Abstract
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-1β 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.
Highlights
Mycobacterium tuberculosis is a global health problem in part as a result of extensive cytotoxicity caused by the infection
Despite loss of lysosomal pH and Gal-3 recruitment indicating lysosomal damage after blue-light excitation in the presence of TPCS2a, we did not observe Apoptosis-Linked Gene 2 (ALG-2) events at the plasma membrane (PM) or ASC-speck formation. These data show that PM damage is a central event upstream of NLRP3 inflammasome activation by Mycobacterium tuberculosis (Mtb) and silica, and that lysosomal damage itself is not sufficient to activate NLRP3. Both absent in myeloma 2 (AIM2) and NLRP3 have been implicated in IL-1β release during Mtb infection of macrophages[14,15,16,39], while the occurrence of pyroptosis as a distinct route of cell death has been less clear[15,48,49,80]
We establish that ESX-1-mediated PM damage causes K+ efflux, NLRP3 activation and subsequent caspase-1mediated IL-1β release in THP-1 cells and human primary monocytes and macrophages
Summary
Mycobacterium tuberculosis is a global health problem in part as a result of extensive cytotoxicity caused by the infection. A type VII secretion system (ESX-1) mediated, contact-induced plasma membrane damage response occurs during phagocytosis of bacteria. 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-1β release and pyroptosis, facilitating the spread of bacteria to neighbouring cells. Our findings identify a common mechanism where plasma membrane (PM) damage caused by Mtb or crystals triggers inflammasome activation, IL-1β release and pyroptosis, unless the membrane damage is balanced by repair mediated by the endosomal sorting complexes required for transport (ESCRT) machinery[45]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
