The picture theory of seven pathways associated with COVID-19 in the real world

doi:10.21203/rs.3.rs-3849399/v2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. Interactions between the host and virus govern induction, resulting in multiorgan impacts. In 2021, as normal life was challenging during the pandemic era, we analyzed SCI journals according to L. Wittgenstein's Tractatus Logi-co-Philosophicus. The pathophysiology of coronavirus disease 2019 (COVID-19) involves the following steps: 1) the angiotensin-converting enzyme (ACE2) and Toll-like receptor (TLR) pathways: 2) the neuropilin (NRP) pathway, with seven papers and continuing with twenty-four: 3) the sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) tetramerization pathway, with two papers and continuing with twelve: 4) inflammasome activation pathways, with five papers and continuing with thirteen: 5) the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS–STING) signaling pathway, with six papers and successful with eleven: 6) the spike protein pathway, with fourteen and continuing with twenty-three: 7) the immunological memory engram pathway, with thirteen papers and successive with eighteen: 8) the excess acetylcholine pathway, with three papers and successful with nine. We reconfirmed that COVID-19 involves seven (1-7) pathways and a new pathway involving excess acetylcholine. Therefore, it is necessary to therapeutically alleviate and block the pathological course harmoniously with modulating innate lymphoid cells (ILCs) if diverse SARS-CoV-2 variants are subsequently encountered in the future.

ACE2

cGAS–STING

Immunologic engram

Inflammasome

NLRP3

SAMHD1

SARS-CoV-2

Spike protein

TLR4

Acetylcholine

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. The symptoms of these patients are distributed across multiple geographical limits. Interactions between the host and virus govern induction, resulting in various consequences ¹. Blood levels of cytokines during infection with COVID-19 are characterized by distinct C-reactive protein (CRP), interleukin-6 (IL-6), or triglyceride levels and significantly increased circulation ² ³ ⁴ ⁵ ⁶.

The pathophysiologic mechanisms include direct toxicity through virus-dependent means, including invasion of alveolar epithelial and endothelial cells by SARS-CoV-2 and microvascular endothelial injury. Other virus-induced indirect conditions might be encountered during infection in the elderly with dementia drugs, such as immunological damage by suppressed muscarinic receptor and a dysregulated hyperinflammatory state, including perivascular inflammation and hypercoagulability with resultant thrombotic occlusions, effects on the renin-angiotensin-aldosterone system (RAAS), and the endothelium as well as maladaptation to the angiotensin-converting enzyme 2 (ACE2) pathway ⁷. Hypercoagulability and hyperinflammation may favor stroke via microvascular circulation abnormalities, microthrombus formation, and multifocal lesions ⁸. This pathological combination contributes to the breakdown of the endothelial–epithelial barrier ⁹.

Seven pathways and a novel excess acetylcholine pathway describe acute kidney injury, hepatic, cardiac, neurological, and gastrointestinal injury: acute coronary syndrome, myocarditis, arrhythmia, Takotsubo cardiomyopathy, stroke, encephalopathy, anosmia, transaminitis, diarrhea, nausea, vomiting, and anorexia ¹⁰. We have vigilantly monitored for underlying conditions. Our study describes the important molecular pathways associated with SARS-CoV-2 infection and provides detailed descriptions of pathological metabolic pathways based on eight tracks.

For 2023, two years after 2021, we checked the final experimental results and found that they matched precisely within the seven pathways. The experimental results for 2022 and 2023 are underlined along with the cited papers. Papers published before 2020 were excluded from the analysis. Only papers published from 2020 to 2024 are described (Table 1).

1. Of the eight papers cited on the ACE2 and TLR pathways, five were used, and three were not used. Six papers were added to the last version. Nineteen papers were added that described ACE2, TLRs, and inflammasome activation. Six papers were rediscovered between 2022 and 2023.

2. In the neuropilin‑1 pathway, all seven cited papers were used. Twenty-four papers were successive. Papers 54 and 58 were added while explaining the engrams. These findings provide insight into the distribution of NRP1 in brain cells. It was rediscovered by seven papers between 2022 and 2023.

