Chlamydia Type III Effectors Affecting the Host Actin-based Cytoskeleton

Grant title: Type III secretion-mediated manipulation of branched actin by intracellular Chlamydia Abstract: Chlamydia trachomatis is a significant concern for human health world-wide due to its prevalence and the combined health and socioeconomic impact of acute and chronic disease. Chlamydiae are obligate intracellular pathogens that possess the ability to modulate host-cell biology while sequestered within a membrane-bound parasitophorous vacuole. Accumulating evidence indicates that a type III secretion system (T3SS) represents a significant mechanism employed by chlamydiae to manipulate these critical host cell functions. The host actin cytoskeleton and vesicular transport machinery represent major targets for Chlamydia-mediated alterations. We have identified a novel pathway by which intracellular chlamydiae redirect host cell vesicular trafficking. This mechanism requires the branched actin network and at least two type III secretion effectors designated TmeA and TmeB. We propose to address the hypothesis that these effectors differentially modulate branched actin networks to accomplish trafficking of host-cell resources to the mature inclusion by imposing an axis of host Arp2/3 activation. We propose to elucidate molecular details by which the combined activities of C. trachomatis TmeA and TmeB affect host cells to promote intracellular development and evasion of cell-intrinsic host defenses. Corresponding C. muridarum mutant strains will be employed to elucidate the contributions of these effectors to pathogenesis in an animal model. A balanced combination of genetic, biochemical, cell-biology, and animal-based studies are proposed that will define the overall role of these effectors in establishing and maintaining infectivity that culminates in Chlamydia-mediated disease. Completion of this work will lead to an enhanced understanding of the molecular mechanisms employed by Chlamydia to impact host-pathogen interactions igoverning disease.