Gasdermin D mediates host cell death but not interleukin-1\u03b2 secretion in Mycobacterium tuberculosis-infected macrophages

Sebastian J Theobald,Jessica Gräb,Isabelle Suárez,Hannah S Eisfeld,Hamid Kashkar,Manolis Pasparakis,Sandra Winter,Jan Rybniker,Maximilian Koch,Christoph Hölscher,Melanie Fritsch

doi:10.1038/s41420-021-00716-5

Abstract

Necrotic cell death represents a major pathogenic mechanism of Mycobacterium tuberculosis (Mtb) infection. It is increasingly evident that Mtb induces several types of regulated necrosis but how these are interconnected and linked to the release of pro-inflammatory cytokines remains unknown. Exploiting a clinical cohort of tuberculosis patients, we show here that the number and size of necrotic lesions correlates with IL-1β plasma levels as a strong indicator of inflammasome activation. Our mechanistic studies reveal that Mtb triggers mitochondrial permeability transition (mPT) and subsequently extensive macrophage necrosis, which requires activation of the NLRP3 inflammasome. NLRP3-driven mitochondrial damage is dependent on proteolytic activation of the pore-forming effector protein gasdermin D (GSDMD), which links two distinct cell death machineries. Intriguingly, GSDMD, but not the membranolytic mycobacterial ESX-1 secretion system, is dispensable for IL-1β secretion from Mtb-infected macrophages. Thus, our study dissects a novel mechanism of pathogen-induced regulated necrosis by identifying mitochondria as central regulatory hubs capable of delineating cytokine secretion and lytic cell death.

Highlights

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) is a leading cause of morbidity and mortality
Mtb induces necrotic cell death by manipulation of the mitochondrial permeability transition pore (mPTP) representing an important gatekeeper of pore opening [29]
We detected 62 proteins that were the preservation of tetramethyl rhodamine methyl ester (TMRM) in infected cells (Fig. 2a, b). altered in response to the infection, which are associated with Bcl-2 overexpression significantly increased host cell host cell death and mitochondrial damage

Summary

Introduction

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) is a leading cause of morbidity and mortality. Mtb is highly dependent on the human as a host and has developed different immune modulation and evasion mechanisms to survive [1]. A major mechanism of pathogenesis in Mtb is the induction of necrotic host cell death, which leads to bacterial spread, hyperinflammation, and tissue damage [2]. In the past decade various regulated forms of necrosis have been identified, such as necroptosis, ferroptosis, and pyroptosis [4]. Several of these cell death pathways have been independently associated with Mtb infection [5,6,7,8,9,10,11,12,13]

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