Rickettsia-host interface and multiple paths to invasion

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PROJECT SUMMARY Species in the genus Rickettsia are Gram-negative obligate intracellular bacteria with both symbiotic and pathogenic lifecycles. The global impact of rickettsial infections is illustrated by the resurgence of infections of humans with R. rickettsia (etiologic agent of Rocky Mountain Spotted Fever) in South and Central America, or R. conorii (Boutonneuse fever) in Europe, the Middle East, and Africa. Strikingly, tick- and flea-borne rickettsial diseases are also on the rise in the United States, as exemplified by recent outbreaks of R. rickettsii in Arizona and R. typhi (etiologic agent of murine typhus) in California and Texas, further highlighting the threats of rickettsial diseases. There are currently no vaccines to prevent rickettsioses and our insufficient understanding of rickettsial intracellular lifestyle hinders the progression towards the development of effective therapeutics against these increasingly recognized bacterial pathogens. Over the past four years, we identified a complex mechanism by which pathogenic rickettsiae utilize secreted effectors to facilitate colonization by manipulating ER structures or by modulating intracellular trafficking to subvert host defense pathways. However, the precise mechanisms by which virulent Rickettsia species utilize this effector arsenal to subvert host innate defense pathways to support intracellular lifestyle in endothelial cells or macrophages (MΦ) remains ill-defined. To address these knowledge gaps, this renewal application proposes to: i) decipher how virulent Rickettsia species utilize their effector repertoire to manipulate autophagic responses to colonize host cells, and ii) determine the mechanism(s) by which effectors of virulent, but not avirulent, Rickettsia species suppress inflammasome activation and manipulate MΦ polarization to promote host dissemination. Our overall goal is to test the hypothesis that effectors from virulent species of Rickettsia, like Risk1, induce autophagy to negatively regulate inflammasome activation and skews MΦ polarization from a M1 to M2 bias to facilitate host colonization. To test our hypothesis, in Aim 1, we will define the mechanism(s) by which pathogenic Rickettsia subvert autophagosomal maturation to promote host colonization. In Aim 2, we will decipher the mechanism(s) underlying subversion of inflammasome responses and manipulation of MΦ polarization by pathogenic Rickettsia species. These Aims are intended to unveil a link by which effectors of pathogenic Rickettsia species manipulate autophagy to subvert inflammasome-dependent proinflammatory cytokine signaling and skew MΦ polarization from a microbicidal milieu (M1-MΦ) to a more favorable pro- microbial environment (M2-MΦ). These studies will lead to the identification of a link that could be exploited for anti-virulence strategy.