Cryptosporidium parvum -Specific Mucosal Immune Response in C57BL/6 Neonatal and Gamma Interferon-Deficient Mice: Role of Tumor Necrosis Factor Alpha in Protection

Abstract

ABSTRACT Both neonatal and C57BL/6 gamma interferon (IFN-γ) knockout (C57BL/6-GKO) mice are susceptible to Cryptosporidium parvum , but the course of infection is different. Neonatal mice are able to clear the parasite within 3 weeks, whereas C57BL/6-GKO mice, depending on age, die rapidly or remain chronically infected. The mechanism by which IFN-γ leads to a protective immunity is yet poorly understood. In order to investigate the effect of IFN-γ on other cytokines expressed in the intestinal mucosa during C. parvum infection, we studied cytokine mRNA expression in the neonates and GKO (neonatal and adult) mice by quantitative reverse transcription-PCR (RT-PCR) at 4 and 9 days after infection. IFN-γ mRNA levels were quickly and strongly up-regulated in the mucosa of neonatal mice. In GKO mice, the Th1-type response was dramatically altered during the infection, whereas the mRNA expression levels of the Th2-type cytokines interleukin 4 (IL-4) and IL-10 were increased in both mouse models. In the absence of IFN-γ, the adult knockout mice up-regulated the mRNA levels of inflammatory cytokines, such as IL-1β, IL-6, and granulocyte-macrophage colony-stimulating factor, in the mucosa, but not tumor necrosis factor alpha (TNF-α), whereas all these cytokines were up-regulated in the infected neonatal mice. Further experiments indicated that injections of TNF-α into GKO adult mice significantly reduced oocyst shedding. The results of the present study indicate that the resolution of infection is dependent on the expression of Th1-type cytokines in the mucosa of C57BL/6 mice and that TNF-α may participate in the control of parasite development.