Subversion of macrophage autophagy and inflammatory pathways by Coxiella burnetii

Abstract

Abstract Coxiella burnetii is the causative agent of human Q fever, a debilitating flu like illness that can progress to chronic disease presenting as endocarditis. After inhalation, C. burnetii is phagocytosed by alveolar macrophages and generates a lysosome-like replication niche known as the parasitophorous vacuole (PV). A type IV secretion system (T4SS) is required for generation of the PV and is one of the pathogen’s few known virulence factors. We previously showed that C. burnetii actively recruits autophagosomes to the PV using the T4SS, but does not alter macroautophagy. Interestingly, the cargo receptor p62 localizes to the PV in a T4SS-dependent manner and co-localizes with LC3. p62 and LC3 interact to select cargo for autophagy-mediated degradation, resulting in p62 degradation and LC3 recycling. In C. burnetii-infected macrophages, p62 is not degraded when cells are starved. We hypothesized that stabilization of p62 was due to activation of the NRF2-KEAP1 pathway, a cytoprotective response to oxidative stress and xenobiotics. Indeed, the NRF2-KEAP1 pathway was activated during infection as evidenced by translocation of NRF2 to the nucleus. A downstream target of the NRF2-KEAP1 pathway is NF-kB, and the role of this inflammatory signaling cascade in C. burnetii pathogenesis is unclear. However, previous studies showed differences in inflammasome activation when macrophages were infected with avirulent or virulent C. burnetii isolates. Therefore, we assessed NF-kB activation in alveolar macrophages infected by avirulent or virulent C. burnetii. Collectively, our studies highlight important host cell signaling pathways exploited by C. burnetii and differences in the innate immune response to differing pathotypes.