Cytosolic serpins act in a cytoprotective feedback loop that limits ESX-1-dependent death of Mycobacterium marinum -infected macrophages

• Published in: mBio 2024-09, Vol.15 (9), p.e0038424
• Main Authors: Nobs, Esther, Laschanzky, Katie, Munke, Kristina, Movert, Elin, Valfridsson, Christine, Carlsson, Fredric
• Format: Article
• Language: English
• Subjects: Animals; bacterial pathogenesis; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Basic Medicine; Cell Death; Cytosol - metabolism; Cytosol - microbiology; cytosolic surveillance pathways; Feedback, Physiological; Female; host cell death; Host-Pathogen Interactions; Humans; Interferon Type I - metabolism; Macrophages - microbiology; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; membrane permeabilization; Mice; Mice, Inbred C57BL; Microbial Pathogenesis; Microbiology in the medical area; Mikrobiologi inom det medicinska området; Mycobacterium Infections, Nontuberculous - microbiology; Mycobacterium marinum - genetics; Mycobacterium marinum - metabolism; Mycobacterium marinum - pathogenicity; Research Article; Serpins - genetics; Serpins - metabolism; Signal Transduction; type VII secretion system; Type VII Secretion Systems - genetics; Type VII Secretion Systems - metabolism
• ISSN: 2150-7511; 2161-2129; 2150-7511
• DOI: 10.1128/mbio.00384-24

Serine protease inhibitors (serpins) constitute the largest family of protease inhibitors expressed in humans, but their role in infection remains largely unexplored. In infected macrophages, the mycobacterial ESX-1 type VII secretion system permeabilizes internal host membranes and causes leakage into the cytosol of host DNA, which induces type I interferon (IFN) production via the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) surveillance pathway, and promotes infection . Using the infection model, we show that ESX-1-mediated type I IFN signaling in macrophages selectively induces the expression of and , two cytosolic serpins of the clade A3. The membranolytic activity of ESX-1 also caused leakage of cathepsin B into the cytosol where it promoted cell death, suggesting that the induction of type I IFN comes at the cost of lysosomal rupture and toxicity. However, the production of cytosolic serpins suppressed the protease activity of cathepsin B in this compartment and thus limited cell death, a function that was associated with increased bacterial growth in infected mice. These results suggest that cytosolic serpins act in a type I IFN-dependent cytoprotective feedback loop to counteract the inevitable toxic effect of ESX-1-mediated host membrane rupture. The ESX-1 type VII secretion system is a key virulence determinant of pathogenic mycobacteria. The ability to permeabilize host cell membranes is critical for several ESX-1-dependent virulence traits, including phagosomal escape and induction of the type I interferon (IFN) response. We find that it comes at the cost of lysosomal leakage and subsequent host cell death. However, our results suggest that ESX-1-mediated type I IFN signaling selectively upregulates and and that these cytosolic serpins limit cell death caused by cathepsin B that has leaked into the cytosol, a function that is associated with increased bacterial growth . The ability to rupture host membranes is widespread among bacterial pathogens, and it will be of interest to evaluate the role of cytosolic serpins and this type I IFN-dependent cytoprotective feedback loop in the context of human infection.