Yersinia pestis OmpX virulence factor and role in host cell attachment, internalization, and immune modulation /by Anna Maria Kolodziejek.


Yersinia pestis is the causative agent of plague. Multiple virulence determinants contribute to its highly efficient transmission and pathogenicity. These include factors inherited from its enteric predecessors; Y. entrocolitica and Y. pseudotuberculosis, as well as phenotypes that were acquired or lost during Y. pestis evolution. Representatives of a large Enterobacteriaceae Ail/Lom family of outer membrane proteins (Omp) are found in the genomes of all pathogenic Yersiniae . They promote adherence and internalization to epithelial cells, resistance to complement, and survival in macrophages. Even though well studied in enteric Yersiniae, their role in Y. pestis pathogenesis is unknown. To investigate the role of Y. pestis OmpX protein, an Ail homologue, in adherence and internalization to epithelial cells, resistance to complement, and virulence, we generated site-directed mutations in ompX and tested them for loss of any of these phenotypes. Our results demonstrated that OmpX was required for adherence and internalization to epithelial cells, and serum resistance. Infection studies revealed that loss of OmpX delayed the time-to-death in the mouse infection model of pneumonic plague. Because murine serum was not bactericidal for the ompX mutant, the mechanism underlying the delay in time-to-death in mice may be attributed to loss of adhesion/internalization properties, but not serum resistance. When OmpX virulence was assessed in the rat model complete attenuation of virulence was observed. This highlighted the critical role of serum resistance in primary pneumonic plague and showed its relevance for human disease. To resolve conflicting evidence for Y. pestis LPS and OmpX contributions to serum resistance, we expressed the protein in E. coli and its isogenic derivatives with progressively truncated LPS core saccharides. Our results showed that OmpX-mediated serum resistance, adhesiveness, and invasiveness were dependent on LPS core length, but recombinant OmpX displayed these functions in E. coli, independently of other Yersinia proteins and/or LPS. Also, our results showed that OmpX-mediated autoaggregation was required for efficient adhesiveness and internalization but not for serum resistance. Overall, our data present an important contribution to understanding mechanisms of Y. pestis pathogenesis and their significance to human species.Thesis (Ph. D., Microbiology, Molecular Biology and Biochemistry)--University of Idaho, July 2010

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