The production of IFN-gamma is crucial for control of multiple enteric infections, but its impact on intestinal epithelial cells (IEC) is not well understood. Cryptosporidium parasites exclusively infect epithelial cells and the ability of interferons to activate the transcription factor STAT1 in IEC is required for parasite clearance. The use of single cell RNA sequencing to profile IEC during infection revealed induction of IFN-gamma-dependent gene signatures that was comparable between uninfected and infected cells, and IEC expression of the IFN-gamma receptor was required for parasite control. Unexpectedly, treatment of Ifng-/- mice with IFN-gamma demonstrated the IEC response to this cytokine correlates with a delayed reduction in parasite burden but did not affect parasite development. These data sets provide insight into the impact of IFN-gamma on IEC and suggest a model in which IFN-gamma-mediated bystander activation of uninfected enterocytes is important for control of Cryptosporidium.

Analysis of intestinal epithelial cell responses to Cryptosporidium highlights the temporal effects of IFN-gamma on parasite restriction