Cell death pathways in response to Mycobacterium tuberculosis and other mycobacterial infections

Abstract

Cell death mechanisms play a fundamental role in mycobacterial pathogenesis. We critically reviewed 94 research manuscripts, 44 review articles, and 4 book chapters to analyze important discoveries, background literature, and potential shortcomings in the field. The focus of this review is the pathogen Mycobacterium tuberculosis (Mtb) and other Mtb and Mycobacterium avium complex microorganisms. Virulent strains hijack cell death processes by inhibiting autophagy, apoptosis, and pyroptosis while eliciting necrosis and ferroptosis to multiply intracellularly and spread within and between hosts. In addition, virulent strains may induce apoptosis in epithelial cells or secondary infected macrophages to spread. Autophagy does not control Mtb intracellular replication in vivo but suppresses macrophage and T cell responses in Mtb infections, with a predominant role in preventing neutrophil infiltration. In contrast, attenuated vaccine strains promote apoptosis in macrophages, leading to the activation of innate immunity and, eventually, the acquired immune response. Although Mtb infection activates necroptosis, studies with mutant cell lines have indicated that this process is not essential for cell lysis and that Mtb promotes unprogrammed necrosis. Ferroptosis is discussed in the context of necrotic processes involving lipid peroxidation. Recent research indicated that pyroptosis is more akin to apoptosis as Mtb proteins induce cell membrane repair to prevent inflammasome activation. In the supplementary tables, homologs of mycobacterial cell death pathways and virulence factors were identified using a basic local alignment search tool protein followed by a conserved domain database search to determine the presence of functional domains. Finally, prospects for therapeutic interventions are discussed.

Keywords: Mycobacterium; apoptosis; autophagy; cell death; ferroptosis; macrophages; necrosis; pyroptosis.

Fig 1

Inhibition of autophagy by Mtb in macrophages. The main Mtb and host components are displayed. The black pointed head arrows indicate activating processes while red blunt head arrows indicate inhibition. Generated by Biorender.com.

Fig 2

The host’s innate IR to Mtb infection triggers apoptosis and necroptosis. Apoptosis can occur via the extrinsic or intrinsic caspase-dependent and -independent pathways. Necroptosis is mediated by the phosphorylation of the MLKL protein. The black pointed head arrows indicate activating processes, while red blunt head arrows indicate inhibition. The green pointed head arrows show caspase-independent apoptotic pathways. Generated by Biorender.com.

Fig 3

Events leading to ferroptosis by oxidative damage of cell membrane fatty acids. The black pointed head arrows indicate activating processes, while red blunt head arrows indicate inhibition. Generated by Biorender.com.

Fig 4

Mtb infection leads to the activation of NLRP3 and NLRC4 inflammasomes causing pyroptosis, while the Mtb PtpB protein inhibits this process. The black (canonical pathway) or green (noncanonical pathway) pointed head arrows indicate activating processes, while red blunt head arrows indicate inhibition. Generated by Biorender.com.