–790 (2021).

    Article  CAS  PubMed  Google Scholar 

  108. Potiron, L. et al. Batf3-dependent intestinal dendritic cells play a critical role in the control of Cryptosporidium parvum infection. J. Infect. Dis. 219, 925–935 (2019). Demonstrates an important functional role for dendritic cells, in particular CD103+ dendritic cells, in mediating control of Cryptosporidium.

    Article  CAS  PubMed  Google Scholar 

  109. Dudziak, D. et al. Differential antigen processing by dendritic cell subsets in vivo. Science 315, 107–111 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Auray, G., Lacroix-Lamande, S., Mancassola, R., Dimier-Poisson, I. & Laurent, F. Involvement of intestinal epithelial cells in dendritic cell recruitment during C. parvum infection. Microbes Infect. 9, 574–582 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Boher, Y. et al. Enumeration of selected leukocytes in the small intestine of BALB/c mice infected with Cryptosporidium parvum. Am. J. Trop. Med. Hyg. 50, 145–151 (1994).

    Article  CAS  PubMed  Google Scholar 

  112. Farache, J. et al. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 38, 581–595 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2, 361–367 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345–349 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Deets, K. A., Nichols Doyle, R., Rauch, I. & Vance, R. E. Inflammasome activation leads to cDC1-independent cross-priming of CD8 T cells by epithelial cell-derived antigen. eLife 10, e72082 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ungar, B. L., Kao, T. C., Burris, J. A. & Finkelman, F. D. Cryptosporidium infection in an adult mouse model. Independent roles for IFN-γ and CD4+ T lymphocytes in protective immunity. J. Immunol. 147, 1014–1022 (1991). Highlights the existence of a CD4+ T cell-dependent, IFNγ-independent mechanisms of resistance to Cryptosporidium.

    Article  CAS  PubMed  Google Scholar 

  117. Aguirre, S. A., Mason, P. H. & Perryman, L. E. Susceptibility of major histocompatibility complex (MHC) class I- and MHC class II-deficient mice to Cryptosporidium parvum infection. Infect. Immun. 62, 697–699 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Culshaw, R. J., Bancroft, G. J. & McDonald, V. Gut intraepithelial lymphocytes induce immunity against Cryptosporidium infection through a mechanism involving gamma interferon production. Infect. Immun. 65, 3074–3079 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Parsa, R. et al. Newly recruited intraepithelial Ly6A+CCR9+CD4+ T cells protect against enteric viral infection. Immunity 55, 1234–1249.e6 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Aguirre, S. A., Perryman, L. E., Davis, W. C. & McGuire, T. C. IL-4 protects adult C57BL/6 mice from prolonged Cryptosporidium parvum infection: analysis of CD4+αβ+IFN-γ+ and CD4+αβ+IL-4+ lymphocytes in gut-associated lymphoid tissue during resolution of infection. J. Immunol. 161, 1891–1900 (1998).

    Article  CAS  PubMed  Google Scholar 

  121. Finkelman, F. D. et al. Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models. Annu. Rev. Immunol. 15, 505–533 (1997).

    Article  CAS  PubMed  Google Scholar 

  122. Sellers, M. et al. [Hirschsprung-associated enterocolitis: observational study in a paediatric emergency care unit]. An. Pediatr. 88, 329–334 (2018).

    Article  Google Scholar 

  123. Cosyns, M. et al. Requirement of CD40–CD40 ligand interaction for elimination of Cryptosporidium parvum from mice. Infect. Immun. 66, 603–607 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hayward, A. R. et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J. Immunol. 158, 977–983 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Ridge, J. P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).

    Article  CAS  PubMed  Google Scholar 

  126. Schoenberger, S. P., Toes, R. E. M., van der Voort, E. I. H., Offringa, R. & Melief, C. J. M. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998).

    Article  CAS  PubMed  Google Scholar 

  127. Bennett, S. R. M. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998).

    Article  CAS  PubMed  Google Scholar 

  128. Van Grol, J., Muniz-Feliciano, L., Portillo, J. A., Bonilha, V. L. & Subauste, C. S. CD40 induces anti-Toxoplasma gondii activity in nonhematopoietic cells dependent on autophagy proteins. Infect. Immun. 81, 2002–2011 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Pasqual, G. et al. Monitoring T cell-dendritic cell interactions in vivo by intercellular enzymatic labelling. Nature 553, 496–500 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Drinkall, E., Wass, M. J., Coffey, T. J. & Flynn, R. J. A rapid IL-17 response to Cryptosporidium parvum in the bovine intestine. Vet. Immunol. Immunopathol. 191, 1–4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhao, G. H. et al. The expression dynamics of IL-17 and Th17 response relative cytokines in the trachea and spleen of chickens after infection with Cryptosporidium baileyi. Parasit. Vectors 7, 212 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Zhao, G. H. et al. Dynamics of Th17 associating cytokines in Cryptosporidium parvum-infected mice. Parasitol. Res. 115, 879–887 (2016).

