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Review
. 2022 Oct 31;23(21):13260.
doi: 10.3390/ijms232113260.

COVID-19 Molecular Pathophysiology: Acetylation of Repurposing Drugs

Jong Hoon Lee  1 , Badar Kanwar  2 , Asif Khattak  2 , Jenny Balentine  2 , Ngoc Huy Nguyen  3 , Richard E Kast  4 , Chul Joong Lee  5 , Jean Bourbeau  6 , Eric L Altschuler  7 , Consolato M Sergi  8 , Tuan Ngoc Minh Nguyen  9 , Sangsuk Oh  10 , Mun-Gi Sohn  11 , Michael Coleman  12
Affiliations
Review

COVID-19 Molecular Pathophysiology: Acetylation of Repurposing Drugs

Jong Hoon Lee et al. Int J Mol Sci. .

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated type 1 interferon (IFN-1) production, the pathophysiology of which involves sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) tetramerization and the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. As a result, type I interferonopathies are exacerbated. Aspirin inhibits cGAS-mediated signaling through cGAS acetylation. Acetylation contributes to cGAS activity control and activates IFN-1 production and nuclear factor-κB (NF-κB) signaling via STING. Aspirin and dapsone inhibit the activation of both IFN-1 and NF-κB by targeting cGAS. We define these as anticatalytic mechanisms. It is necessary to alleviate the pathologic course and take the lag time of the odds of achieving viral clearance by day 7 to coordinate innate or adaptive immune cell reactions.

