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Aggravating mechanisms from COVID-19

Virology Journal volume 21, Article number: 228 (2024) Cite this article

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.

Highlights

1.      DNA-driven immune response connects with NLRP3 and controls its inflammasome activity, which leads to IFN-I production via STING. The NLRP3 with cGAS-STING constitutes the primary immune response.

2.      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.

3.      Plastic and allosteric nucleic acid binding of SAMHD1 reduces the magnitude of IFN and induction of virus-specific cytotoxic T cells. SAMHD1-deficient cells detect and activate IFN-I-mediated self ISG gene expression via cGAS–STING.

4.      SAMHD1 autonomously controls viral infection through innate and adaptive immunity at the level of the infected cell.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. They play important roles in the infectivity and pathogenesis of chronic diseases, including cancer, coagulation disorders, neurodegenerative disorders, and cardiovascular diseases. SARS-CoV-2 can stimulate pathological intracellular signaling pathways by triggering transcription factors, which play important roles in the progression of neurodegenerative diseases, epilepsy, multiple sclerosis, and multiple cancers, such as glioblastoma, lung malignancies, and leukemias [1]. These diseases are distributed across multiple geographical limits. Interactions between the host and virus govern induction, resulting in various consequences [2]. Blood levels of cytokines during infection with coronavirus disease 2019 (COVID-19) are characterized by distinct C-reactive protein (CRP), interleukin-6 (IL-6), or triglyceride levels and significantly increased circulation [3,4,5,6,7].

The NLR family pyrin domain containing-3 (NLRP3) inflammasome contains 1. NLRP3 is a sensor protein; 2. Apoptosis-associated speck-like protein with the caspase recruitment domain (ASC) as an adaptor protein, and 3. Caspase-1 is an effector protein [8].

  1. 1.

    The NLRP3 protein has three domains: ① the pyrin domain (PYD), ② the nucleotide-binding domain, and ③ the leucine-rich repeat domain. PYD interacts with ASC [8].

  2. 2.

    The ASC platform induces caspase-1 activation, which catalyzes the conversion of pro- interleukin 1β (IL-1β) to mature IL-1β. Excessive IL-1β activates various signaling pathways, such as the NF-κB and Jun N-terminal kinase (JNK) signaling pathways, and as a result, it stimulates systemic inflammatory responses. Interferon-α (IFN-α), interferon- β (IFN- β), IL-6, tumor necrosis factor (TNF), and TGFβ1 can lead to cytokine storms [8].

  3. 3.

    Caspase-1 is the most direct marker of inflammasome activation, and processes the inflammatory cytokines pro-IL-1β and pro-interleukin-18 (IL-18) into their biologically active forms, IL-1β and IL-18. Caspase-1 cleaves gasdermin D to generate pore-forming N-terminal fragments to induce cell pyroptosis by oligomerizing with and targeting the plasma membrane [9].

SARS-CoV-2 activates the cytosolic DNA (cDNA) sensor, cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS–STING) signaling in endothelial cells. The cGAS–STING pathway controls immunity to cDNA and drives aberrant IFN-I responses in patients with COVID-19 [10]. The useful cellular functions of cGAS–STING are mediated by canonical and a few noncanonical pathways, but dysfunction of cGAS–STING-mediated cellular functions and noncanonical signaling underlie disease pathogenesis [11]. Severe COVID-19-related inflammation is associated with excessive lung tissue damage and syncytial pneumocyte formation. Cultured epithelial cells expressing ACE2 and the SARS-CoV-2 spike protein (SP) formed multinucleated syncytial cells. The fused cells exhibited DNA damage and micronuclei expressing cGAS–STING, which colocalized with and stimulated IFNs and IFN-stimulated genes [12].

The sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) is a deoxyribonucleotide triphosphate triphosphohydrolase (dNTPase) that cleaves deoxynucleotide triphosphates (dNTPs) to deoxynucleosides and triphosphates. SAMHD1 operates at stalled replication forks to prevent the induction of IFN, a significant regulator of dNTP concentrations in human cells [13]. High dNTP levels can cause problems in maintaining mitochondrial function, which might occur in Aicardi–Goutières syndrome (AGS) patients [14]. AGS mutations in the SAMHD1 gene reduce catalytic activity or allosteric activation by dGTP and increase intracellular dNTP levels [15]. This genetic inflammatory encephalopathy resembles congenital viral infections and certain autoimmune disorders [16]. SAMHD1 mutations could lead to a more robust viral infection because of the loss of the dNTP triphosphohydrolase activity of SAMHD1 [17]. Viruses can replicate their viral genome with their polymerase.

