Pathogenic Effector Protein Modulation of Host Innate Immune Signaling

Intestinal enterocolitis caused by food borne pathogens is a substantial health burden in the United States and internationally. Certain disease causing pathogens establish themselves within the host cells because they have evolved sophisticated mechanisms to evade host innate immunity. For example, pathogens secrete preformed effector proteins that influence innate immune and apoptotic signaling pathways thus inhibiting cytokine production, neutrophil recruitment, and/or activation of apoptosis. <P> One group of bacterial effector proteins which usurp innate immune signaling is the AvrA-like family. These soluble proteins have potent inhibitory effects on the activation of the MARK and NF-kB signaling pathways, thereby modulating host inflammatory and apoptotic responses. This biochemical family is represented in multiple enteric pathogens including Salmonella, Yersinia, Vibrio and Aeromonas. <P>We propose to<BR> 1) characterize the inhibitory profile of each AvrA-like protein using the Drosophila, a powerful genetic model which has functionally conserved innate immune and apoptotic pathways with mammals. We hypothesize that targeted blockade of distinct components of innate immune and apoptotic signaling controls differential effects on inflammatory or apoptotic outcomes in the whole organism. <P>2) We also propose to model the effects of AvrA-like proteins by their direct expression in the Drosophila gut epithelium, and in Drosophila hemocytes (which are analogous to human phagocytes) during pathogenic infection. We hypothesize that AvrA-like protein mediated inhibition of innate immune pathways localized to barrier epithelia or phagocytes facilitates pathogenic processes and untimely mediates the pathogenic outcome of infection by bacteria that secrete the particular AvrA-like protein. <P> 3) Finally, we propose to use phenotypes resulting from the expression of AvrA-like proteins in Drosophila in a forward genetic screen for the discovery of novel innate immune and apoptotic regulatory genes. Together, these studies will further advance the understanding of the evasion strategies developed by enteric pathogens to escape the host immune response, and will contribute to our understanding of many intestinal inflammatory disorders.