3. In the SAMHD1 tetramerization pathway, two papers were used. Twelve papers were successive. Papers 64 and 81 were added while explaining the characteristics of the inflammatory response and IFN action caused by the spike protein. These findings were rediscovered by seven papers dated from 2022-2023.

4. In the inflammasome activation pathway, three of the five cited papers were still used. Paper 204 was not used, and paper 117 was used to explain why the spike protein activates the inflammasome. Thirteen papers were successive to the last version, and the findings were rediscovered by six papers from 2022-2023.

5. In the cGAS–STING signaling pathway, three of the six cited papers were still used. Papers 206 and 207 were not used, and paper 119 went on to explain the generation of an immune response by the spike protein. Eleven papers were published successively, and the findings were rediscovered by five papers from 2022-2023.

6. In the spike protein pathway, seven out of fourteen papers were continuously used. Papers 210, 211, 212, and 213 were not used; paper 16 went on to explain the mechanism by which ACE2 activates the inflammasome; and papers 64 and 81 went on to describe SAMHD1, which prevents virus invasion. Twenty-three papers were successive, 117 of which explained the inflammasome and 119 of which explained the cGAS–STING inflammasome; these findings were rediscovered by eight papers from 2022-2024.

7. In the immunological memory engram pathway, nine out of the thirteen papers were continuously used. Papers 214 and 215 were not used, and papers 54 and 58 were used to explain the clinical correlation between NRP1 in the brain and ARDS in the lung. Eighteen papers were published, and the findings were rediscovered by five papers published between 2022 and 2024.

8. Three papers were added to the excess acetylcholine pathway in 2022, and new results were rediscovered by nine papers from 2022-2023.

1. ACE2 and TLR pathways

The life cycle of SARS-CoV-2 begins after binding to ACE2 in the epithelium of the oral mucosa, lung, heart, and kidney, and the expression of ACE2 increases with age ¹¹ ¹². Smoking affects ACE2 expression and induces mineral dust‑induced gene (MDIG) expression, which alters the transcription of several essential proteins implicated in exacerbating COVID-19 ¹³ ¹⁴. This type of epigenetic gene expression alters gene locus function without changing the underlying DNA sequence. Instead, it relies on posttranslational chemical changes in chromatin, RNA, and DNA. These changes include acetylation, methylation, phosphorylation, ubiquitination and SUMOylation. These changes are linked to genotype and phenotype ¹⁵. The interaction of ACE2 with the SARS-CoV-2 spike protein (SP) in tiny numbers of embryonic-like stem cells (VSELs) and hematopoietic stem cells (HSCs) activates the NLR family PYRIN domain containing-3 (NLRP3) inflammasome. The exposure of human umbilical cord blood (UCB)-purified VSELs to recombinant SP can lead to the upregulation of NLRP3 mRNA expression ¹⁶. Human VSELs in adult tissues can be damaged by SARS-CoV-2, which has downstream and subsequent effects on tissue/organ regeneration ¹⁶. SARS-CoV-2 activates mitochondrial reactive oxygen species (ROS) production and glycolytic shift. SP alone can damage vascular endothelial cells by downregulating ACE2 and inhibiting mitochondrial function ¹⁷.

