Dynamics of gut mucosal and systemic Th1/Th2 cytokine responses in interferon-gamma and interleukin-12p40 knock out mice during primary and challenge Cryptosporidium parvum infection

Cryptosporidium parvum is an intracellular parasite causing enteritis which can become life-threatening in the immunocompromised host. CD4+ T cells and interferon (IFN)-gamma play dominant roles in host immune response to infection. However, effector mechanisms that are responsible for recovery from infection are poorly understood. In the present study we analyzed mice deficient in IFN-gamma or interleukin (IL)-12 in parallel to C57BL/6 wild type mice as models for murine cryptosporidiosis. Our results identified IFN-gamma as the key cytokine in the innate as well as adaptive immunity during primary and also challenge C. parvum infection. Furthermore, both Th1 and Th2 cytokines appear to contribute to the resolution of a primary infection, the former being dominant over the latter. Dramatic changes in the expression of cytokine genes were seen in the ileum (the site of infection) but not in the mesenteric lymph nodes and spleen. During re-challenge, a significant increase of IFN-gamma was recorded in IL-12 deficient mice (IL-12KO). Additionally, we present data suggesting a contribution of IL-18 in resistance of C. parvum infection even in the absence of IFN-gamma. Anti-IL-18 antibody treatment led to increased susceptibility to infection in both strains of immunodeficient mice. Besides its function in inducing IFN-gamma in IL-12 knock out mice, IL-18 appears to be involved in the regulation of the Th1/Th2 responses in C parvum. Neutralization resulted in a cytokine imbalance with up regulation of systemic (spleen) Th2 cytokine genes, notably IL-4 and IL-13. These data demonstrate that susceptibility or resistance to C parvum infection depends on a delicate balance between the production of Th1 cytokines, needed to control parasite growth, and Th2 cytokines, to limit pathology. (C) 2008 Elsevier GmbH. All rights reserved.