A Protective Role for Interleukin 18 in Interferon γ–Mediated Innate Immunity to Cryptosporidium parvum That Is Independent of Natural Killer Cells

Abstract

Innate immunity against some intracellular parasitic protozoa involves interleukin 18 (IL-18)-mediated interferon γ (IFN-γ) production by natural killer (NK) cells, but the role of IL-18 in innate resistance to Cryptosporidium infection is unknown. Adult Rag2(-/-)γc(-/-) mice that lack NK cells, T cells, and B cells demonstrated resistance to Cryptosporidium parvum infection that was IFN-γ dependent. Treatment with anti-IL-18-neutralizing antibodies resulted in loss of resistance correlating with reduced intestinal IFN-γ expression. Intestinal mature IL-18 expression increased in vivo during infection and also in the intestinal epithelial cell line CMT-93 following combined IFN-γ treatment/infection. Peritoneal macrophages produced IFN-γ when stimulated with IL-18 combined with interleukin 12, and the latter was expressed in vivo during infection. Macrophage depletion in infected mice caused a rapid growth of infection with no increase in IFN-γ expression. These findings provide evidence of an NK cell-independent, IFN-γ-mediated innate immune pathway against C. parvum in which IL-18 and macrophages play prominent parts.