Interferon-γ Is Required for Innate Immunity to Cryptosporidium parvum in Mice

Although CD4 T cells are required for recovery from cryptosporidial infection, mice with severe combined immunodeficiency (SCID) remain infected for long periods without ill effect. In contrast, mice whose ability to use interferon(IFN)‐g is impaired, by neutralization or gene knockout, experience heavy cryptosporidial infection that may lead to death. To determine whether the innate immunity of SCID mice to Cryptosporidium parvum (CP) requires IFNg, doubly immunodeficient C57BL/6 SCID‐IFN-g knockout mice were bred. These mice experienced heavy CP infections of the gut; a significantly greater number became moribund or died, compared with mice carrying the SCID mutation alone or carrying disrupted IFNg genes alone. Mice with gene disruptions of inducible nitric oxide synthetase or Fas/Fas ligand recovered normally from CP infection. The results indicate that mice unable to produce specific immune responses because of the SCID mutation require IFN-g to avoid death after infection with CP. Cryptosporidium parvum (CP) is an apicomplexan parasite that infects epithelial cells in the intestine and the biliary tree. CP has attracted attention recently because it is difficult to eradicate from water supplies and can cause large outbreaks of infection. CP causes only transient diarrhea in healthy individuals, but it is responsible for severe enteritis and cholangitis in immunodeficient individuals, including individuals infected with AIDS. Experience in humans indicates that CD4 cells and an intact CD40‐CD154 pathway [1] are required for recovery from CP infections. These conclusions are confirmed in mice, where cytokine neutralization studies have identified interleukin (IL)‐12 and interferon (IFN)‐g as important or essential cytokines [2‐4]. Roles of these potentially separate effector mechanisms have been explored, in part, by infecting gene-knockout mice with CP. B6 mice with disrupted IFN-g genes have been