Coxiella burnetiiactively blocks IL-17-induced oxidative stress in macrophages

Abstract

Coxiella burnetii is a highly infectious pathogen that causes Q fever, a leading cause of culture-negative endocarditis. Coxiella first targets alveolar macrophages and forms a phagolysosome-like compartment called the Coxiella-Containing Vacuole (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 that Coxiella T4BSS blocks IL-17 signaling in macrophages. Given that IL-17 is known to protect against pulmonary pathogens, we hypothesize that C. burnetii T4BSS 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 that Coxiella T4BSS blocks IL-17 transcription activation. Assessment of the phosphorylation state of NF-κB, MAPK, and JNK revealed that Coxiella downregulates 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. burnetii T4SS effector proteins block the IL-17-mediated oxidative stress, suggesting that Coxiella blocks IL-17 signaling to avoid direct killing by the macrophages.

Type 4 secretion system in Clostridioides difficile: Structural features and its role as a pathogenicity factor

“…Так, у Helicobacter pylori эффекторные молекулы СС4Т-А запускают провоспалительный ответ в эпителиальных клетках желудка [41] и обусловливают неконтролируемое деление клеток хозяина [42]. В отличие от СС4Т-А A. tumefaciens, секреторные системы В-типа доставляют в эукариотические клетки-мишени преимущественно белковые эффекторы [43] и определяют патогенез таких заболеваний, как болезнь легионеров [26] и лихорадка Ку [44,45]. Среди СС4Т-B грамотрицательных бактерий наиболее изученным является секреторный аппарат Dot/Icm у L. pneumophila -внутриклеточного патогена и возбудителя легионеллёза.…”