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

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.

Interplay Between NLRP3 Inflammasome and Autophagy

“…Live intracellular Mycobacterium tuberculosis infection induced NLRP3-dependent IL-1β secretion and pyroptosis in human monocytes and macrophages ( 57 , 58 ). M. tuberculosis was shown to damage host cell plasma membrane either during phagocytosis or following phagocytosis and phagosome rupture from cytosolic side.…”

“…M. tuberculosis was shown to damage host cell plasma membrane either during phagocytosis or following phagocytosis and phagosome rupture from cytosolic side. The damage caused by M. tuberculosis made plasma membrane permeable to both K + and Ca 2+ ions, which results in the NLRP3 inflammasome activation ( 58 ). M. tuberculosis was also shown to induce NLRP3-dependent pyroptosis in human monocytes which enables bacteria to spread immediately after cell death ( 58 ) However, a different study reported the NLRP3-dependent necrotic cell death that is independent of caspase-1 in primary human macrophages and THP-1 monocytes ( 59 ).…”

Cross talk between intracellular pathogens and cell death

“…Interestingly, once efferocytosis is blocked, cells undergo secondary necrosis, which promotes M. tuberculosis dissemination. Conversely, a recent publication showed that phagocytosis of trapped M. tuberculosis in pyroptotic cells triggers inflammasome activation and cell death in the new host cell that promote local spread of infection 118 . Neutrophilic efferocytosis of infected macrophages is also beneficial for the host upon Mycobacterium marinum infection in a zebrafish model, 119 but efferocytosis does not always need to involve professional phagocytes.…”

Pleural Fluid GSDMD is a Novel Biomarker for the Early Differential Diagnosis of Pleural Effusion

“…Similarly, through pyroptosis macrophage infected with Mtb can destroy the survival environment of Mtb, and eventually prevent Mtb replication [19,20]. Mtb activated the canonical NLRP3 in ammasome by inducing potassium e ux upon infection of monocytes and macrophages, followed by GSDMD-dependent pyroptosis [21]. NLRP3 and AIM2 are considered two crucial kinds of pattern recognition receptors (PRR) which can activate cell pyroptosis after recognizing pathogen-associated molecular patterns (PAMP) [22,23].…”