ACE2 and Toll-like receptor 4 (TLR4, CD284) on the cell surface belong to the pattern recognition receptor (PRR) family. ACE2 and TLR4 are highly expressed in hematopoietic stem and progenitor cells. These cells are highly susceptible to SP. ACE2 and TLR4 produce inflammatory cytokines and activate innate immune responses. Erythroid precursor cells (from CD 34⁺) differentiate into red blood cell (RBC) precursors and subsequently express ACE2. The SARS-CoV-2 SP interacts with RBC precursors, leading to dysregulation of hemoglobin and degradation of Fe-heme ¹⁸ ¹⁹. Blocking the interaction of SP with cell surface-expressed ACE2 and TL4 decreased the activation of the downstream mediator of NLRP3, caspase-1. This suppression was even more noticeable after blocking the interaction of the SP with both receptors. Exposure to SP upregulates the expression of proteins participating in the positive stimulation of the TLR4 signaling pathway ¹⁸. The SP has been proposed to have the most substantial protein‒protein interaction with TLR4. TLR2 and TLR4 are expressed intracellularly in dendritic, epithelial, and endothelial cells ²⁰ ²¹. The molecular influence of TLR4 is understood as a prime regulatory factor associated with immunity ²². TLR4 mediates anti-gram-negative bacterial immune responses by recognizing lipopolysaccharide (LPS) from bacteria ²³. Staphylococcus aureus triggers an inflammatory response in innate immune cells via TLR4 and the inflammasome ²⁴. SARS-CoV-2 infection results in viral sepsis and provokes an antibacterial-like response at the very early stage of infection via TLR4 ²⁵ (Fig. 1).

TLRs are a class of membrane pattern recognition receptors that detect microbes on the cell surface and in the cytoplasm, and a cytokine surge is induced by TLRs, mainly through the activation of TLR3, TLR4, TLR7, and TLR8²⁶. Subunit 1 of the SARS-CoV-2 spike protein (S1) induces sickness behavior and a subacute neuroinflammatory response for approximately 24 hours and a chronic neuroinflammatory response for approximately 7 days. Moreover, S1 directly induces a proinflammatory response in primary microglia and activates TLR4 signaling ²⁷. Neuroinflammation induced by microglia is mediated through the activation of nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) due to TLR2 and TLR4 activation ²⁶ ²⁷ ²⁸. TLR4 has been shown to play a role in mediating the neurotoxicity induced by α-synuclein (α-Syn) oligomers. Misfolded α-Syn induces inflammatory responses; however, α-Syn uptake is independent of TLR4. Furthermore, extracellular α-Syn can activate the proinflammatory TLR4 pathway in astrocytes ²⁹. The interaction between the SARS-CoV-2 SP and TLR4 can trigger an intracellular TLR4 signaling cascade. The NF-κB-mediated transcriptional activation of specific genes induces the release of proinflammatory cytokines, which can damage neurons and pathologically modify α-Syn ³⁰. The final sequence of NF-κB activation involves a range of cytokine receptor- and TLR-mediated signaling cascades. SARS-CoV-2 induces TLR4-mediated NF-κB activation, and erythroreticulum (ER) stress induces NF-κB activation and the production of immature IL-1β (pro-IL-1β) ³¹.

2. The neuropilin‑1 pathway

Neuropilin-1 (NRP1) is a pleiotropic single-transmembrane coreceptor for class 3 semaphorins and vascular endothelial growth factors. Along with ACE2, NRP1 facilitates the entry of SARS‑CoV‑2 into host cells. NRP1 is a highly conserved transmembrane receptor lacking a cytosolic protein kinase domain ³² ³³. In combination with host transmembrane protease serine 2 (TMPRSS2), SARS-CoV-2 uses the ACE2 receptor for cell entry, which cleaves the viral spike glycoprotein ³⁴ ³⁵. The expression of ACE2 and NRP1 with TMPRSSs has been observed in various human tissues and organs, thus facilitating viral activation and representing the essential host factors for SARS-CoV-2 pathogenicity. These viruses contribute to the tropism of SARS-CoV-2 in diverse tissues and organs and its related symptoms.

NRP1 is expressed in all vertebrates. NRP1 is the primary coreceptor for ACE2. NRP1 contributes to the primary tissue or organ tropism of SARS-CoV-2. NRP1 and 2 are involved in angiogenesis, axon control, cell proliferation, immune function, neuronal development, and vascular permeability because NRP1 is a coreceptor for vascular endothelial growth factors ³⁶. NRP1 plays a complex role in the secondary CD8+ T-cell response to control VRDs and tumors ³⁷. A complete understanding of NRP1 or NRP2 and its associated mechanical pathways will facilitate understanding of SARS-CoV-2 infectivity and improve patient treatments; however, ACE2 is the primary receptor for entry of SARS-CoV-2 into cells (Fig. 2).

