Coxiella burnetiiactively blocks IL-17-induced oxidative stress in macrophages
Abstract
Coxiella burnetiiis a highly infectious pathogen that causes Q fever, a leading cause of culture-negative endocarditis.Coxiellafirst targets alveolar macrophages and forms a phagolysosome-like compartment called the<underline>C</underline>oxiella-<underline>C</underline>ontaining<underline>V</underline>acuole (CCV). Successful host cell infection requires the Type 4B Secretion System (T4BSS), which translocates bacterial effector proteins across the CCV membrane into the host cytoplasm, where they manipulate numerous cell processes. Our prior transcriptional studies revealed thatCoxiellaT4BSS blocks IL-17 signaling in macrophages. Given that IL-17 is known to protect against pulmonary pathogens, we hypothesize thatC. burnetiiT4BSS downregulates intracellular IL-17 signaling to evade the host immune response and promote bacterial pathogenesis. Using a stable IL-17 promoter reporter cell line, we confirmed thatCoxiellaT4BSS blocks IL-17 transcription activation. Assessment of the phosphorylation state of NF-κB, MAPK, and JNK revealed thatCoxielladownregulates IL-17 activation of these proteins. Using ACT1 knockdown and IL-17RA or TRAF6 knockout cells, we next determined that IL17RA-ACT1-TRAF6 pathway is essential for the IL-17 bactericidal effect in macrophages. In addition, macrophages stimulated with IL-17 generate higher levels of reactive oxygen species, which is likely connected to the bactericidal effect of IL-17. However,C. burnetiiT4SS effector proteins block the IL-17-mediated oxidative stress, suggesting thatCoxiellablocks IL-17 signaling to avoid direct killing by the macrophages.
Importance
Bacterial pathogens are constantly evolving mechanisms to modulate the hostile host environment encountered during infection.Coxiella burnetii, the causative agent of Q fever, is a fascinating example of intracellular parasitism.Coxiellasurvives in a phagolysosome-like vacuole and uses the Dot/Icm type IVB secretion system (T4BSS) to deliver bacterial effector proteins into the host cell cytoplasm to manipulate several host cell functions. We recently demonstrated thatCoxiellaT4BSS blocks the IL-17 signaling in macrophages. Here, we found thatCoxiellaT4BSS inhibits IL-17 activation of the NF-κB and MAPK pathways and blocks IL-17-mediated oxidative stress. These findings reveal a novel strategy employed by intracellular bacteria to escape the immune response during initial stages of infection. Further identification of virulence factors involved in this mechanism will bring to light new therapeutic targets to prevent Q fever development into a chronic life-threatening endocarditis.
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