Results

Inflammasome activation mechanism

The SARS-CoV-2 genome is enclosed by a nucleocapsid (N) protein in phospholipid bilayers. The membrane and envelope proteins are located among the SP in the virus envelope. There are four main types of inflammasomes, NLRP1, NLRP3, NLR family CARD domain containing 4 (NLRC4), and absent in melanoma 2 (AIM2), which are classified after being regarded as distinct sensing proteins. Inflammasomes consist of at least three components: the inflammasome caspase (caspase-1, caspase-4/11), an adapter molecule (ASC), and a sensor/receptor protein (NLRP1, NLRP3, NAIP1/2/5, NLRP12, AIM2, etc.) [8].

Active NLRP3 was detected in tissues and peripheral blood mononuclear cells (PBMCs) from postmortem patients with moderate or severe COVID-19. The serum levels of IL-6, lactate dehydrogenase (LDH), caspase-1, caspase-4/11, and IL-18 are correlated with disease severity [18]. SARS-CoV-2 engages in Caspase 4/11-mediated noncanonical activation of NLRP3 and contributes to COVID-19 exacerbation [19]. Moreover, higher Caspase-1, Caspase-4/11, and IL-18 levels are associated with poor clinical outcomes [18, 19].

The N protein facilitated ASC oligomerization by increasing the interaction between NLRP3 and ASC. The N protein, NLRP3, and ASC form a complex and activate NLRP3. The N protein triggered A549 cells to release more serum cytokines than did SP and amplified NLRP3 activation and trimethylamine N-oxide (TMAO)-induced lipogenesis [20,21,22].

SP triggers the priming and activation of NLRP3 resulting in mature IL-1β formation in both cell types and the production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor in human umbilical vein endothelial cells and monocytes [23]. Monocytes are differentiated by SARS-CoV-2 spike protein subunit 1 (S1), not the N protein. Monocytes exposed to S1 induced significantly greater proportions of T helper type 1 (Th1) and T helper type 17 (Th17) CD4 + T cells. CD4 + IFN-producing Th1 cells play a role in the induction of tissue inflammation and many organ-specific autoimmune diseases. Th17 cells are highly differentiated by specific cytokines, are auto pathogenic, can induce tissue inflammation, and are characterized by a unique cytokine signature [24]. An increase in Th1 and Th17 cells was observed in patients with COPD compared with current smokers without COPD and healthy subjects. The increase in the Th17 response and the loss of balance between CD4 + T-cell subsets in COPD patients contribute to a lack of regulation of the systemic inflammatory response [25]. Pyroptosis by SARS-CoV-2 is associated with caspase-1, caspase-4/11, IL-1β, and gasdermin D expression and cytokine levels in primary monocytes [19, 26] (Table 1).

Table 1 The signaling and aggravating mechanisms of COVID-19
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SP induces neuroinflammation in BV-2 microglia and TLR4 expression is increased when BV-2 microglia, a microglial cell line derived from C57BL/6 mice, are simulated with S1. The purified SP activated NLRP3 in lipopolysaccharide (LPS)-primed microglia in an ACE2-dependent manner. Microglial NLRP3 activation is a major driver of neurodegeneration [50,51,52,53,54] (Table 2).

Table 2 Three pathways basically implicated and associated with SARS-CoV-2 [188]
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AIM2 senses potentially dangerous cytoplasmic DNA and cytosolic DNA (cDNA) triggers the formation of the AIM2 inflammasome by inducing AIM2 oligomerization. It leads to the activation of the ASC pyroptosome and caspase-1 [86]. The detection of cDNA via the cGAS–STING axis induces a cell death program that initiates potassium efflux upstream of NLRP3. The combination of NLRP3 with cGAS–STING constitutes the primary inflammasome response during viral and bacterial infections in human myeloid cells and ameliorates the pathology of inflammatory conditions linked with cDNA sensing [87]. Mitochondrial antiviral signaling protein (MAVS) connects with NLRP3 and controls its inflammasome activity [27].

cGAS–STING signaling mechanism

This cGAS–STING mechanism induces microglial activation to resolve inflammation in the brain. However, excessive engagement can lead to neuroinflammation and neurodegeneration [37]. cGAS–STING signaling is strongly related to the pathogenesis of neuroinflammation-driven disease progression [88]. Due to cellular senescence, autoimmune disorders, and mitotic stress in cancers, cytosolic DNA levels increase, and a vast array of germline-encoded innate immune receptors facilitate innate immune recognition. These lead to the activation of cGAS–STING and the exacerbation of pathological mechanisms [88, 89].

