Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection

Abstract

<jats:title>Abstract</jats:title><jats:p><jats:italic>Mycobacterium tuberculosis</jats:italic> (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.</jats:p><jats:sec><jats:title>Graphical abstract</jats:title><jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="747014v1_ufig1" position="float" orientation="portrait" /></jats:fig></jats:sec>

Frontline Science: Antibiotic treatment routes Mycobacterium avium to phagolysosomes without triggering proinflammatory cytokine production in human Mϕs

“…20,30 We therefore investigated if Mav or MavCs are phagosomal rupture and plasma membrane damage. 29 As expected, Galectin-3 recruitment and ubiquitination was associated with auxo-TB-BFP 24 h post infection (Fig. 3C and D).…”

“…We and others have shown that Mtb is able to destabilize the phagosomal membrane and establish contact with the cytosol. [26][27][28][29] However, no such ability has been shown for Mav, likely because Mav lacks the type VII secretion system ESX-1 thought to mediate the membrane perturbations by Mtb. 26 Galectins are cytosolic proteins that bind to galactosides on the luminal side of endomembranes.…”

Mycobacterium tuberculosis-macrophage interaction: Molecular updates

“…Still elusive, these mechanisms may need more study. Mtb-induced excessive pyroptosis also aids in the spread of Mtb (Beckwith et al, 2020;Fu et al, 2021;Li et al, 2022). This process relies on the NLRP3/ caspase-1/ GSDMD axis connected with the potassium efflux, but also strongly on the ERS induction linked with TXNIP downstream upregulation and the PERK/eIF2/CHOP axis (Gong et al, 2019;FIGURE 2 Manipulation of macrophage intracellular processes by Mtb.…”

“…Section 5 provides more details. Beckwith et al, 2020;Li et al, 2022). Inhibiting pyroptosis in Mtbinfected macrophages through the PERK/eIF2/TXNIP/NLRP3/ caspase-1/GSDMD axis reduces lung tissue damage and Mtb dissemination (Fu et al, 2021;Li et al, 2022).…”

Necrosis drives susceptibility toMycobacterium tuberculosisin POLG mtDNA mutator mice

“…Several studies have mechanistically shown how distinct flavors of necrosis (e.g. inflammasome-mediated pyroptosis, RIPK-dependent necroptosis, ferroptosis) promote Mtb pathogenesis (17)(18)(19)(20)(21). We and others have begun to link cell death during Mtb infection with disruptions in mitochondrial homeostasis (14,(22)(23).…”