    Article  CAS  PubMed  Google Scholar 

  133. Ishigame, H. et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30, 108–119 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Ahern, P. P., Izcue, A., Maloy, K. J. & Powrie, F. The interleukin-23 axis in intestinal inflammation. Immunol. Rev. 226, 147–159 (2008).

    Article  PubMed  Google Scholar 

  135. Harty, J. T., Tvinnereim, A. R. & White, D. W. CD8+ T cell effector mechanisms in resistance to infection. Annu. Rev. Immunol. 18, 275–308 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Guk, S. M., Yong, T. S. & Chai, J. Y. Role of murine intestinal intraepithelial lymphocytes and lamina propria lymphocytes against primary and challenge infections with Cryptosporidium parvum. J. Parasitol. 89, 270–275 (2003).

    Article  PubMed  Google Scholar 

  137. Wyatt, C. R. et al. Activation of intestinal intraepithelial T lymphocytes in calves infected with Cryptosporidium parvum. Infect. Immun. 65, 185–190 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Pantenburg, B. et al. Human CD8+ T cells clear Cryptosporidium parvum from infected intestinal epithelial cells. Am. J. Trop. Med. Hyg. 82, 600–607 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. McDonald, V., Robinson, H. A., Kelly, J. P. & Bancroft, G. J. Cryptosporidium muris in adult mice: adoptive transfer of immunity and protective roles of CD4 versus CD8 cells. Infect. Immun. 62, 2289–2294 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Simmons, C. P. et al. Central role for B lymphocytes and CD4+ T cells in immunity to infection by the attaching and effacing pathogen Citrobacter rodentium. Infect. Immun. 71, 5077–5086 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. O’Donnell, H. & McSorley, S. J. Salmonella as a model for non-cognate Th1 cell stimulation. Front. Immunol. 5, 621 (2014).

    PubMed  PubMed Central  Google Scholar 

  142. Smith, C. M. et al. Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat. Immunol. 5, 1143–1148 (2004).

    Article  CAS  PubMed  Google Scholar 

  143. Crotty, S. T follicular helper cell biology: a decade of discovery and diseases. Immunity 50, 1132–1148 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chen, K., Magri, G., Grasset, E. K. & Cerutti, A. Rethinking mucosal antibody responses: IgM, IgG and IgD join IgA. Nat. Rev. Immunol. 20, 427–441 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Bai, X. et al. T follicular helper cells regulate humoral response for host protection against intestinal Citrobacter rodentium infection. J. Immunol. 204, 2754–2761 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Chen, W., Harp, J. A. & Harmsen, A. G. Cryptosporidium parvum infection in gene-targeted B cell-deficient mice. J. Parasitol. 89, 391–393 (2003).

    Article  PubMed  Google Scholar 

  147. Okhuysen, P. C., Chappell, C. L., Sterling, C. R., Jakubowski, W. & DuPont, H. L. Susceptibility and serologic response of healthy adults to reinfection with Cryptosporidium parvum. Infect. Immun. 66, 441–443 (1998). Demonstrates the development of antibody responses and increased resistance to secondary Cryptosporidium challenge in human volunteers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Dann, S. M., Okhuysen, P. C., Salameh, B. M., DuPont, H. L. & Chappell, C. L. Fecal antibodies to Cryptosporidium parvum in healthy volunteers. Infect. Immun. 68, 5068–5074 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Chappell, C. L. et al. Cryptosporidium hominis: experimental challenge of healthy adults. Am. J. Trop. Med. Hyg. 75, 851–857 (2006).

    Article  CAS  PubMed  Google Scholar 

  150. Tarazona, R., Lally, N. C., Dominguez-Carmona, M. & Blewett, D. A. Characterization of secretory IgA responses in mice infected with Cryptosporidium parvum. Int. J. Parasitol. 27, 417–423 (1997).

    Article  CAS  PubMed  Google Scholar 

  151. Allison, G. M. et al. Antibody responses to the immunodominant Cryptosporidium gp15 antigen and gp15 polymorphisms in a case-control study of cryptosporidiosis in children in Bangladesh. Am. J. Trop. Med. Hyg. 85, 97–104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Borad, A. J. et al. Systemic antibody responses to the immunodominant p23 antigen and p23 polymorphisms in children with cryptosporidiosis in Bangladesh. Am. J. Trop. Med. Hyg. 86, 214–222 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Gilchrist, C. A. et al. Cryptosporidium antigens associated with immunity to reinfection identified by a protein array. J. Clin. Invest. https://doi.org/10.1172/JCI166814 (2023). An in-depth study into the development of antibody responses to Cryptosporidium in early life and identification of seroreactive proteins that could form the basis for vaccine development.

