Host Immunity to Intestinal Amebiasis

Entamoeba histolytica infection remains a worldwide health problem that particularly affects people in the developing countries. A major unanswered question is why some individuals are resistant to this infection. We hypothesized that differential susceptibility was due to individual variation in the nature of host immunity to the parasite. By using a mouse model for amebic colitis, we defined a rapid and sustained upregulation of Th2 response that was associated with the persistent cecal infection. IL-4 blockade resulted in clearance of infection that correlated with a restored IFN- response. Vaccination with amebic Gal/GalNAc lectin or the recombinant subunit "LecA" elicited antigen-specific responses and protected mice from amebic colitis. Protection by vaccines was transferable by T cells but not antibodies; IFN- and IL-17 were both required for protection. The frequency of IFN-- or IFN-/IL-2/TNF-- producing CD4 T cells in blood correlated with LecA/alum-mediated protection. LecA formulated with different regimens elicited responses that differed greatly, suggesting the existence of multiple mechanisms for vaccine protection. The role of the innate immune system in protection was also explored, based on the hypothesis that association between malnutrition and susceptibility to amebiasis could be explained partly by the diminished function of leptin, an adipocytokine that links nutrition to immunity. Here we showed that leptin mediated resistance to amebic infection by preventing intestinal epithelial apoptosis. A genetic polymorphism (Q223R) in the leptin receptor affected susceptibility to amebiasis in both human and mice. Leptinmediated resistance was via its actions on intestinal epithelium rather than immune cells or hypothalamus. PI3K/Akt, STAT3 and SHP2/ERK pathways were important for leptinmediated protection. Contrary to its protective role in amebiasis, leptin signaling was pathogenic in Clostridium difficile-associated colitis, which is likely attributed to the differed pathogenesis of these two infections. III The overall conclusion is that differential susceptibility to amebiasis can be explained in part by genetic heterogeneity in the intestinal response initiated by leptin signaling, as well as by the character of the acquired cell-mediated immunity. These results provide insight into how host immune responses influence the infection outcome of amebiasis, and more broadly provide a mechanistic understanding of the immunodeficiency of malnutrition.

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