Coxiella burnetii deubiquitinates host TRAF6 to modulate the macrophage innate immune response

Coxiella burnetii is a highly infectious, aerosol-transmitted obligate intracellular bacterium that causes human Q fever and replicates within alveolar macrophages during pulmonary infection. Successful infection requires the C. burnetii Type IVB secretion system (T4BSS), which delivers bacterial effector proteins into the host cytoplasm to remodel host processes and suppress the innate immune response. In the lung, IL-17 promotes antibacterial immunity by activating ACT1-TRAF6-dependent pathways that drive inflammatory gene expression, reactive oxygen species production, and neutrophil recruitment. However, how intracellular pathogens subvert IL-17 signaling pathways to promote survival within macrophages remains poorly understood. Here, we show that C. burnetii evades IL-17-mediated host defense by targeting TRAF6, a central ubiquitin-dependent regulator of innate immune signaling. IL-17 signaling through ACT1-TRAF6 restricts C. burnetii viability in macrophages; however, C. burnetii impairs IL-17-induced NF-κB and MAPK activation, particularly JNK phosphorylation. C. burnetii T4BSS activity suppresses IL-17-driven reactive oxygen species production and neutrophil recruitment. We identify the C. burnetii T4BSS effector EmcB as a TRAF6-targeting deubiquitinase that disrupts IL-17-dependent antimicrobial and chemotactic responses. Together these findings reveal that C. burnetii downregulates intracellular innate immune signaling by targeting TRAF6, enabling evasion of the macrophage antimicrobial response and limiting neutrophil-mediated immunity.