cGAS catalyzes the conversion of cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) to cDNA. It triggers STING–TANK binding kinase 1 (TBK1)—IFN regulatory factor 3 (IRF3) signaling [90]. cGAS also appears in the nucleus, where cGAS in an inactive state is isolated from chromatin. Upon viral infection, nuclear cGAS recruits protein arginine methyltransferase 5 (PRMT5). In innate immunity, nucleus-localized cGAS interacts with PRMT5 to catalyze the symmetric demethylation of histone H3 arginine 2 at IRF3-responsive genes, such as IFNβ 1 (IFNβ1) and IFNα 4 (IFNα4). As a result, PRMT5 facilitates IRF3 access [91]. Activated cGAS releases cGAMP, which binds to STING; thus, STING relocalizes and forms a clustered platform at the perinuclear Golgi. The kinase TBK1 phosphorylates IRF3, and IRF3 then enters the nucleus. Moreover, NF-κB triggers the expression of IFN-1 and proinflammatory cytokine genes [32, 35].

The papain-like proteases (PLpros) have deubiquitinase activities that enable human-infecting coronaviruses to evade innate defenses. PLpro suppressed antiviral signaling in cells by deubiquitinating the stimulator of STING [92]. Activated STING triggers membrane permeabilization and thus lysosomal cell death [87]. The SARS-CoV-2 ORF3a can interact with STING. It selectively blocks cGAS–STING-induced autophagy by disrupting the STING-light chain 3 (LC3) interaction [93].

SARS-CoV-2 nonstructural protein 6 (NSP6) promotes the degradation of macroautophagy/autophagy-mediated STING1 and inhibits IFN production [94]. ORF9b, nonstructural protein 7 (NSP7), and nonstructural protein 8 (NSP8) antagonize the production of IFN-I and IFN-III by targeting retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5), toll-like receptor 3 (TLR3)-interleukin-1 receptor (TIR)-domain-containing adapter-inducing IFN-β (TRIF), and cGAS–STING signaling. The expression of ORF3a, NSP6, NSP7, and NSP8 blocks innate immune activation and facilitates virus replication [93,94,95,96,97,98]. Mitochondrial DNA is released and leads to IFN-I production. Blocking STING reduces severe lung inflammation [10, 27, 99] (Fig. 1).

Fig. 1
figure 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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SAMHD1 tetramerization mechanism

SAMHD1 forms tetramers of GTP and all four dNTPs are controlled by the combined action and inactive apo-SAMHD1 interconverts between monomers and dimers through dGTP-induced tetramerization of two inactive dimers. The protein assembles into catalytically active tetramers in the presence of dGTP [100]. The binding of dGTP to four allosteric sites stimulates and causes a conformational change in the substrate-binding pocket, which results in a catalytically active tetramer [100]. A phosphomimetic environment generates electrostatic repulsive movement. This repulsive electrostatic phosphorylation allosterically decreases dNTPase activity and may modify antiviral functions [42].

When SANHD1 in the nucleus degrades endogenous dGTP, deoxyguanosine kinase (dGK) inside mitochondria is recycled from deoxyguanosine. Genetic mutations of dGK inside mitochondria can cause mtDNA depletion in noncycling cells: hepato-cerebral mtDNA depletion syndrome in humans [44]. However, phosphorylation of SAMHD1 at residue threonine 592 (T592) modulates the ability of SAMHD1 to block retroviral infection [45].

SAMHD1 can restrict retroviruses and protect cells from viral infections by catalyzing the hydrolysis of dNTPs in the dNTP pool. SAMHD1 depletes intracellular dNTPs into 20-deoxynucleoside and triphosphate products [43, 45]. Cyclin-dependent kinases (CDKs) are protein kinases that play key roles in cell division, transcriptional regulation, and viral infections [101]. SARS-CoV-2 infection triggers and redistributes cyclin D1 and D3 from the nucleus to the cytoplasm and subsequent proteasomal degradation [102]. Cyclin D3 prevents the efficient incorporation of the envelope protein into virions during assembly. Its degradation during SARS-CoV-2 infection relieves cyclin interference with virion assembly [102].