The genetic susceptibility locus in respiratory failure patients with COVID-19 is located on chromosomes 3p21.31 and 9q34.2 and is related to severity; the 3p21.31 gene cluster can be found on chromosome 3 ³⁸. The risk locus is inherited from Neanderthals, which are segmented by a genomic size of approximately 50 kilobases, and there is no evidence that genetic haplotypes progressed from Neanderthals into African populations ³¹. According to the protein docking crystal structures, the receptor binding domain (RBD) of the SARS-CoV-2 spike protein has a potentially high affinity for dipeptidyl peptidase-4 (DPP4). The present genetic variants from a Neanderthal heritage plant were located in six genes on chromosome 3p21.31, which is in the proximal promoter region of DPP4. The DPP4 gene encodes the enzyme dipeptidyl peptidase IV. Dipeptidyl peptidase IV serves as a receptor for MERS-CoV ³⁹, but a genetic variant in the promoter region of the DPP4 gene has been shown to double the risk of developing critical COVID-19 pathogenesis. Moreover, DPP9, a homolog of DPP4, was significantly associated with severe COVID-19. These findings suggested a potential role for DPP4 in COVID-19 ⁴⁰. A haplotype on chromosome 12 from Neanderthals is associated with an approximately 22% decrease in the relative risk of developing severe illness ⁴¹. MDIGs are mainly responsible for the expression of inflammatory cytokines, the critical component of the inflammasome, and most of the genes involved in glycan metabolism for hyaluronan generation and glycosylation. MIDGs are crucial determinants of viral infection and cytokine storms ⁴². MDIG is an environmentally induced lung cancer oncogene whose entry into MDA-MB-231 and A549 cells depends on NRP1 and NRP2 expression in the cell membrane ⁴². MDIG is also an essential regulator of NRP1 and NRP2. In MDIG knockout cells, researchers observed strong H3K9me3 and H4K20me3 upstream of the DPP4 gene from the Neanderthal haplotype region at chromosome 3p21.31 and chromosome 2q24.2 on the proximal promoter region of DPP4, which is another Neanderthal variant gene ⁴². Moreover, these effects are attributable to pulmonary fibrosis in some COVID-19 survivors. Among patients with a history of environmental exposure, MDIG plays a critical role in preventing SARS-CoV-2 infection and reducing the severity of COVID-19. The MDIG-dependent expression of NRP1 or NRP2 enhances SARS-CoV-2 infection in cells with lower ACE2 expression ⁴². Knockout of MDIG does not affect the enrichment of the repressive histone trimethylation markers H3K9me3, H3K27me3, or H4K20me3 on the protective Neanderthal haplotypes on chromosome 12, which reduces the risk of exacerbating COVID-19 ⁴¹.

NRP1 is a tissue-specific marker of lung 2 ILC2s and is induced postnatally and sustained by lung-derived transforming growth factor-β1 (TGFβ1). TGFβ1–NRP1 signaling enhances ILC2 functions and type 2 immunity, suggesting that NRP1 is a tissue-specific regulator of lung-resident ILC2s and that the NRP1 regulator is a potential therapeutic agent for pulmonary fibrosis ⁴³. In addition, NRP1 and NRP2 support competent viral entry into host cells in the lung. MDR complex access to two additional cell lines (MDA-MB-231 and A549) depends on NRP1 and NRP2. Moreover, MDIG has a role in preventing SARS-CoV-2 infection and reducing the severity of COVID-19 in patients who are experiencing environmental exposure to toxins. These effects explain the observed pulmonary fibrosis in some COVID-19 survivors; MDIG-dependent expression of NRP1 or NRP2 increases SARS-CoV-2 infection despite reduced ACE2 expression ⁴². ILC2s are involved in virus-induced exacerbation of airway inflammation and are critical in pulmonary fibrosis and autoimmune disease ⁴⁴ ⁴⁵. Human ILC2s are flexible and adapt to the cytokine microenvironment by changing cytokine outputs to meet existing requirements ⁴⁶. ILC2s and eosinophils play vital roles in pulmonary arterial hypertrophy ⁴⁷.

