PT  - JOURNAL ARTICLE
AU  - Kai S. Beckwith
AU  - Marianne S. Beckwith
AU  - Sindre Ullmann
AU  - Ragnhild Sætra
AU  - Haelin Kim
AU  - Anne Marstad
AU  - Signe E. Åsberg
AU  - Trine A. Strand
AU  - Harald A. Stenmark
AU  - Trude H. Flo
TI  - Plasma membrane damage causes NLRP3 activation and pyroptosis during <em>Mycobacterium tuberculosis</em> infection
AID  - 10.1101/747014
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 747014
4099  - http://biorxiv.org/content/early/2019/08/28/747014.short
4100  - http://biorxiv.org/content/early/2019/08/28/747014.full
AB  - Mycobacterium tuberculosis (Mtb) is a major global health problem and causes extensive cytotoxicity in patient cells and tissues. Here we define an NLRP3, caspase-1 and gasdermin D-mediated pathway to pyroptosis in human monocytes following exposure to Mtb. We demonstrate an ESX-1 mediated, contact-induced plasma membrane (PM) damage response that occurs during phagocytosis or from the cytosolic side of the PM after phagosomal rupture in Mtb infected cells. This PM injury in turn causes K+ efflux and activation of NLRP3 dependent IL-1β release and pyroptosis, facilitating the spread of Mtb to neighbouring cells. Further we reveal a dynamic interplay of pyroptosis with ESCRT-mediated PM repair. Collectively, these findings reveal a novel mechanism for pyroptosis and spread of infection acting through dual PM disturbances both during and after phagocytosis. We also highlight dual PM damage as a common mechanism utilized by other NLRP3 activators that have previously been shown to act through lysosomal damage.