Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19

Abstract

Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some immunopathogenic mechanisms characterizing the present coronavirus disease (COVID-19). Lymphopenia and monocytopenia are important contributors to COVID-19 immunopathogenesis. The fine mechanisms underlying these phenomena are still unknown, and several hypotheses have been raised, some of which assign a role to cell death as far as the reduction of specific types of immune cells is concerned. Thus, we discuss three major pathways such as apoptosis, necroptosis, and pyroptosis, and suggest that all of them likely occur simultaneously in COVID-19 patients. We describe that SARS-CoV-2 can have both a direct and an indirect role in inducing cell death. Indeed, on the one hand, cell death can be caused by the virus entry into cells, on the other, the excessive concentration of cytokines and chemokines, a process that is known as a COVID-19-related cytokine storm, exerts deleterious effects on circulating immune cells. However, the overall knowledge of these mechanisms is still scarce and further studies are needed to delineate new therapeutic strategies.

Keywords: COVID-19; apoptosis; cell death.

Figure 1

Principal mechanisms involved in pyroptosis, necroptosis, and apoptosis triggered by viral infections. Damage-associated molecular patterns (DAMPS), pathogen associated molecular patterns (PAMPS), NLR family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), interleukin1β (IL1β), interleukin18 (IL18), tumor necrosis factor (TNF), tumor necrosis factor receptor (TNFR), tumor necrosis factor receptor type 1-associated death domain protein (TRADD), Fas-associated protein with death domain (FADD), TNF receptor-associated factor 2 (TRAF2), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonine-protein kinase 3 (RIPK3), p-MLKL: phosphorylated mixed lineage kinase domain-like, CD95 ligand (CD95L), apoptotic protease activating factor-1 (APAF-1), death-inducing signaling complex (DISC), mitochondrial outer membrane permeabilization (MOMP), Hepatitis C virus (HCV), Middle East Respiratory Syndrome Coronavirus (Mers-CoV), Human Immunodeficiency virus 1 (HIV-1), Hepatitis B virus (HBV), Varicella Zoster virus (VZV), Human Cytomegalovirus (hCMV), Epstein–Barr virus (EBV), Sendai virus (SeV), Influenza A virus (IAV), Encephalomyocarditis virus (EMCV), Vesicular Stomatitis virus (VSV), West Nile virus (WNV), Herpes Simplex virus 1 (HSV-1), Adenovirus type 5 (Ad5).

Figure 2

Possible cell death mechanisms induced by SARS-CoV-2 proteins and cytokine production. (A) SARS-CoV-2 E protein stimulates the nuclear factor kappa B (NF-kB) signaling pathway, leading to the production and release of inflammatory cytokines. Tumor necrosis factor (TNF) and interferon gamma (IFN-γ), binding their receptor, can trigger three different mechanisms: (1) apoptosis via the extrinsic pathway; (2) necroptosis through the phosphorylation of mixed lineage kinase domain-like (MLKL); (3) pyroptosis by the cleavage of inactive full-length gasdermin into its active form that can form membrane pores. (B) E protein contributes to the loss of ionic balance by facilitating Ca2+ leakage from endoplasmic reticulum into the cytosol, together with viral membrane-associated protein ORF3a that mediates the efflux of K+. The consequent mitochondrial damages and reactive oxygen species (ROS) production activate NLR family pyrin domain-containing 3 (NLRP3) inflammasome which induces pyroptosis. (C) Cytosolic ORF3a can activate NLRP3 by the promotion of TNFR-associated factor 3 (TRAF3) -mediated ubiquitination of apoptosis-associated speck-like protein containing a CARD (ASC), enhancing the pyroptosis pathway. (D) Crosstalk between the main cell death pathways that occurs during SARS-CoV-2 infection leads to the phenomenon of PANoptosis.