Group 3 ILCs (ILC3s) produce greater amounts of cytokines than ILC3s that do not express NRP1. NRP1⁺ ILC3s are present in fetal tissues and ectopic lymphoid aggregates and play a role in inflammation and vascularization ⁴⁸. SARS-CoV-2 targets ciliated cells in the respiratory mucosa, but in the olfactory mucosa, the primary target is nonneuronal sustentacular cells. NRP1 is expressed in olfactory‑related neuronal regions ⁴⁹ ⁵⁰. Compared with other brain regions, SARS-CoV-2 may exhibit tropism to the brainstem, which has relatively high expression of the ACE2 receptor ³² ^33,51 ⁵². The recognized pathways involve transsynaptic transfer via peripheral, olfactory, or cranial nerves and blood‒brain barrier (BBB) penetration from the systemic circulation to invade the brainstem ⁵¹ ⁵² ⁵³. The recognized pathways invade the brainstem and involve transsynaptic transfer via peripheral, olfactory, or cranial nerves (Fig. 3).

Clinically, COVID-19-related acute respiratory distress syndrome (ARDS) is characterized by relatively preserved aeration on chest computed tomography (CT) despite severe respiratory hypoxemia. However, this early, high-compliance phenotype can develop into a low-compliance phenotype with poor aeration as L-type, characterized by low elastance, high compliance, and preserved aeration; and H-type, characterized by high elastance, low compliance, and poor aeration ⁵⁴. Patients with cryptococcus-associated immune reconstitution inflammatory syndrome can suffer from pulmonary dysfunction caused by T-cell-driven neurodegeneration in the vital medullary nucleus responsible for respiratory control ⁵⁵ ⁵⁶. The paralysis of the pre-Bötzinger complex on the medullar oblongata in the brainstem might affect L-type ARDS and COVID-19-associated fatality ⁵⁷. NRP-1 might induce the tropism of SARS-CoV-2 in the brainstem ⁵¹ ⁵⁷ ⁵⁸.

3. The SAMHD1 tetramerization pathway

VRDs produce interferon (IFN)-1, which exacerbates their pathological course, but interferon treatment reduces inhibitory M2 muscarinic receptor function ⁵⁹. The genesis of the acetylcholine (ACh) receptor requires interferon ⁶⁰. Muscarinic and nicotinic ACh receptors regulate immune function ⁶¹. The sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) operate at stalled replication forks to prevent the induction of IFN, a significant regulator of deoxynucleotide triphosphate (dNTP) concentrations in human cells ⁶². The concentrations of dNTPs, substrates for DNA-polymerizing enzymes, are limited in cells. However, SAMHD1 is a deoxyribonucleotide triphosphate triphosphohydrolase (dNTPase) that cleaves dNTPs to deoxynucleosides and triphosphates. The induction of SAMHD1 in differentiated cells requires low levels of dNTPs in nonproliferating cells to mediate DNA repair and maintain mitochondria. High dNTP levels can cause problems in maintaining mitochondrial function, which might occur in Aicardi–Goutières syndrome (AGS) patients. This genetic inflammatory encephalopathy resembles congenital viral infections and certain autoimmune disorders. AGS mutations in the SAMHD1 gene reduce catalytic activity or allosteric activation by dGTP. They also increase intracellular dNTP levels. These mutations may contribute to the dysfunctional differentiation of innate immune cells. The phenotype of SAMHD1 mutations is consistent with that of AGS, which increases dNTP levels. This could lead to a more robust viral infection because of the loss of the dNTP triphophohydrolase activity of SAMHD1. Viruses can replicate their viral genome with their polymerase ⁶³. Elevated intracellular levels of dNTPs are biochemical markers of cancer cells. Many multifunctional dNTPase and SAMHD1 mutations have been reported in various cancers. The SAMHD1 R366C/H mutant has been found in colon cancer and leukemia, as shown in Supplemental Fig. 1 of Supplement 1 ⁶⁴. R366C/H mutants retain dNTPase-independent functions, such as mediating dsDNA break repair, interacting with C-terminal binding protein 1 interacting protein (CtIP) and cyclin A2, and suppressing innate immune responses. The SAMHD1 R366 mutation does not alter the cellular protein levels of the enzyme but does inhibit the dNTPase activity and nucleotide density at the catalytic site on the X-ray structure. R366C/H does not restrict HIV-1 replication, which is a function of SAMHD1 that is dependent on the ability to hydrolyze dNTPs ⁶⁴. SAMHD1 negatively regulates the IFN-1 signaling pathway, and genetic loss of SAMHD1 elevates the innate immune response and IFN activation. The antiviral IFN responses induced by SAMHD1 suppressed SARS-CoV-2 replication and elevated cellular innate immunity ⁶⁵. Suppressing innate immune responses is essential for the survival of SARS-CoV-2 and HIV-1. Viral protein X (Vpx) performs several functions during infection, including downregulating SAMHD1 ⁶⁶ ⁶⁷ ⁶⁸. This function of Vpx is conserved among the HIV-2/simian immunodeficiency virus (SIV) accessory protein Vpx ⁶⁹. The lentiviral Vpx variant suppresses SARS-CoV-2 RNA expression in primary human monocyte–derived macrophages ⁶⁵. Moreover, Vpx inhibits STING signalosomes and interferes with the nuclear translocation of NF-κB and the induction of innate immune genes ⁶⁸.

