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Host cell-mediated responses to infection with Cryptosporidium
1St Bartholomew's and The Royal London School of Medicine and Dentistry, Digestive Diseases Research Centre, London, UK. v.mcdonald@mds.qmw.ac.uk
Abstract:
The coccidian Cryptosporidium infects epithelial cells of a variety of vertebrate hosts and is the causative agent of cryptosporidiosis. In mammals, including humans and domestic animals, C. parvum infects the gastrointestinal tract producing an acute watery diarrhoea and weight loss. CD4+ T-cell-deficient hosts have increased susceptibility to infection with the parasite and may develop severe life-threatening complications. The host responses which induce protective immunity and contribute to pathogenesis are poorly understood. In the immunological control of infection, recent studies with murine infection models suggest that IFN-gamma plays a key role in a partially protective innate immunity against infection identified in immunocompromised mice and also in the elimination of infection mediated by CD4+ T-cells. At the mucosal level, CD4+ intraepithelial lymphocytes are involved in the control of cryptosporidial infection, acting at least in part through production of IFN-gamma which has a direct inhibitory effect on parasite development in enterocytes. Primary infection of ruminants induces an intestinal inflammatory response in which increased numbers of various T-cell subpopulations appear in the villi. In addition, infection results in increased intestinal expression of pro-inflammatory cytokines such as IL-12, IFN-gamma and TNF-alpha. Because these cytokines appear to be important in the aetiology of inflammatory bowel disease, it is possible that they are involved in the mucosal pathogenesis of cryptosporidiosis.
Insights
Cryptosporidium infection causes diarrhea and weight loss in mammals. Interferon-gamma (IFN-γ) is crucial for immune control, with CD4+ T-cells and intraepithelial lymphocytes playing key roles in parasite elimination.
Area of Science:
- Immunology
- Parasitology
- Gastroenterology
Background:
- Cryptosporidium is a coccidian parasite causing cryptosporidiosis, an intestinal infection in vertebrates.
- In mammals, infection leads to diarrhea and weight loss, with CD4+ T-cell deficient hosts showing increased susceptibility and severe complications.
- The host immune responses driving protective immunity and pathogenesis remain poorly understood.
Purpose of the Study:
- To elucidate the immunological mechanisms controlling Cryptosporidium infection.
- To investigate the role of cytokines, particularly Interferon-gamma (IFN-γ), in host defense and pathogenesis.
- To understand the contribution of CD4+ T-cells and intraepithelial lymphocytes to Cryptosporidium control.
Main Methods:
- Studies utilizing murine infection models to assess immune responses.
- Analysis of T-cell subpopulations and cytokine expression in infected hosts (murine and ruminant models).
- Investigation of the direct effects of IFN-γ on parasite development within host enterocytes.
Main Results:
- IFN-γ appears critical for partially protective innate immunity in immunocompromised mice and for CD4+ T-cell mediated parasite elimination.
- CD4+ intraepithelial lymphocytes contribute to infection control, partly via IFN-γ production, which directly inhibits parasite development.
- Ruminant infection models show increased intestinal inflammatory responses, including elevated pro-inflammatory cytokines like IL-12, IFN-γ, and TNF-α.
Conclusions:
- IFN-γ is a key mediator in the immunological control of Cryptosporidium infection.
- CD4+ T-cells and intraepithelial lymphocytes are important for parasite clearance.
- Pro-inflammatory cytokines may play a role in the mucosal pathogenesis of cryptosporidiosis, potentially linking to inflammatory bowel disease mechanisms.