YopM and protective innate defenses against plague

University Of Kentucky, Lexington KY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of plague and a significant concern to public health and safety due to its potential abuse as a bioterrorist weapon. This proposal focuses on how the plague virulence protein YopM undermines host innate defenses early in plague. The studies of Aim 1 will establish a sequence and hierarchy for the roles of macrophages, dendritic cells, PMNs, natural killer cells, and CD8+ T cells in the innate host response to plague and determine how this response is modulated by YopM. Mice will be depleted of specific immune cell populations, infected with Y. pestis KIMS or a YopM- mutant, and assessed for their cellular, histopathological, and cytokine gene and protein expression as well as bacterial numbers in organs during the initial days of systemic plague. The experiments of Aim 2 will map the cytokine circuitry in the presence and absence of YopM by ablating and reconstituting mice for key cytokines of three major antimicrobial pathways and analyzing the outcome of infection by parent and YopM- mutant Y. pestis as in Aim 1. The studies of Aim 3 build upon the discovery of a plague-resistant inbred mouse strain that appears to by-pass the effects of YopM. The proposed studies will map the genes responsible for resistance by determining dominance and then conducting backcross and SSLP marker linkage analysis. In parallel, the host responses that are altered in these mice will be analyzed by using the methods of Aims 1 and 2 to aid in identification of the responsible resistance gene(s) in these mice as well as to reveal how innate defenses can be altered to confer resistance to plague. The proposed studies will determine how YopM modulates the innate immune response to Y. pestis and, in the process, develop a systematic characterization of the innate immune response to plague. The project will enrich our understanding of both basic immunology and the pathogenesis of plague as well as provide the foundation for therapies to enhance resistance to plague in humans. [unreadable] [unreadable]