The major focus of research in my laboratory is centered on bacterial pathogenesis of Yersinia enterocolitica and Y. pestis, etiologic agents of yersiniosis and bubonic plague respectively. The hallmark of these infectious agents is their ability to suppress the innate immune response of mammalian hosts. This is accomplished actively by injecting protein anti-host factors directly into white blood cells to circumvent cytokine induction, and passively by repressing or modifying bacterial surface components recognized by toll-like receptors (TLRs). Deacylation of lipidA reduces activation of TLR-4. Transcriptional arrest (Y. enterocolitica) or permanent mutational silencing of flagellin (Y. pestis) circumvents activation of host cell TLR-5. Flagellin, the major filament protein of the bacterial flagellin is exported to the cell surface via a type III protein secretion system (TTSS), the same type of export mechanism used to deliver virulence proteins to macrophages. We have shown that flagellin, if artificially expressed under host conditions, is actively secreted by virulence TTSS, so repression of this protein may be essential in evasion of innate immunity. We are actively testing this hypothesis. We have also shown that exposure of immunologically naïve mice to synthetic lipid A compounds that induce TLR-4 mediated cytokine responses, are protective when mice are challenged with lethal doses of Y. pestis. Furthermore, these lipid A mimetics have powerful adjuvant properties and their use with two Y. pestis protective antigens has a powerful potential as a protective vaccine. Our goal is to adapt these observations for novel protective measures and vaccine strategies.
