Pyroptotic cell death in SARS-CoV-2 infection: revealing its roles during the immunopathogenesis of COVID-19

Abstract

The rapid dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), remains a global public health emergency. The host immune response to SARS-CoV-2 plays a key role in COVID-19 pathogenesis. SARS-CoV-2 can induce aberrant and excessive immune responses, leading to cytokine storm syndrome, autoimmunity, lymphopenia, neutrophilia and dysfunction of monocytes and macrophages. Pyroptosis, a proinflammatory form of programmed cell death, acts as a host defense mechanism against infections. Pyroptosis deprives the replicative niche of SARS-CoV-2 by inducing the lysis of infected cells and exposing the virus to extracellular immune attack. Notably, SARS-CoV-2 has evolved sophisticated mechanisms to hijack this cell death mode for its own survival, propagation and shedding. SARS-CoV-2-encoded viral products act to modulate various key components in the pyroptosis pathways, including inflammasomes, caspases and gasdermins. SARS-CoV-2-induced pyroptosis contriubtes to the development of COVID-19-associated immunopathologies through leakage of intracellular contents, disruption of immune system homeostasis or exacerbation of inflammation. Therefore, pyroptosis has emerged as an important mechanism involved in COVID-19 immunopathogenesis. However, the entangled links between pyroptosis and SARS-CoV-2 pathogenesis lack systematic clarification. In this review, we briefly summarize the characteristics of SARS-CoV-2 and COVID-19-related immunopathologies. Moreover, we present an overview of the interplay between SARS-CoV-2 infection and pyroptosis and highlight recent research advances in the understanding of the mechanisms responsible for the implication of the pyroptosis pathways in COVID-19 pathogenesis, which will provide informative inspirations and new directions for further investigation and clinical practice. Finally, we discuss the potential value of pyroptosis as a therapeutic target in COVID-19. An in-depth discussion of the underlying mechanisms of COVID-19 pathogenesis will be conducive to the identification of potential therapeutic targets and the exploration of effective treatment measures aimed at conquering SARS-CoV-2-induced COVID-19.

Keywords: COVID-19; SARS-CoV-2; cytokine storm; immunopathogenesis; inflammasomes; pyroptosis; therapeutic targets.

Figure 1

Schematic representation of the SARS-CoV-2 life cycle. The binding of SARS-CoV-2 spike (S) protein to the ACE2 receptor on the host cell surface leads to the fusion of viral and cellular membrane. The cellular surface serine protease TMPRSS2 is required for the priming of viral S protein. SARS-CoV-2 enters the host cell through the endosomal pathway, followed by the release of nucleocapsid into the cytoplasm. The virus then dissolves its protein shells and releases its genome inside the cell. The viral RNA attaches to the cell translation machinery to synthesize two large polyproteins (pp1a and pp1ab). These polyproteins are broken down into smaller NSPs by host and viral proteases. Among them, RdRp is the core catalytic subunit that drives the replication and amplification of viral RNA genome. The resultant negative-sense RNA acts as a template to produce genomic RNA and a collection of subgenomic RNAs (sgRNAs) that encode viral structural and accessory proteins. The viral RNA and N protein are synthesized in the cytoplasm. Viral S, M and E proteins are translated from sgRNAs by the ribosomes present in the endoplasmic reticulum (ER) and are subsequently embedded in an intermediate compartment of ER with Golgi (ERGIC). The viral genome is encapsulated by N proteins and assembled with the structural proteins in ERGIC. The mature virion is formed by budding from the lumen of ERGIC. The progeny virus is then liberated into the extracellular environment via exocytosis. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane protease serine 2; ACE2, angiotensin-converting enzyme 2; RdRp, RNA-dependent RNA polymerase; ERGIC, endoplasmic reticulum-Golgi intermediate compartment; N, nucleocapsid; S, spike; M, membrane; E, envelope.

