Necroptosis in bacterial infections

Abstract

Necroptosis, a recently discovered form of cell-programmed death that is distinct from apoptosis, has been confirmed to play a significant role in the pathogenesis of bacterial infections in various animal models. Necroptosis is advantageous to the host, but in some cases, it can be detrimental. To understand the impact of necroptosis on the pathogenesis of bacterial infections, we described the roles and molecular mechanisms of necroptosis caused by different bacterial infections in this review.

Keywords: bacterial infection; inflammatory cells; mlkl; necroptosis; ripk1; ripk3.

Figure 1

The classical mechanism of necroptosis. After TNF binds to its receptor, it can recruit RIPK1 and TRADD to form a complex. Subsequently, RIPK1 and TRADD dissociate from the TNF receptor and recruit LUBAC, TRAF2, and cIAPs to form complex I. At this stage, RIPK1 undergoes ubiquitination by LUBAC and cIAPs, which stabilizes the complex. When cIAPs are inhibited or when the ubiquitin chains on RIPK1 are removed using CYLD, a complex called complex IIa/b, consisting of TRADD, RIPK1, and FADD, is formed. Complex IIa/b activates caspase-8, which then induces cell apoptosis. When caspase-8 activity is blocked, cell apoptosis is inhibited. Subsequently, RIPK1 recruits RIPK3 through interactions between their RHIM domains. RIPK3 then recruits MLKL, forming necrosomes. MLKL is phosphorylated, and phosphorylated MLKL molecules aggregate and translocate to the plasma membrane, thereby triggering necroptosis. (Created with BioRender.com).

Figure 2

Mechanisms of bacterial induction of necroptosis. (A) Toxic virulence factors secreted by Staphylococcus aureus, such as Hla, PAM, PVL, and LukAB, can induce necroptosis in macrophages through the RIPK1-RIPK3-MLKL pathway. Among them, PSMα can induce TNFα secretion, leading to MLKL-dependent necroptosis in neutrophils. In addition, the virulence factor PFT can induce necroptosis in macrophages. The S. aureus-secreted SSL-10 binds to TNFR on the cell membrane to induce RIPK3-dependent necroptosis in HEK293T cell and HUVECs. S. aureus can induce necroptosis in gEECs, and the trigger is Ca²⁺ influx. (B) Mycobacterium tuberculosis triggers SIRPα in macrophages, leading to the inhibition of autophagy and the promotion of necroptosis. Additionally, M. tuberculosis can downregulate the expression of FAK in macrophages to evade host immunity. M. tuberculosis also shapes an environment that promotes necroptosis in macrophages by upregulating MLKL, TNFR1, ZBP1 expression and downregulating cIAP1 expression. (C) Following invasion of the heart by the TIGR4 strain of Streptococcus pneumoniae, the secretion of Ply can induce necroptosis in both cardiac myocytes and recruited macrophages. During the asymptomatic colonization of S. pneumoniae in the nasopharynx, Ply can induce necroptosis in nasopharyngeal epithelial cells (nECs). In the case of coinfection with influenza A virus and S. pneumoniae, the surface protein A (PspA) of S. pneumoniae acts as a cell adhesin and binds to GAPDH in dying cells, thereby increasing the localization of S. pneumoniae in the lower airways and exacerbating secondary infection following influenza. (D) The pSLT-encoded SpvB effector factor inhibits K-48-mediated ubiquitination of RIPK3, thereby mediating the formation of cell membrane pores through the RIPK3-MLKL pathway, resulting in necroptosis of intestinal epithelial cells (IECs). The effector factor SopF of the T3SS can induce necroptosis of IECs by blocking the activity of caspase-8, thereby enabling Salmonella enterica to spread to the intestinal lamina propria. SopB, encoded by SPI-1, can prevent the necroptosis of goblet cells, LS174T cells, and epithelial cells. S. typhimurium utilizes the host’s IFN-I response to induce necroptosis in macrophages mediated by RIPK1-RIPK3. Additionally, S. typhimurium induces the expression of miR-155, which promotes macrophages necroptosis. This effect is a result of miR-155 targeting of the RIPK1-RIPK3 pathway, which further promote apoptosis. (E) During sepsis, the lipopolysaccharide (LPS) by Escherichia coli can upregulate the expression of the necrosis-related proteins RIPK1, RIPK3, and MLKL, leading to intestinal epithelial cells necroptosis. (F) After infection with Enterococcus faecalis, DsbA can induce microinjury in the heart of Caenorhabditis elegans. Subsequently, at the site of microinjury in the heart, E. faecalis can induce the apoptosis and necroptosis of cardiomyocytes. In refractory apical periodontitis, E. faecalis can induce necroptosis in macrophages mediated by RIPK3-MLKL. Strains of E. faecalis isolated from root canals (CA1, CA2) and the OGERF strain can induce apoptosis, pyroptosis, and necroptosis in RAW264.7 macrophages. (Created with BioRender.com).