SAMHD1 has a target motif for cyclin-dependent kinase 1 (CDK1, 592TPQK595) [45]. CDK1 activity is required for SAMHD1 phosphorylation. SAMHD1 phosphorylated at residue T592 does not block retroviral infection, but it does not affect the ability of SAMHD1 to decrease the cellular dNTP level [45].

Single-gene recessive inborn errors can result in uncontrolled inflammatory cytokine production by mononuclear phagocytes after SARS-CoV-2 infection, potentially explaining the origins of multisystem inflammatory syndrome in some children [16]. SAMHD1 mutations result in autoinflammatory AGS. AGS secretes chronic IFN-I despite the absence of viral infections [14, 15, 103]. The degradation of SAMHD1 in human primary-activated/dividing CD4 + T cells contributes to the increase in dNTP levels [104]. Plastic and allosteric nucleic acid binding promotes the immunomodulatory effects of the antiretroviral activity of SAMHD1 [105]. Phosphorylation modulates the ability of SAMHD1 as an HIV restriction factor to block retroviral infection without affecting its ability to decrease cellular dNTP levels [43], but SAMHD1-depleted cells release single-stranded DNA fragments from stalled forks and accumulate DNA fragments in the cytosol, where they activate reverse transcription, cGAS and STING, and signaling through the IFN receptor to induce the expression of proinflammatory IFN-I [13].

SAMHD1 autonomously controls viral infection through innate and adaptive immunity at the level of the infected cell and limits virus-induced production of IFNs and the induction of costimulatory markers: virus-induced IFN production in myeloid cells. SAMHD1 reduces the magnitude of IFN and the induction of virus-specific cytotoxic T cells [106]. The SAMHD1 tetramer structure could provide a mechanistic understanding of its rapid function in SARS-CoV-2 pathogenesis. SAMHD1-deficient cells detect and activate IFN-I-mediated antiviral gene expression in SAMHD1 KO cells via cGAS–STING [107]. SAMHD1 links with MAVS and suppresses MAVS aggregation in response to viral infection, which increases the phosphorylation of TBK1, an inhibitor of NF-κB kinase epsilon (IKKε), and IRF3 [108]. It inhibits NF-κB activation and IFN-I induction in response to viral infection [47, 109]. The antiviral IFN responses induced by SAMHD1 suppress SARS-CoV-2 replication and increase cellular innate immunity, but genetic loss of SAMHD1 increases the innate immune response and IFN activation [109]. Low levels of IFN-I could drive more severe SARS‐CoV‐2 infection [110]. SAMHD1 occurs more frequently in severe ventilation-associated COVID-19 patients than in nonventilated patients [111]. SAMHD1 regulates the innate immune response and adaptive IFN activation [34, 112]. Further research is still needed for the management of COVID-19 to study the regulatory functions of SAMHD1.

Limitations

Too many complex and diverse pathways are involved in IFN, making it difficult to find treatments that can effectively and efficiently manage it [112]. Because of the rapid and lethal nature of these three deterioration pathways, research to explain their interrelationships remains limited.

A major key limitation is the rapidly evolving nature of the SARS-CoV-2 virus. As new variants emerge, their specific mechanisms of infection and pathogenesis may differ from those of earlier strains, and further research is needed to understand the dynamics of these changes.

Conclusion

In viral diseases, excessive production, or decreased production of IFN should be an important factor in ultimately worsening pathology. The mechanisms of inflammasome activation, cGAS–STING signaling, and SAMHD1 modulation of innate and adaptive immunity explain the diverse exacerbations of COVID-19.

Method

In 2021, as external activities were difficult during the pandemic era, we analyzed SCI journals about COVID-19 and SARS-CoV-2 through an information search. Key words were connected on the basis of the research results. The inclusion criteria were as follows: (1) ACE2 and TLR, (2) NRP, (3) spike protein, (4) inflammasome activation, (5) cGAS–STING signaling, (6) SAMHD1 tetramerization, (7) immunological memory engram, and (8) excess acetylcholine. Three years after 2021, we checked the experimental results with keywords.

Pathogenesis was analyzed through the first approach (2021) and the second approach (2024). (1) ACE2 and TLR were analyzed in thirteen and six papers; (2) NRP was analyzed in seventeen and seven papers; (3) spike protein was analyzed in fifteen and eight papers; (4) inflammasome activation was analyzed in seven and six papers; (5) cGAS–STING signaling was analyzed in six and five papers; (6) SAMHD1 tetramerization was analyzed in five and seven papers; (7) immunological memory engram was analyzed in thirteen and five papers; and (8) excess acetylcholine was analyzed in three and nine papers. The papers were published on January 4, 2024. Papers published before 2020 were excluded from the presentation to avoid confusion in understanding the pathogenesis of COVID-19 and SARS-CoV-2. Only papers published from 2020 to 2024 are described (Table 3).

