Cytokine storm induced by SARS-CoV-2

Abstract

Coronavirus disease 2019 (COVID-19), caused by the virus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread widely throughout the world. Despite the strict global outbreak management and quarantine measures that have been implemented, the incidence of COVID-19 continues to rise, resulting in more than 290,000 deaths and representing an extremely serious threat to human life and health. The clinical symptoms of the affected patients are heterogeneous, ranging from mild upper respiratory symptoms to severe pneumonitis and even acute respiratory distress syndrome (ARDS) or death. Systemic immune over activation due to SARS-CoV-2 infection causes the cytokine storm, which is especially noteworthy in severely ill patients with COVID-19. Pieces of evidence from current studies have shown that the cytokine storm may be an important factor in disease progression, even leading to multiple organ failure and death. This review provides an overview of the knowledge on the COVID-19 epidemiological profile, the molecular mechanisms of the SARS-CoV-2-induced cytokine storm and immune responses, the pathophysiological changes that occur during infection, the main antiviral compounds used in treatment strategies and the potential drugs for targeting cytokines, this information is presented to provide valuable guidance for further studies and for a therapeutic reduction of this excessive immune response.

Keywords: COVID-19; Clinical manifestations; Coronavirus; Cytokine storm; Pneumonia; SARS-CoV-2.

Fig. 1

(a) IL-6 binds to the transmembrane receptor IL-6R to generate the IL-6/IL-6R complex, which induces homodimerization of gp130, leading to activation of the downstream signaling molecules, including TYK2,JAK1,JAK2 and STAT3, promoting IL-6 transcription; (b) the binding of IFN-α/β to the dimer receptor IFNAR activates the JAK-STAT signal transduction pathway, in which STAT1, STAT2 and IRF9 form a complex and then enter the nucleus to initiate the transcription of IFN-stimulated genes (ISG). However, NSP1 can inhibit the IFNs response by blocking STAT1 phosphorylation; (c) TLR3 specifically recognizes the viral ds-RNA followed by the recruitment of signal transfer proteins MyD88, IRAK, IKKε and TRAF6, and eventually the NF-κB complex is activated to promote the transcription of inflammatory cytokines; (d) IL-1 and TNF-α can also activate the NF-κB single pathway to initiate the transcription of inflammatory cytokines. PRR activates the transcription of multiple cytokines and delays IFN-α and -β responses.

Fig. 2

TLR recognizes extracellular PAMPs and initiates the transcription of NLRP3, proIL-1β, and proIL-18 through the NF-κB signaling pathway, and oligomerized NLRP3, ASC and pro-caspase-1 form a multiprotein complex that activates caspase-1. Activated caspase-1 cleaves the pro-IL-1β and pro-IL-18, forming active IL-1β and IL18, which are released, and simultaneously, the active cleavage fragment of GSDMD causes cell perforation by inserting into the lipid bilayer, resulting in cell swelling and lysis, followed by the release of contents such as the cellular matrix and cytokines. Intracellular signaling mechanism of cell pyroptosis induced by PAMPs.