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Review
. 2024 Sep 27;21(1):228.
doi: 10.1186/s12985-024-02506-8.

Aggravating mechanisms from COVID-19

Jong Hoon Lee  1   2 , Consolato Sergi  3 , Richard E Kast  4 , Badar A Kanwar  5 , Jean Bourbeau  6 , Sangsuk Oh  7 , Mun-Gi Sohn  8 , Chul Joong Lee  9 , Michael D Coleman  10
Affiliations
Review

Aggravating mechanisms from COVID-19

Jong Hoon Lee et al. Virol J. .

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. The pathophysiology of COVID-19 uses the following three mechanisms: (1) inflammasome activation mechanism; (2) cGAS-STING signaling mechanism; and (3) SAMHD1 tetramerization mechanism, which leads to IFN-I production. Interactions between the host and virus govern induction, resulting in multiorgan impacts. The NLRP3 with cGAS-STING constitutes the primary immune response. The expression of SARS-CoV-2 ORF3a, NSP6, NSP7, and NSP8 blocks innate immune activation and facilitates virus replication by targeting the RIG-I/MDA5, TRIF, and cGAS-STING signaling. SAMHD1 has a target motif for CDK1 to protect virion assembly, threonine 592 to modulate a catalytically active tetramer, and antiviral IFN responses to block retroviral infection. Plastic and allosteric nucleic acid binding of SAMHD1 modulates the antiretroviral activity of SAMHD1. Therefore, inflammasome activation, cGAS-STING signaling, and SAMHD1 tetramerization explain acute kidney injury, hepatic, cardiac, neurological, and gastrointestinal injury of COVID-19. It might be necessary to effectively block the pathological courses of diverse diseases.

Keywords: CGAS–STING; COVID-19; Inflammasome; NLRP3; SAMHD1; SARS-CoV-2.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Activation of Inflammasome, cGAS–STING, and SAMHD1. Angiotensin-converting enzyme 2 (ACE2) combined with Toll-like receptor 4 (TLR4) increases the expression of the NLR family pyrin domain-containing 3 (NLRP3), and exposure to the spike protein increases TLR4 signaling and the inflammasome pathway. This induction is mediated through nuclear factor kappa-B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) due to TLR4 activation. TLR4 is a critical mediator of the neurotoxicity induced by α-synuclein oligomers. α-Synuclein uptake is independent of TLR4. Increased cytosolic DNA levels due to mitotic stress in cancers, cellular senescence or autoimmune disorders may lead to cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS–STING) activation and the aggravation of pathological progression [34]. cGAS is an inactive protein in the cell but is activated upon binding to aberrant DNA, which results from viral invasion and senescence. Activated cGAS catalyzes the conversion of cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) to cytosolic DNA. cGAMP binds to STING and triggers STING–tank-binding kinase 1 (TBK1)–interferon regulatory factor 3 (IRF3) signaling. TBK1 kinase phosphorylates IRF3, and phosphorylated IRF3 enters the nucleus. At that point, nuclear factor kappa-B (NF-κB) triggers the expression of interferon-1 (IFN-1) and proinflammatory cytokine genes. The cGAS–STING pathway is a significant nucleic acid recognition pathway. Activated cGAMP is a secondary messenger that activates the STING-dependent IFN-1 response. The sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein (SAMHD1) function at stalled replication forks to prevent interferon (IFN) induction and have a target motif for cyclin-dependent kinase 1 (CDK1), and a CDK-targeted motif that drives threonine 592 (T592) phosphorylation. Phosphorylation of SAMHD1 at residue T592 modulates the ability of SAMHD1 to block retroviral infection. CDK1 activity is required for SAMHD1 phosphorylation, which on residue T592 prevents SAMHD1 from blocking retroviral infection. SAMHD1 limits the release of single-stranded DNA and prevents the cGAS–STING pathway inducing the expression of proinflammatory IFN-I. Genetic mutations or unstable four allosteric sites make SAMHD1 tetramerization dangerous and block the cytosolic DNA-sensing pathway
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