Table 3 Approach of COVID-19 papers from 2024-01-04
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Exclusion criteria: If we could not find direct repeated mechanisms with experimental data in SCI journals, those were excluded [187]. The immunological memory engram and excess acetylcholine were analyzed to determine their causal relationships in clinical practice. We temporarily excluded two from the pathogenesis of COVID-19.

Availability of data and materials

No data associated with the manuscript

Abbreviations

A549 cell:

A549 cells are adenocarcinomic human alveolar basal epithelial cells, and constitute a cell line.

ACE:

Angiotensin-converting enzyme

AD:

Alzheimer’s disease

AESI:

Adverse events of special interest

AIDS:

Acquired immune deficiency syndrome

AGS:

Aicardi–Goutières syndrome

AIM2:

Absent in melanoma 2

ALI:

Air–liquid interface

ALP:

Alkaline phosphatase

α-Syn:

α-Synuclein

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

APC:

Antigen-presenting cells

ARDS:

Acute respiratory distress syndrome

ASC:

Apoptosis-associated speck-like protein containing a CARD

ATF4:

Activated parkin via protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4

BBB:

Blood‒brain barrier

BDNF:

Brain-derived neurotrophic factor

BV-2:

A type of microglial cell derived from C57/BL6 mice

CAPS:

Cryopyrin-associated periodic syndromes

CARD:

Caspase activation and recruitment domain

CCNE2:

Essential for the control of the cell cycle at the late G1 and early S phases; belongs to the cyclin family

CCR5:

C–C motif chemokine receptor 5

CH:

Clonal hematopoiesis, hematopoietic stem and progenitor cells

CDK1:

Cyclin-dependent kinase 1

CI:

Confidence interval

CK-MB:

Creatine kinase-MB fraction

COPD:

Chronic obstructive pulmonary disease

COX-1:

Cyclooxygenase 1

CRP:

C-reactive protein

CRS:

Cytokine release syndrome

CtIP:

C-terminal binding protein 1 (CtBP1) interacting protein

Cyclin a2:

A protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in the mitotic division of somatic cells

Cyclin D1:

A protein required for progression through the G1 phase of the cell cycle

Cyclin D3:

A cofactor of retinoic acid receptors, modulating their activity in the presence of cellular retinoic acid-binding protein II

Cyclin E2:

Cyclin E2 is a protein that in humans is encoded by the CCNE2 gene

Cyclin-G1:

A protein that in humans is encoded by the CCNG1 gene

CXCR-4:

C-X-C chemokine receptor type 4

DDS:

4,4′-Diaminodiphenyl sulfone (dapsone)

DPP4:

Dipeptidyl peptidase-4

DIC:

Disseminated intravascular coagulation

ECG:

Electrocardiogram

ER:

Endoplasmic reticulum

cGAMP:

2′,3′-Cyclic GMP-AMT

cGAS–STING:

Cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)

G6PDH:

Glucose-6-phosphate dehydrogenase

HIV:

Human immunodeficiency virus

HLA:

Human leukocyte antigen

HLA-DRB1:

Major histocompatibility complex, class II, DR beta 1

HSPC:

Hematopoietic stem/progenitor cell

ICU:

Intensive care unit

IFN:

Interferon

IFNAR2:

Interferon-alpha and beta receptor subunit 2

IL:

Interleukin

IL-1β:

Interleukin-1 beta

IMV:

Intensive mechanical ventilation

IRF3:

Interferon regulatory factor 3

ISG:

Interferon-stimulated gene

JNK:

Jun N-terminal kinases

LDH:

Lactate dehydrogenase

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MDIG:

Mineral dust-induced gene

N protein:

Nucleocapsid protein

MDA5:

Melanoma differentiation-associated gene 5

mRNA:

Messenger RNA

mtDNA:

Mitochondrial DNA

NACHT:

Domain conserved in NAIP, CIITA, HET-E, and TP1

NFL:

Neurofilament light chain

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NLRC4:

NLR Family CARD Domain Containing 4

NLRP3:

NOD-, LRR-, and pyrin domain-containing protein 3, NLR family pyrin domain-containing 3

NRP:

Neuropilin

PAMPs:

Pathogen-associated molecular patterns

PBMCs:

Human peripheral blood mononuclear cells

PEDF:

Pigment epithelium-derived factor

PEDFR/iPLA2:

PEDF/calcium-independent phospholipase A2

Phosphomimetics:

Amino acid substitutions that mimic a phosphorylated protein.

