The secreted virulence factors of pathogenic microorganisms and their role in manipulating host cells have been the subject of intense study. However, almost nothing is known regarding the manipulation of host protein localization by pathogens and how this alters innate immune function. The Isberg lab recently showed that YopT, a secreted Yersinia virulence factor that removes the prenylated tail of host Rho family GTPases, promotes relocalization of Raci from the cytoplasm to the nucleus. Raci is associated with control of a number of immune signaling pathways, including direct binding to the transcription factor STAT3. In this application, I hypothesize that the YopT-induced Raci nuclear accumulation shifts immune cells to a state having a lowered inflammatory response, allowing pathogenic Yersinia to establish a persistent bacterial infection. To test this hypothesis I will first determine the consequences of YopT- induced Raci nuclear localization on STAT3 localization, nuclear export, and phosporylation. I will then determine the effect of Raci nuclear localization on host immune cell function, including the transmission of signals through the lL-10 and lL-6 receptors and the induction of inflammatory immune responses upon infection with Yersinia pseudotuberculosis. Finally, I will examine the role this manipulation of host protein localization plays in Yersinia pseudotuberculosis pathogenesis. These experiments will provide detailed information on how a pathogen controls the balance between states of lower and higher virulence by forcing altered compartmentalization of a host protein. Relevance to public health: Bacterial infectious diseases continue to cause sickness and death around the world. The pathogenic Yersinia species, which include the species that caused the Black Plague and the gastro-intestinal pathogens Yersinia pseudotuberculosis and Yersinia enterocolitica, all share a common factor that they inject into their mammalian host. Better understanding of how this bacterial factor interacts with the mammalian immune system will lead to better treatment of infectious diseases as well as increased understanding of our immune system.
|Crimmins, Gregory T; Isberg, Ralph R (2012) Analyzing microbial disease at high resolution: following the fate of the bacterium during infection. Curr Opin Microbiol 15:23-7|