Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-16143-6
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Funding
- Faculty of Medicine at NTNU
- Central Norway Regional Health Authority
- Research Council of Norway [245963/F5]
- Centre of Excellence grant [223255]
- FRIPRO project [287696]
- NTNU Enabling Technologies [81771297]
- National Institutes of Health (NIH) [R01 AI121354]
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Mycobacterium tuberculosis is a global health problem in part as a result of extensive cytotoxicity caused by the infection. Here, we show how M. tuberculosis causes caspase-1/NLRP3/gasdermin D-mediated pyroptosis of human monocytes and macrophages. A type VII secretion system (ESX-1) mediated, contact-induced plasma membrane damage response occurs during phagocytosis of bacteria. Alternatively, this can occur from the cytosolic side of the plasma membrane after phagosomal rupture in infected macrophages. This damage causes K+ efflux and activation of NLRP3-dependent IL-1 beta release and pyroptosis, facilitating the spread of bacteria to neighbouring cells. A dynamic interplay of pyroptosis with ESCRT-mediated plasma membrane repair also occurs. This dual plasma membrane damage seems to be a common mechanism for NLRP3 activators that function through lysosomal damage. Inflammasome activation is a response to bacterial infection but can cause damage and spread infection. Here, the authors use live single-cell imaging to show two mechanisms by which M. tuberculosis causes damage to human macrophage cell plasma membranes, resulting in activation of the NLRP3 inflammasome, pyroptosis and release of infectious particles.
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