Phospho-p65:

Anti-phospho-NFkB p65 (Ser536) monoclonal antibody (T.849.2)

Phospho-IκBα:

Phospho-IκBα (Ser32/36) (5A5) mouse mAb #9246

PRMT5:

Protein arginine methyltransferase 5

PTGS2:

Prostaglandin synthase 2

RIG-I:

Retinoic acid-inducible gene I

ROS:

Reactive oxygen species

SP:

Spike glycoprotein of SARS-CoV-2

S1:

SARS-CoV-2 spike protein subunit 1

SAMHD1:

Sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein

RCT:

Randomized controlled trial

SOD:

Superoxide dismutase

TBK1:

Tank-binding kinase 1

TGFβ:

Transforming growth factor-β

THP-1:

A spontaneously immortalized monocyte-like cell line

TNF:

Tumor necrosis factor

TLR:

Toll-like receptor

TMPRSS2:

Transmembrane protease serine subtype 2

TRIF:

TLR3-TIR-domain-containing adapter-inducing interferon-β

TTS:

Thrombosis with thrombocytopenia syndrome

TREX1:

Tthree-prime repair exonuclease 1

TYK2:

Tyrosine kinase 2

UCB:

Umbilical cord blood

VRD:

Viral respiratory disease

VSEL:

Very small embryonic-like stem cell

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Authors and Affiliations

  1. Science and Research Center, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea

    Jong Hoon Lee

  2. Department of Geriatrics, Gyeonggi Medical Center Pocheon Hospital, 1648 Pocheon-ro Sin-eup-dong, Pocheon-si, Gyeonggi-do, 11142, Republic of Korea

    Jong Hoon Lee

  3. Division of Anatomical Pathology, Children’s Hospital of Eastern Ontario (CHEO), University of Ottawa, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada

    Consolato Sergi

  4. IIAIGC Study Center, 11 Arlington Ct, Burlington, 05408 VT, USA

    Richard E. Kast

  5. Haider Associates, 1999 Forest Ridge Dr, Bedford, TX, 76021, USA

    Badar A. Kanwar

  6. Respiratory Epidemiology and Clinical Research Unit, McGill University Health Centre, Montréal, QC, Canada

    Jean Bourbeau

  7. Department of Food Engineering, Food Safety Laboratory, Memory Unit, Ewha Womans University, Seoul, 03670, Korea

    Sangsuk Oh

  8. Department of Food Science, KyungHee University College of Life Science, Seoul, 17104, Republic of Korea

    Mun-Gi Sohn

  9. Department of Anesthesiology, Seoul National University Hospital, Seoul, Republic of Korea

    Chul Joong Lee

  10. College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK

    Michael D. Coleman

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  1. Jong Hoon Lee
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  2. Consolato Sergi
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  4. Badar A. Kanwar
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  5. Jean Bourbeau
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  6. Sangsuk Oh
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  8. Chul Joong Lee
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  9. Michael D. Coleman
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Contributions

Jong Hoon Lee: Conceptualisation, Methodology, Software, Data curation, Visualization, Investigation, Writing- Original draft preparation. Consolato Sergi: Data curation, Writing—Reviewing and Editing. Richard E. Kast: Investigation, Writing- Reviewing and Editing. Badar A. Kanwar: Investigation,Writing—Reviewing and Editing. Jean Bourbeau: Writing- Reviewing and Editing. Sangsuk Oh: Investigation, Writing- Reviewing and Editing. Mun-Gi Sohn: Investigation, Chul Joong Lee: Writing- Reviewing and Editing, Michael D. Coleman: Supervision, Writing—Reviewing and Editing.

Corresponding authors

Correspondence to Jong Hoon Lee or Michael D. Coleman.

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The National Agency approved this study for the Management of Life-sustaining Treatment, which certified that life-sustaining treatments were managed properly (Korea National Institute for Bioethics Policy (KoNIBP) approval number P01-202007-22-006).

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Lee, J.H., Sergi, C., Kast, R.E. et al. Aggravating mechanisms from COVID-19. Virol J 21, 228 (2024). https://doi.org/10.1186/s12985-024-02506-8

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ISSN: 1743-422X