Host and parasite factors contributing to variation in immunity and pathology in giardiasis.
Infection with the flagellated protozoan Giardia duodenalis is a major cause of parasitic diarrheal disease worldwide. G. duodenalis is grouped into 8 assemblages (A through H) but only assemblage A and B parasites infect humans. Infection with G. duodenalis is typically self-limiting although chronic infections do develop in malnourished and immunocompromised hosts. Most cases of giardiasis are asymptomatic, but patients typically present with diarrhea, vomiting, nutrient malabsorption and cramps and these symptoms collectively amount to malnutrition. Giardiasis is estimated to affect 2% of adults and 6% to 8% of children in the developed world nearly 33% of the underdeveloped world. Pediatric cases can lead to growth stunting and this has global health and economic implications for impoverished endemic regions of the world. Attempts to correlate disease severity to a particular assemblage have been contradictory, likely due to variable host and parasite factors. A hallmark of immunopathology in the mouse model of giardiasis is the reduction of intestinal digestive enzymes which is due to CD8+ T cells. We report that the pathological reduction of intestinal sucrase and increased intestinal T cell presence is parasite strain-specific and is associated with assemblage B infection. A comparison of infections in C57BL/6 and BALB/c mouse strains revealed host-dependent variation in immunity against G. duodenalis. C57BL/6, but not BALB/c mice exhibited increased duodenal CD4+ T cell presence following infection with G. duodenalis. Both mouse strains exhibited activated CD4+ and CD8+ T cells within the duodenum but C57BL/6 mice also mounted responses in other immune compartments such as the intestinal epithelium and Peyer's patches. We found that the intestinal microbiota is an important host factor that plays a central role in determining disease severity in the mouse model. Antibiotic treatment ablated intestinal CD8+ T cell activation and alleviated sucrase deficiency in G. duodenalis infected mice. G. duodenalis-activated CD8+ T cells exhibit cytotoxic potential by expressing granzyme A and IFN-&gamma. These cells, however, differentiate into an unconventional phenotype as they lack the surface expression of death receptor ligands FasL and TRAIL and do not express the canonical cytotoxic molecule granzyme B. An in depth understanding of the biology of Giardia-activated CD8+ T cells will lead to the development of novel therapeutic techniques aimed at alleviating diarrheal disease caused by Giardia. Further, identifying key host and parasite factors that contribute to clinical outcomes is imperative for effective control strategies.
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