This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The purpose of this project is to understanding mechanisms of host defense against acute Campylobacter jejuni intestinal infection, a major cause of human intestinal illness worldwide, with an annual prevalence of 1 to 2 million cases in the US. Although the acute stage of the infection is characterized by recruitment of polymorphonuclear neutrophils (PMNs) into the intestine, the interactions of PMNs with C. jejuni are incompletely understood. This is attributable to a lack of animal model that recapitulates acute C. jejuni intestinal infection and disease. Campylobacter jejuni produces a nuclease enzyme called cytolethal distending toxin (CDT) that may contribute to disease. We hypothesize that the CDT contributes to disease by mediating resistance to PMN bacterial killing. The proposed experiments will examine the interaction of C. jejuni with PMNs during acute intestinal infection of adult marmosets and also following inoculation of fetal marmoset intestinal xenografts implanted in immunodeficient mice. A related project will assess the relative contribution of serum antibody response of marmosets to C. jejuni and CDT in disease. These models of C. jejuni intestinal infection will provide tools necessary for hypothesis-driven analysis of a broadly conserved bacterial toxin in resistance against host defense during acute intestinal infection. Moreover, these models will form the basis for development of more effective preventative and therapeutic control strategies for intestinal bacterial pathogens of major clinical importance.
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