Keywords: ACE2 (angiotensin-converting enzyme 2); SAMHD1 (sterile alpha motif and histidine-aspartate domain-containing protein 1); SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2); TLR4 (Toll-like receptor 4); aspirin; cGAS–STING (cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)–stimulator of interferon genes (STING)); dapsone; dexamethasone; immunologic engram; inflammasome; spike protein.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The roles of cyclin-dependent kinase and cGAS–STING signaling. Cyclin-dependent kinase 1 (CDK1), CDK2, and CDK6 inhibit SAMHD1 antiviral function via phosphorylation and inactivation. HBV recruits cyclin E2 to bind CDK2 and further phosphorylates SAMHD1 to abrogate its restriction of HBV replication. SARS-CoV-1 suppresses the activity of cyclin d-CDK4 and cyclin A/E–CDK2 complexes, and SARS-CoV-2 enhances the phosphorylation of CDK2 to inhibit cellular mitosis. Pattern recognition receptors are essential in sensing pathogen-associated molecular patterns (PAMPs) and DAMPs. For example, Toll-like receptors (TLRs) recognize a variety of PAMPs and DAMPs that initiate the inflammatory process via NF-κB (nuclear factor-kappa B cells) and the synthesis and release of cytokines and IFNs. Inflammasomes are a separate class of intracellularly expressed pattern recognition receptors (PRRs) that recognize nucleic acids and mediate proinflammatory responses. Cell surface–expressed ACE2 and TLR4 increase the NLRP3 inflammasome downstream mediator caspase-1, and exposure to spike proteins upregulates the protein expression involved in the positive stimulation of TLR4 signaling and the inflammasome pathway. The induction of neuroinflammation in microglia is mediated through the activation of NF-κB and p38 MAPK (mitogen-activated protein kinase), possibly due to TLR4 activation. TLR4 has been found to play a critical role as a mediator of the neurotoxicity induced by α-synuclein oligomers. Misfolded α-synuclein (α-Syn) induces inflammatory responses, and extracellular α-Syn can activate proinflammatory TLR4 pathways in astrocytes, but α-Syn uptake is independent of TLR4. The interaction between TLR4 and the SARS-CoV-2 spike protein can trigger an intracellular TLR4 signaling cascade. NF-kB’s transcriptional activation of specific genes induces the release of proinflammatory cytokines, which can cause neuronal damage and the pathological modification of α-Syn. Serum neurofilament light chain (NFL) is a biomarker of neuronal injury. NFL was higher in COVID-19 patients than in the control groups. Higher NFL levels were associated with neuronal injury. This is common in critically ill patients. The hyperinflammatory state of COVID-19 has high levels of proinflammatory cytokines, and this might have triggered central nervous system neuroinflammation through the activation of astrocytes and microglia, which could have facilitated prion-like pathology. In addition, similar to other prion proteins, the spike protein also contains several prionogenic domains. Thus, direct toxic action of the spike protein, triggering a neurodegenerative condition mimicking a prion disease-like pathology, is also possible. The biological implications of nuclear cGAS and its interaction with chromatin, including various mechanisms for nuclear cGAS inhibition, the release of chromatin-bound cGAS, the regulation of different cGAS pools in the cell, and chromatin structure/chromatin protein effects on cGAS activation, could lead to cGAS-induced autoimmunity. Cytosolic DNA recognition leads to active cGAS by clustering and forming large liquid—liquid phase-separated cGAS–DNA condensates, excluding the ER-directed exonuclease three-prime repair exonuclease 1 (TREX1). Nuclear cGAS is sequestered at chromatin in an inactive state. Active cGAS produces cyclic GMP-AMP (cGAMP), which binds to STING. STING relocalizes to the perinuclear Golgi and forms a clustered platform where the tank-binding kinase 1 (TBK1) kinase phosphorylates the transcription factor IRF3 (interferon regulatory factor 3). Phosphorylated IRF3 enters the nucleus and, along with NF-κB, triggers the expression of type I interferon and proinflammatory cytokine genes (reproduced from [27]) (HBV, hepatitis B virus; P, phosphate; the green arrows indicate enhancement and the dashed arrow indicates the effect is uncertain; CDK, cyclin-dependent kinase; SAMHD1, sterile alpha motif histidine-aspartic acid domain-containing protein 1).
Figure 2
Figure 2
Immune-to-brain communication. The perivascular space contains a single or double layer of invaginated pia in the brain, forming an interstitial fluid-filled space representing an extension of the extracellular fluid space around the intracranial vessels as they move down into the brain parenchyma. Human sensory stimuli affect the breathing sensation passing through the cerebral cortex and hypothalamus. The respiratory muscles are not purposely activated in healthy breathing. Neuropilin-1 (a pleiotropic single-transmembrane coreceptor for class-3 semaphorins and vascular endothelial growth factors) has been confirmed as a coreceptor that facilitates SARS-CoV-2 infection into cells and may be expressed in the brainstem. Activated microglia were observed in the olfactory bulb, midbrain (particularly in the substantia nigra), hindbrain, dorsal motor nucleus of the vagus nerve, and pre-Bötzinger complex in the medulla. Neuroinflammation with microgliosis and T-cell infiltration in COVID-19 brains was significantly greater than that in patients who did not have COVID-19. This might trigger inflammasomes and pyroptosis in the CNS. The pre-Bötzinger complex involvement in the brainstem could account for the respiratory failure and sudden high death rate of COVID-19 ARDS patients. The neurovirulent potential of SARS-CoV-2 is not restricted to patients with mild or severe diseases that can develop neurological complications. Microglia and astrocytes play specific and dynamic roles during immune activation. This immune-to-brain communication occurs when glia, microglia, and astrocytes interpret and propagate inflammatory signals in the brain, and influence physiological and behavioral-change responses. Activating the peripheral immune system with a coordinated brain response elicits and influences physiological and behavioral responses in the immunological memory engram pathway.
Figure 3
Figure 3
Aspirin strongly inhibited cGAS-mediated TBK1–IRF3 signaling. The sensing of cytosolic DNA by cGAS is central to the pathogenesis of several autoinflammatory syndromes and some autoimmune diseases, such as systemic lupus erythematosus (SLE), because the presence of DNA in the cytoplasm is usually a sign of microbial infections and is quickly detected by cGAS, eliciting anti-infection immune responses. However, the chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is yet available. The activation of cGAS signaling requires its deacetylation, while acetylation inhibits cGAS activation, and the compulsory acetylation of cGAS by aspirin forcefully suppresses self-DNA–induced autoimmunity, giving aspirin therapeutic potential in this context. Recently, the unique role of the cGAS–stimulator of the STING pathway in orchestrating innate and adaptive immunity has led to vast interest in employing antagonists of the cGAS–STING pathway as SARS-CoV-2 therapeutic adjuvants. The DNA sensor cGAS detects pathogenic or cytosolic nucleic acids and produces the second messenger, 2′3′-cGAMP, which binds to STING. Activated STING dimerizes and translocates from the endoplasmic reticulum (ER) to the Golgi apparatus. STING is ubiquitinated at the Golgi apparatus, an anchor for TBK1. Stimulation of the cGAS–STING pathway by cytosolic nucleic acids can activate interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB), and promote the transcription of type I interferons (IFNs) and other proinflammatory cytokines, modulating antigen presentation and immune responses. Therefore, cGAS–STING antagonists are promising adjuvants for constructing effective SARS-CoV-2 therapeutics. Acetylation inhibits cGAS activation, and enforced acetylation of cGAS by aspirin robustly suppresses self-DNA–induced autoimmunity. Aspirin inhibited cGAS-mediated IFN production [39]. The acute or chronic use of ibuprofen and other NSAIDs was not associated with worse COVID-19 disease outcomes [50]. NSAID use might confer a modest benefit concerning survival [51]. Early aspirin prescription may be associated with lower odds of in-hospital mortality among hospitalized patients with moderate COVID-19 in 2,446,650 COVID-19–positive patients [52]. Aspirin is associated with decreased mechanical ventilation, ICU admission, and in-hospital mortality in hospitalized COVID-19 patients. NSAID use might confer a modest benefit concerning survival [51].
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