  154. Boehm, U., Klamp, T., Groot, M. & Howard, J. C. Cellular responses to interferon-γ. Annu. Rev. Immunol. 15, 749–795 (1997).

    Article  CAS  PubMed  Google Scholar 

  155. Pollok, R. C., Farthing, M. J., Bajaj-Elliott, M., Sanderson, I. R. & McDonald, V. Interferon gamma induces enterocyte resistance against infection by the intracellular pathogen Cryptosporidium parvum. Gastroenterology 120, 99–107 (2001).

    Article  CAS  PubMed  Google Scholar 

  156. Regis, G., Conti, L., Boselli, D. & Novelli, F. IFNγR2 trafficking tunes IFNγ–STAT1 signaling in T lymphocytes. Trends Immunol. 27, 96–101 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Pfefferkorn, E. R. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. Proc. Natl Acad. Sci. USA 81, 908–912 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Saeij, J. P. & Frickel, E. M. Exposing Toxoplasma gondii hiding inside the vacuole: a role for GBPs, autophagy and host cell death. Curr. Opin. Microbiol. 40, 72–80 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Coers, J., Brown, H. M., Hwang, S. & Taylor, G. A. Partners in anti-crime: how interferon-inducible GTPases and autophagy proteins team up in cell-intrinsic host defense. Curr. Opin. Immunol. 54, 93–101 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Sawant, M. et al. Persistent Cryptosporidium parvum infection leads to the development of the tumor microenvironment in an experimental mouse model: results of a microarray approach. Microorganisms 9, 2569 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Xia, Z. et al. m6A mRNA methylation regulates epithelial innate antimicrobial defense against cryptosporidial infection. Front. Immunol. 12, 705232 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Yamamoto, M. et al. A cluster of interferon-gamma-inducible p65 GTPases plays a critical role in host defense against Toxoplasma gondii. Immunity 37, 302–313 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Haldar, A. K. et al. IRG and GBP host resistance factors target aberrant, “non-self” vacuoles characterized by the missing of “self” IRGM proteins. PLoS Pathog. 9, e1003414 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Wilke, G. et al. A stem-cell-derived platform enables complete Cryptosporidium development in vitro and genetic tractability. Cell Host Microbe 26, 123–134.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Heo, I. et al. Modelling Cryptosporidium infection in human small intestinal and lung organoids. Nat. Microbiol. 3, 814–823 (2018). Demonstrates the sexual replication of Cryptosporidium in an in vitro system and identifies induction of a type I interferon gene signature in Cryptosporidium-infected organoids.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Bhalchandra, S., Lamisere, H. & Ward, H. Intestinal organoid/enteroid-based models for Cryptosporidium. Curr. Opin. Microbiol. 58, 124–129 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Coutinho, B. P. et al. Cryptosporidium infection causes undernutrition and, conversely, weanling undernutrition intensifies infection. J. Parasitol. 94, 1225–1232 (2008).

    Article  CAS  PubMed  Google Scholar 

  168. Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Matheis, F. et al. Adrenergic signaling in muscularis macrophages limits infection-induced neuronal loss. Cell 180, 64–78.e16 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Lavelle, E. C. & Ward, R. W. Mucosal vaccines—fortifying the frontiers. Nat. Rev. Immunol. 22, 236–250 (2022).

    Article  CAS  PubMed  Google Scholar 

  171. Bartelt, L. A. et al. Cryptosporidium priming is more effective than vaccine for protection against cryptosporidiosis in a murine protein malnutrition model. PLoS Negl. Trop. Dis. 10, e0004820 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Gut, J. & Nelson, R. G. Cryptosporidium parvum: synchronized excystation in vitro and evaluation of sporozoite infectivity with a new lectin-based assay. J. Eukaryot. Microbiol. 46, 56S–57S (1999).

    CAS  PubMed  Google Scholar 

  173. Vinayak, S. et al. Genetic modification of the diarrhoeal pathogen Cryptosporidium parvum. Nature 523, 477–480 (2015). Establishes the capacity to genetically modify Cryptosporidium, a crucial advanced that has facilitated studies of parasite genetics and the ability to track parasite burden and infected cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Pawlowic, M. C. et al. Genetic ablation of purine salvage in Cryptosporidium parvum reveals nucleotide uptake from the host cell. Proc. Natl Acad. Sci. USA 116, 21160–21165 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Gallego-Lopez, G. M. et al. Dual transcriptomics to determine gamma interferon-independent host response to intestinal Cryptosporidium parvum infection. Infect. Immun. 90, e0063821 (2022).

