Abstract
Autophagy can either antagonize or promote intracellular bacterial growth, depending on the pathogen. Here, we investigated the role of autophagy during a pulmonary infection with the obligate intracellular pathogen, Chlamydia pneumoniae (CP). In mouse embryonic fibroblasts (MEFs) or macrophages, deficiency of autophagy pathway components led to enhanced CP replication, suggesting that autophagy exerts a bactericidal role. However, in vivo, mice with myeloid-specific deletion of the autophagic protein ATG16L1 suffered increased mortality during CP infection, neutrophilia, and increased inflammasome activation despite no change in bacterial burden. Induction of autophagy led to reduced CP replication in vitro, but impaired survival in CP-infected mice, associated with an initial reduction in IL-1β production, followed by enhanced neutrophil recruitment, defective CP clearance, and later inflammasome activation and IL-1β production, which drove the resulting mortality. Taken together, our data suggest that a delicate interplay exists between autophagy and inflammasome activation in determining the outcome of CP infection, perturbation of which can result in inflammatory pathology or unrestricted bacterial growth.
Highlights
Autophagy, the process by which cellular material is recycled [1], has been increasingly found to play a central role in diverse diseases and pathologies [2]
This discrepancy between Atg16l1+/− mouse embryonic fibroblasts (MEFs) and Atg5−/− MEFs was surprising as both ATG16L1 and ATG5 participate in the same autophagic complex, along with ATG12
While it was clear that autophagic machinery played a role in Chlamydia pneumoniae (CP) growth in both MEFs and macrophages, the effect of loss of pathway components differed between cell types
Summary
The process by which cellular material is recycled [1], has been increasingly found to play a central role in diverse diseases and pathologies [2]. Loss of autophagic function can lead to enhanced inflammation via greater NLRP3 inflammasome activation and secretion of IL-1β Release of this pro-inflammatory cytokine is tightly regulated, because IL-1β is critical in controlling many microbial infections, over production can lead to enhanced pathology and chronic inflammation [9, 10]. In addition to regulating cytokine production, autophagy can play a direct role in microbial clearance in a process known as xenophagy [11] This is important for intracellular bacteria such as Salmonella typhimurium, group A Streptococcus, and Mycobacterium tuberculosis. In these cases, the autophagic phagophore forms around the invading bacteria, and the resulting autophagosome is targeted for fusion with the lysosome [12,13,14]. Some bacterial agents can co-opt components of the autophagosomal machinery in order to survive and replicate [20, 21]
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