Activation of Toll-like receptors (TLRs) by pathogens triggers cytokine production and T cell activation, immune defense mechanisms that are linked to immunopathology. Here we show that IFN-γ production by CD4+ TH1 cells during mucosal responses to the protozoan parasite Toxoplasma gondii results in dysbiosis and the elimination of Paneth cells. Paneth cell death led to loss of antimicrobial peptides and occurred in conjunction with uncontrolled expansion of the Enterobacteriaceae family of Gram-negative bacteria. The expanded intestinal bacteria were required for the parasite-induced intestinal pathology. The investigation of cell type-specific factors regulating TH1 polarization during T. gondii infection identified the T cell intrinsic TLR pathway as a major regulator of IFN-γ production in CD4+ T cells responsible for Paneth cell death, dysbiosis and intestinal immunopathology.

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IFN-γ is a major cytokine that is critical for host resistance to a broad range of intracellular pathogens. Production of IFN-γ by natural killer and T cells is initiated by the recognition of pathogens by Toll-like receptors (TLRs). In an experimental model of toxoplasmosis, we have identified the presence of a nonlymphoid source of IFN-γ that was particularly evident in the absence of TLR-mediated recognition of Toxoplasma gondii . Genetically altered mice lacking all lymphoid cells due to deficiencies in Recombination Activating Gene 2 and IL-2Rγ c genes also produced IFN-γ in response to the protozoan parasite. Flow-cytometry and morphological examinations of non-NK/non-T IFN-γ + cells identified neutrophils as the cell type capable of producing IFN-γ. Selective elimination of neutrophils in TLR11 −/− mice infected with the parasite resulted in acute susceptibility similar to that observed in IFN-γ–deficient mice. Similarly, Salmonella typhimurium infection of TLR-deficient mice induces the appearance of IFN-γ + neutrophils. Thus, neutrophils are a crucial source for IFN-γ that is required for TLR-independent host protection against intracellular pathogens.

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Toxoplasma gondii and Cryptosporidium parvum are intracellular protozoan parasites that establish infection through the small intestinal bowel after the ingestion of contaminated food products. These Apicomplexan parasites have emerged as an important cause of chronic and fatal disease in immunodeficient individuals, in addition to being investigated as possible triggers of inflammatory bowel disease. T. gondii disseminates to the brain and other tissues after infection, whereas C. parvum remains localized to the intestine. In the following review, we will discuss the pathogenesis of these parasitic diseases in the small intestine, the site of initial invasion. Themes include the sequence of invasion, the structure of Th1 immunity provoked by these parasites and the contribution of intestinal microbiota to the development of the mucosal immune response.