    Article  PubMed  Google Scholar 

  176. Haskins, B. E. et al. Dendritic cell-mediated responses to secreted Cryptosporidium effectors are required for parasite-specific CD8+ T cell responses. Preprint at bioRxiv https://doi.org/10.1101/2023.08.16.553566 (2023).

  177. Lundie, R. J. et al. Blood-stage plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8α+ dendritic cells. Proc. Natl Acad. Sci. USA 105, 14509–14514 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Pepper, M., Dzierszinski, F., Crawford, A., Hunter, C. A. & Roos, D. Development of a system to study CD4+-T-cell responses to transgenic ovalbumin-expressing Toxoplasma gondii during toxoplasmosis. Infect. Immun. 72, 7240–7246 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Douglas, B. et al. Transgenic expression of a T cell epitope in Strongyloides ratti reveals that helminth-specific CD4+ T cells constitute both Th2 and Treg populations. PLoS Pathog. 17, e1009709 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Garg, N., Nunes, M. P. & Tarleton, R. L. Delivery by Trypanosoma cruzi of proteins into the MHC class I antigen processing and presentation pathway. J. Immunol. 158, 3293–3302 (1997).

    Article  CAS  PubMed  Google Scholar 

  181. Nikolaev, M. et al. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis. Nature 585, 574–578 (2020).

    Article  PubMed  Google Scholar 

  182. Liu, J., Enomoto, S., Lancto, C. A., Abrahamsen, M. S. & Rutherford, M. S. Inhibition of apoptosis in Cryptosporidium parvum-infected intestinal epithelial cells is dependent on survivin. Infect. Immun. 76, 3784–3792 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. McCole, D. F., Eckmann, L., Laurent, F. & Kagnoff, M. F. Intestinal epithelial cell apoptosis following Cryptosporidium parvum infection. Infect. Immun. 68, 1710–1713 (2000). Demonstrated that Cryptosporidium-infected cells are resistant to apoptosis, which suggests that this pathogen interferes with cell-intrinsic death pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Guesdon, W. et al. Cryptosporidium parvum subverts antimicrobial activity of CRAMP by reducing its expression in neonatal mice. Microorganisms 8, 1635 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Choudhry, N., Korbel, D. S., Edwards, L. A., Bajaj-Elliott, M. & McDonald, V. Dysregulation of interferon-γ-mediated signalling pathway in intestinal epithelial cells by Cryptosporidium parvum infection. Cell Microbiol. 11, 1354–1364 (2009).

    Article  CAS  PubMed  Google Scholar 

  186. Guerin, A. et al. Cryptosporidium uses multiple distinct secretory organelles to interact with and modify its host cell. Cell Host Microbe 31, 650–664.e6 (2023).

    Article  CAS  PubMed  Google Scholar 

  187. Feng, Y., Ryan, U. M. & Xiao, L. Genetic diversity and population structure of Cryptosporidium. Trends Parasitol. 34, 997–1011 (2018).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported, in part, by the National Institutes of Health R01 AI148249. R.D.P. is supported by a Fellowship award from the Canadian Institutes of Health Research and a Postdoctoral Training award from the Fonds de Recherche du Québec–Santé.

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  1. These authors contributed equally: Ryan D. Pardy, Bethan A. Wallbank.

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  1. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Ryan D. Pardy, Bethan A. Wallbank, Boris Striepen & Christopher A. Hunter

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R.D.P. and B.A.W. prepared the initial draft. R.D.P. and C.A.H. revised and edited the manuscript. All authors contributed to the final editing of the manuscript. B.A.W. prepared figures with input from all authors.

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Glossary

Merogony

A form of asexual replication by which the parasite nucleus divides multiple times followed by segmentation into eight daughter parasites.

Micronemes

Secretory organelles located in the apical third of apicomplexan parasites that are associated with parasite motility and cell invasion.

Nitazoxanide

The only drug approved for the treatment of Cryptosporidium in otherwise healthy adults and children.

Parasitophorous vacuole

A cell compartment derived during parasite invasion from the host plasma membrane. Here, the parasite completes its replication cycle, shielded from aspects of intracellular immunity.

Rhoptry

A club-shaped secretory organelle that apicomplexan parasites discharge into the host cell to initiate invasion and to deliver effector proteins into the infected cell.

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Pardy, R.D., Wallbank, B.A., Striepen, B. et al. Immunity to Cryptosporidium: insights into principles of enteric responses to infection. Nat Rev Immunol 24, 142–155 (2024). https://doi.org/10.1038/s41577-023-00932-3

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