A limited number of properties separate bacterial pathogens from non-pathogenic species. One such property exhibited by many pathogens is the ability to enter and replicate within eukaryotic cells. Francisella tularensis (FT) is a Gram negative bacterial pathogen that invades and replicates within a myriad of host cell types including, but not limited to, macrophages, dendritic cells and alveolar epithelial cells. The focu of this project is to understand mechanisms by which pathogenic Francisella adapt to, and manipulate the host cell environment and the implications that these properties have on bacterial virulence. In the previous funding period we investigated the roles of specific proteins in FT intracellular growth. During these studies we found that a robust ATG5- independent autophagic response was mounted in FT Schu S4 infected cells and that the bacteria assimilated amino acids derived through autophagic degradation of host proteins. Autophagy is also an anti-microbial response against cytosolic pathogens. However, even chemically induced autophagy did nothing to control FT intracellular growth. Thus, FT Schu S4 simultaneously evades degradation via autophagy while scavenging nutrients that are produced by this process. In this continuing application we propose to determine the function of the pathogenicity island encoded protein PdpC in protecting FT from autophagy and to define the bacterial metabolic processes that make it possible for virulent FT strains to replicate within monocytes.
Francisella tularensis is a highly virulent bacterial pathogen that infects a wide range of animal species, including humans. One property that contributes to the extraordinary virulence of F. tularensis is its ability to invade and replicate within numerous host cell types. In this application we propose to examine the mechanisms by which F. tularensis inhibits and subverts host cell metabolic processes to create an environment that supports bacterial intracellular growth and immune suppression.
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