Coxiella burnetii is an obligate intracellular bacterium and the etiological agent of Q fever. During natural infection Coxiella targets alveolar macrophages, where the bacterium promotes formation of a phagolysosome-like vacuole called the Coxiella Containing Vacuole (CCV). Successful host cell infection requires the Type IVB Secretion System (T4BSS), which translocates bacterial effector proteins across the CCV membrane and into the host cytoplasm, where they manipulate a variety of cell processes. We recently demonstrated that the Coxiella T4BSS downregulates expression of IL-17 target genes as well as IL-17-stimulated chemokine secretion. IL-17 is a pro-inflammatory cytokine that has a key role in the innate immune response against pulmonary pathogens. Upon IL-17 binding, the macrophage surface IL-17 receptor activates several intracellular signaling pathways through the E3-ubiquitin ligase ACT1. ACT1 ubiquitinates TRAF6, triggering transcriptional activation of IL-17 target genes. The proposed experiments will test our hypothesis that Coxiella T4BSS effector proteins downregulate intracellular IL-17 signaling pathway(s) in order to evade the host innate immune response and promote bacterial pathogenesis.
Aim 1 will determine the host and bacterial proteins involved in downregulation of intracellular ACT1-TRAF6 signaling pathways triggered by IL-17.
Aim 2 will elucidate the role of IL-17 signaling in chemokine secretion and neutrophil recruitment to Coxiella-infected macrophages. Completion of these studies will not only reveal a specific host innate immune response used against C. burnetii, but also a novel strategy employed by pathogens to escape the immune response during the initial stages of infection.
Coxiella burnetii is an obligate intracellular pathogen that causes human Q fever. We propose to elucidate Coxiella?s strategies to evade the host immune response during the initial stages of infection. Completion of this study will greatly advance our understanding on host cell intracellular pathway(s) targeted by Coxiella, which could reveal potential therapeutic targets for Q fever treatment.