The role of cell death in SARS-CoV-2 infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), showing high infectiousness, resulted in an ongoing pandemic termed coronavirus disease 2019 (COVID-19). COVID-19 cases often experience acute respiratory distress syndrome, which has caused millions of deaths. Apart from triggering inflammatory and immune responses, many viral infections can cause programmed cell death in infected cells. Cell death mechanisms have a vital role in maintaining a suitable environment to achieve normal cell functionality. Nonetheless, these processes are dysregulated, potentially contributing to disease pathogenesis. Over the past decades, multiple cell death pathways are becoming better understood. Growing evidence suggests that the induction of cell death by the coronavirus may significantly contributes to viral infection and pathogenicity. However, the interaction of SARS-CoV-2 with cell death, together with its associated mechanisms, is yet to be elucidated. In this review, we summarize the existing evidence concerning the molecular modulation of cell death in SARS-CoV-2 infection as well as viral-host interactions, which may shed new light on antiviral therapy against SARS-CoV-2.

Fig. 1

The apoptosis pathway in SARS-CoV-2 infection. SARS-CoV-2 S protein regulates Bcl-2 and Bax to trigger the intrinsic apoptotic pathway. SARS-CoV-2 M protein stabilizes BOK to trigger intrinsic apoptosis. Additionally, SARS-CoV-2 M interacts with PDK1 and inhibits the activation of PDK1-PKB/AKT signaling to induce caspase-dependent apoptosis. SARS-CoV-2 N improves M-induced apoptosis by interacting with M and PDK1, which can thus strengthen the M-mediated attenuation of PDK1-PKB/AKT interaction. SARS-CoV-2 ORF3a and ORF3b-activated caspase-8 can induce the apoptotic pathway. SARS-CoV-2 ORF6 hinders the nuclear translocation of STAT1. SARS-CoV-2 ORF7b promotes the phosphorylation and nuclear accumulation of IRF3 and STAT1, which activates TNF-α secretion and results in cellular apoptosis through the TNFR1 pathway. SARS-CoV-2 ORF7a recruits Bcl-XL to the ER, activating the cellular ER stress response and enhancing apoptosis. SARS-CoV-2 ORF9b suppresses signaling downstream of MAVS by targeting TOM70. In contrast, SARS-CoV-2 infection activates c-FLIP and NF-κB signaling to hinder apoptosis in infected cells

Fig. 2

The necroptosis pathway during SARS-CoV-2 infection. SARS-CoV-2 ORF7b promotes the expression of death ligands (such as TNF-α, FasL, and IFN-γ). SARS-CoV-2 NSP12 can interact directly with and stimulate RIPK1 activation. SARS-CoV-2 ORF3a and E form a Ca²⁺ permeable cation channel to induce necroptosis. In addition, SARS-CoV-2 stimulates TLRs pathway and viral ZBP1 axis, directly activating RIPK3 to trigger necroptosis

Fig. 3

The pyroptosis pathway in SARS-CoV-2 infection. SARS‐CoV‐2 S triggers NLRP3 inflammasome activation to release the pro‐inflammatory cytokine IL‐1β. SARS-CoV-2 NSP6 stimulates the activation of the NLRP3 inflammasome by interacting with ATP6AP1, a vacuolar ATPase proton pump component. SARS-CoV-2 ORF3a and N facilitated NLRP3 inflammasome assembly induces ASC speck formation. In addition, SARS-CoV-2 N protein can protect GSDMD from caspase-1 cleavage. Moreover, SARS-CoV-2 N, NSP6, and ORF7a promote activation of the NF-κB pathway via interactions with TAK1 and IKK complexes, which stimulate pro-inflammatory cytokine production, containing pro-IL-1 β, pro-IL-18, procaspase-1, and NLRP3, which leads to pyroptosis. SARS-CoV-2 E can activate the NLRP3-dependent inflammasome and TLR2 pathways to trigger pro-inflammatory cytokines through activation of the NF-κB pathway. Additionally, SARS-CoV-2 E activates the NLRP3-dependent inflammasome and TLR2 pathways and forms a cation channel to trigger rapid cell death. SARS-CoV-2 NSP1 and NSP13 hinder the pyroptosis of infected cells by inhibiting the activity of caspase-1

Fig. 4

Ferroptosis pathway in SARS-CoV-2 infection. SARS-CoV-2 infection can activate the hepcidin pathway, inhibiting the output of Fe²⁺, resulting in ferroptosis. The expression of iron accumulation proteins transferrin and hepcidin is facilitated by the high level of IL-6 in COVID-19. Directly, this inhibits the exported protein ferroportin and causes cell ferroptosis. In addition, SARS-CoV-2 significantly reduced the expression of ferroptosis-related genes, containing GPX4, FTH1, FTL, and SAT1, which triggers lipid peroxidation and ferroptosis

Fig. 5

The NETosis pathway in SARS-CoV-2 infection. NETs, released by SARS-CoV-2-triggered NETosis, consist of NE, MPO, histones, and DNA. The IL-1β-IL-1R1, IL-6-IL-6R, and IL-8-IL-CSCR2 axes activate neutrophils. SARS-CoV-2 manipulates histones released to associate with S2 and sialic acid on the cell surface and promotes membrane fusion, ultimately enhancing its infectivity. Meanwhile, SARS-CoV-2 induces NETosis via increased ROS production, which is dependent on human ACE2, transmembrane protease serine 2 (TMPRSS2), and PAD4

Fig. 6

The sophisticated associations of SARS-CoV-2 and cell death: apoptosis, triggered by the extrinsic pathway (death receptor pathway) or the intrinsic pathway (mitochondrial pathway); necroptosis, mediated by RIPK1/RIPK3/MLKL; pyroptosis, induced by NLRP3 inflammasome, consisting of NLRP3, ASC, and caspase-1; ferroptosis, triggered by iron accumulation and overload, or ROS; NETosis, triggered by neutrophils and formed NETs to release of chromatin structures to neutralize intruders