Viral-mediated activation and inhibition of programmed cell death

Abstract

Viruses are ubiquitous intracellular genetic parasites that heavily rely on the infected cell to complete their replication life cycle. This dependency on the host machinery forces viruses to modulate a variety of cellular processes including cell survival and cell death. Viruses are known to activate and block almost all types of programmed cell death (PCD) known so far. Modulating PCD in infected hosts has a variety of direct and indirect effects on viral pathogenesis and antiviral immunity. The mechanisms leading to apoptosis following virus infection is widely studied, but several modalities of PCD, including necroptosis, pyroptosis, ferroptosis, and paraptosis, are relatively understudied. In this review, we cover the mechanisms by which viruses activate and inhibit PCDs and suggest perspectives on how these affect viral pathogenesis and immunity.

Fig 1. A summary of the major components of the extrinsic and intrinsic pathways of apoptosis induction following viral infection.

In response to viral infection, the extrinsic pathway is initiated by death receptors following stimulation by the TNF proteins, resulting in downstream signaling and caspase-8 activation. The intrinsic pathway of apoptosis arises from proapoptotic stimuli, subsequently initiating mitochondrial membrane permeabilization and activation of caspase-9. Both pathways converge at the terminal activation of caspase-3 that executes apoptosis. ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BAK, BCL-2 antagonist or killer; BAX, BCL-2-associated X protein; cGAS/STING, cyclic GMP–AMP synthetase/stimulator of IFN genes; CHOP, CCAAT-enhancer-binding protein homologous protein; DISC, death-inducing signaling complex; EBV, Epstein–Barr virus; ER, endoplasmic reticulum; FMDV, Foot-and-mouth disease virus; HBV, hepatitis B virus; IRE1, inositol-requiring enzyme 1; IRF3, IFN-regulatory factor 3; JEV, Japanese encephalitis virus; MVA, modified vaccinia virus; PERK, PKR-like ER kinase; RIG-I, retinoic acid-inducible gene I; TLR3, Toll-like receptor 3; TNF, tumor necrosis factor; TRIF, Toll/IL-1 receptor domain-containing adapter inducing IFN-beta; WNV, West Nile virus.

Fig 2. A summary of the major components of the necroptosis induction pathway following viral infection.

Necroptosis is activated during viral infection through Toll-like receptor and TNF receptor activation, in addition to viral nucleic acid recognition by the intracellular sensors DAI/ZPB1. Necroptotic stimuli converge on the activation of the RIPK1/RIPK3 necrosome complex, in turn phosphorylating the effector protein MLKL to initiate cell lysis. cGAS, cyclic GMP–AMP synthetase; CIAP1/2, cellular inhibitor of apoptosis 1/2; DAI/ZPB1, DNA-dependent activator of IFN-regulatory factors/Z-DNA/RNA binding protein 1; dsRNA, double-stranded RNA; MCMV, murine cytomegalovirus; MLKL, mixed lineage kinase domain-like pseudokinase; NF-κB, nuclear factor-κB; pMLKL, phosphorylated MLKL; RIF, Toll/IL-1 receptor domain-containing adapter-inducing IFN-beta; RIP1, receptor-interacting protein 1; RIPK1, receptor-interacting serine/threonine-protein kinase 1; RIPK3, receptor-interacting serine/threonine-protein kinase 3; STING, stimulator of IFN genes; TLR3, Toll-like receptor 3; TLR4, Toll-like receptor 4; TNF, tumor necrosis factor; TNF-α, tumor necrosis factor alpha; TNFR, tumor necrosis factor receptor; TRADD, TNF-R-associated protein with death domain; TRAF, TNF-associated factor; 2′3′ cGAMP, 2′3′ cyclic GMP-AMP.

Fig 3. A summary of the major components of the pyroptosis induction pathway following viral infection.

Viral nucleic acids can stimulate pyroptosis through the activation of the NLRP3/6/9 inflammasome, AIM2 inflammasome, and IFI16 inflammasome. Inflammasome activation stimulates the recruitment and activation of pro-caspase-1, resulting in the downstream cleavage of gasdermin proteins into C-terminal and N-terminal portions. The N-terminal gasdermin portion catalyzes pore formation and proinflammatory cytokine release. AIM2, absent in melanoma 2; ASC, Apoptosis-associated speck-like protein containing a CARD; CARD, caspase activation and recruitment domain; DAMP, damage-associated molecular pattern; DV, dengue virus; HBV, hepatitis B virus; HCV, hepatitis c virus; HPV, human papillomavirus; HSV, herpes simplex virus; IAV, influenza A virus; IFI16, IFN-gamma-inducible protein 16; IFN-3, interferon-3; IFN-y, interferon gamma; KSHV, Kaposi sarcoma–associated herpesvirus; MCMV, murine cytomegalovirus; mtDNA, mitochondrial DNA; NF-κB, nuclear factor-κB; NLRP3, Nod-like receptor family pyrin domain containing 3; PAMP, pathogen-associated molecular pattern; ROS, reactive oxygen species; STING, stimulator of IFN genes; TLR, Toll-like receptor; TNF-α, tumor necrosis factor alpha; TRIF, Toll/IL-1 receptor domain-containing adapter inducing IFN-beta; VACV, vaccinia virus; VSV, vesicular stomatitis virus.