Mechanisms of Yersinia Pathogenesis

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MERGE PROJECT 8: Mechanisms of Yersinia Pathogenesis - Ruslan Medzhitov, Ph.D. Cell death following infection by pathogenic organisms can be a host response intended to protect the host and eliminate a niche for bacterial or viral replication, or it can be a process induced by pathogenic virulence factors for the purpose of promoting spread of the pathogen or the elimination of host immune cells. In either case, a particular pathogenic organism presumably has a 'set-point' for the extent of cell death that results from an interaction with a particular host. How this balance or set-point is achieved is a question that has not yet been addressed using established methods of loss-of-function mutations and screens for bacterial virulence factors. Understanding this balance is important for the treatment of pathologies resulting from either infectious agents or pathology induced by disregulation of host immune responses. Literature in the Yersinia field suggests that the three closely related Yersinia pathogenic species, Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica, have different degrees of cytotoxicity and pathology depending on the species, and that cytotoxicity and pathology even differ among serotypes of the Y. enterocolitica species. We initially examined this problem by comparing cytotoxicity of the highly virulent wild-type Y. enterocolitica with a wild-type Y. pseudotuberculosis strain. Our results indicate that the reduced cytotoxicity of Y. pseudotuberculosis depends on limiting the secretion of a particular virulence factor, and that this plays an important role in enhancing the virulence of this organism.