Figure 2

The immunopathology of COVID-19. SARS-CoV-2 infection can directly cause damage to various tissues, such as lungs, kidneys and intestine. Multiple key immunopathological characteristics may be associated with COVID-19 pathogenesis, including cytokine storm, RAAS system dysfunction, autoimmunity, coagulopathy, lymphopenia, neutrophilia, dysregulated monocytes and macrophages, and defective IFN-I response. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE2, angiotensin-converting enzyme 2; NK cell, natural killer cell; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-12, interleukin-12; IL-18, interleukin-18; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; Ang I, Angiotensin I; Ang II, Angiotensin II; ACE1, angiotensin-converting enzyme 1; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor; DABK, des-Arg⁹-bradykinin; Ang 1-9, angiotensin 1-9; Ang 1-7, angiotensin 1-7; RAAS, renin-angiotensin-aldosterone system; IFN-I, interferon-I; ISG, interferon-stimulated gene; NETosis, neutrophil extracellular trap formation; vWF, von-Willebrand factor.

Figure 3

Regulatory mechanisms of pyroptotic cell death during SARS-CoV-2 infection. Pyroptosis has been closely linked with SARS-CoV-2 pathogenesis. SARS-CoV-2 infection coordinates the activation of the pyroptosis pathways through various mechanisms. Once SARS-CoV-2 enters the host cell, the viral genome is released and starts to replicate and manufacture a series of proteins to assemble new virions. Viral NSP6 and ORF3a trigger NLRP3 inflammasome-dependent pyroptosis by impeding the autophagic flux. NSP6 promotes the assembly of NLRP3 inflammasome by inducing K⁺ efflux. SARS-CoV-2 infection may stimulate the NF-κB signaling pathway, hence driving NLRP3 inflammasome-mediated pyroptosis. Moreover, viral attachment protein S and its S1 subunit facilitate the activation of NLRP3 inflammasome and induce GSDMD-executed pyroptosis in infected cells. These events cause the extravasation of proinflammatory mediators (e.g., IL-1β and IL-18), LDH release and eventually prompt robust immune reactions. S protein also has the ability to motivate NLRC4 and AIM2 inflammasomes, suggesting that it may affect diverse pyroptosis-related signaling cascades. Viral NSP1 and NSP13 inhibit caspase-1 activation, while ORF3a and S1-RBD exert opposite effects. N protein supports the formation of NLRP3 inflammasome, while it antagonizes pyroptotic cell death in host cell by inactivating the pyroptosis executioner GSDMD. Likewise, NSP5 can prevent GSDMD-mediated pyroptosis. Instead, NSP5 actuates the NLRP1/caspase-3/GSDME pathway. It is followed by the formation of GSDME-N pores on the cellular membrane, contributing to lytic cell death and the secretion of proinflammatory cytokines, DAMPs and alarmins. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE2, angiotensin-converting enzyme 2; ERGIC, endoplasmic reticulum-Golgi intermediate compartment; NSP6, Non-Structural Protein 6; ORF3a, open reading frame 3a; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; N, nucleocapsid; S, spike; NLRC4, NLR family, caspase activation and recruitment domain (CARD)-containing protein 4; AIM2, absent in melanoma 2; pro-IL-1β; the proform of interleukin-1β; pro-IL-18; the proform of interleukin-18; IL-1β, interleukin-1β; IL-18, interleukin-18; LDH, lactate dehydrogenase; GSDMD, gasdermin D; GSDMD-N, the N-terminal domain of gasdermin D; NSP13, Non-Structural Protein 13; NSP1, Non-Structural Protein 1; S1-RBD, receptor-binding domain in the S1 subunit; NSP5, Non-Structural Protein 5; NLRP1, NLR family, pyrin domain-containing protein 1; pro-IL-16; the proform of interleukin-16; IL-16, interleukin-16; GSDME, gasdermin E; GSDME-N, the N-terminal domain of gasdermin E; DAMPs, damage-associated molecular patterns.