Interferon gamma induces enterocyte resistance against infection by the intracellular pathogen Cryptosporidium parvum

Background & Aims: Interferon (IFN)-gamma plays an important role in the immunologic control of infection by the protozoan enteropathogen Cryptosporidium parvum. We tested the hypothesis that IFN-gamma may directly inhibit infection of enterocytes by this pathogen. Methods: HT-29, Caco-2, and H4 human enterocyte cell lines were drown in monolayers and incubated with IFN-gamma before exposure with C. parvum. IFN-gamma receptor expression in the cell lines was determined by Western blot analysis. Results: IFN-gamma inhibited C. parvum infection of both HT-29 and Caco-2 cells but not H4 cells. Response to IFN-gamma, was related to the expression of the IFN-gamma receptor in the respective cell lines. The effect of IFN-gamma was partially reversed by inhibition of the JAK/STAT signaling pathway. IFN-gamma mediated its action by at least 2 mechanisms: (1) inhibition of parasite invasion and (2) by modification of intracellular Fe2+ concentration. No role for tryptophan starvation or nitric oxide synthase activity was found. TNF-alpha and IL-1 beta also had anti-C. parvum activity but had no synergistic effect with IFN-gamma, Conclusions: IFN-gamma directly induces enterocyte resistance against C parvum infection; this observation may have important consequences for our understanding of the mucosal immune response to invasive pathogens.