The role of gut bacteria in immunological responses to C. parvum infection in mice has not been investigated directly, but studies suggest that bacteria are not so important in establishing the inflammatory response. Following infection of gnotobiotic Cobimetinib order and conventionally reared lambs no differences between the groups in intestinal pathology or clinical signs were observed [68]. With piglets, intestinal inflammation and patent infection lasted longer in gnotobiotic animals than in control animals, suggesting the presence of intestinal bacteria provided a partial barrier to infection and also reduced immunopathology [69]. As Cryptosporidium

is a minimally invasive parasite and infects only epithelial cells whereas T. gondii infects most nucleated cell types, the role of bacteria in the immune response might be expected to differ. The induction of IL-12 expression by murine dendritic cells by T. gondii antigen in the absence of intestinal bacteria has been shown to be dependent largely on TLR11 recognition of the parasite protein profilin

[67]. A recent report described production of exceptionally high levels of IL-12 by cultured mouse spleens after addition of C. parvum profilin but the cell types producing IL-12 and TLR involvement in activation were not identified [70]. However, it has been reported recently that human dendritic IDO inhibitor cells that do not have functional TLR11 produced significant amounts of IL-12 when exposed to C. parvum sporozoite antigen [45]. Results of murine investigations have confirmed a protective role for TLRs against C. parvum infection. Juvenile MyD88−/− mice had heavier infection burdens than control mice [71] while, compared with control animals, TLR4−/− mice took longer to clear infection Florfenicol from the intestine and bile ducts and had an altered and

enhanced hepatic inflammatory response [72]. Weaned malnourished mice had increased susceptibility to infection compared with control animals that correlated with depleted intestinal expression of TLR2 and TLR4, but not TLR9 [73]. In a study with neonatal mice, administration of the TLR9 ligand CpG reduced the parasite load at the peak of infection by up to 95% and these mice had significantly increased expression of IFN-γ and IL-12 compared with controls [74]. In similar experiments with adult malnourished mice, only a modest reduction in the parasite load was obtained after CpG treatment [66]. The variation between degrees of resistance to infection induced by CpG in these two studies could be related to the different infection models employed or might imply that controlling infection by TLR9 stimulation is more readily achieved in the neonatal mouse. Figure 2 summarizes some of the major points regarding innate immune responses during C. parvum infection, combining in vitro and in vivo observations (predominantly with mice).