Cryptosporidium parvum-specific mucosal immune response in C57BL/6 neonatal and gamma interferon-deficient mice: Role of tumor necrosis factor alpha in protection

Both neonatal and C57BL/6 gamma interferon (IFN-gamma) knockout (C57BL/6-GK O) mice are susceptible to Cryptosporidium parvum, but the course of infect ion is different, Neonatal mice are able to clear the parasite within 3 wee ks, whereas C57BL/6-GKO mice, depending on age, die rapidly or remain chron ically infected. The mechanism by which IFN-gamma leads to a protective imm unity is yet poorly understood, In order to investigate the effect of IFN-g amma on other cytokines expressed in the intestinal mucosa during C. parvum infection, we studied cytokine mRNA expression in the neonates and GKO (ne onatal and adult) mice by quantitative reverse transcription-PCR (RT-PCR) a t 4 and 9 days after infection, IFN-gamma mRNA levels were quickly and stro ngly up-regulated in the mucose of neonatal mice. In GKO mice, the Th1-type response was dramatically altered during the infection, whereas the mRNA e xpression levels of the Th2-type cytokines interleukin 4 (IL-4) and IL-10 w ere increased in both mouse models. In the absence of IFN-gamma, the adult knockout mice up-regulated the mRNA levels of inflammatory cytokines, such as IL-1 beta, IL-6, and granulocyte-macrophage colony-stimulating factor, i n the mucosa, but not tumor necrosis factor alpha (TNF-alpha), whereas all these cytokines were upregulated in the infected neonatal mice. Further exp eriments indicated that injections of TNF-alpha into GKO adult mice signifi cantly reduced oocyst shedding. The results of the present study indicate t hat the resolution of infection is dependent on the expression of Th1-type cytokines in the mucosa of C57BL/6 mice and that TNF-alpha may participate in the control of parasite development.