Mutations in the Aicardi–Goutières syndrome protein SAMHD1 are implicated in the pathogenesis of chronic lymphocytic leukemia (CLL) and AGS. SAMHD1 has a target motif for cyclin-dependent kinase 1 (CDK1) (⁵⁹²TPQK⁵⁹⁵: the CDK-targeted motif driving threonine 592 (T592) phosphorylation) ⁷⁰. CDKs are protein kinases that play key roles in cell division, transcriptional regulation, and viral infections ⁷¹. SARS-CoV-2 infection triggers and redistributes cyclin D1 and D3 from the nucleus to the cytoplasm and subsequent proteasomal degradation. 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 ⁷².

Phosphorylation of SAMHD1 at residue T592 modulates the ability of SAMHD1 to block retroviral infection, but SAMHD1 can still decrease cellular dNTP levels⁷⁰. A phosphomimetic environment mimics the phosphorylation of amino acid substitutions. A distinct negatively charged T592 phosphomimetic mutation generates electrostatic repulsive movement and reduces the stability of the SAMHD1 tetramer and the dNTPase activity of the enzyme. This repulsive electrostatic phosphorylation allosterically decreases dNTPase activity and may modify antiviral functions ⁷³.

SAMHD1 forms tetramers of GTP, and all four dNTPs are controlled by the combined action and inactive apo-SAMHD1 interconverts between monomers and dimers. 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 ⁷⁴. The binding sites can adjust oligonucleotides instead of the allosteric activators GTP and dNTPs. The G-nucleotides containing oligonucleotides form a specific tetramer with mixed occupancy of the allosteric sites in the presence of GTP and dNTPs. Plastic and allosteric nucleic acid binding promotes the immunomodulatory effects of the antiretroviral activity of SAMHD1 ⁷⁵. 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 ⁷⁰ ⁷⁶. cell autonomous control of lentivirus infection in myeloid cells by SAMHD1 limits virus-induced production of IFNs and the induction of costimulatory markers. SAMHD1 autonomously controls viral infection through innate and adaptive immunity at the level of the infected cell. SAMHD1 limits lentivirus-induced IFN production in myeloid cells and reduces the induction of virus-specific cytotoxic T cells ⁷⁷. SAMHD1 mutations result in autoinflammatory AGS, and AGS secretes chronic IFN-I despite the absence of viral infections; moreover, this disease is characterized by early-stage brain disease ⁷⁸ ⁷⁹ ⁸⁰. SARS-CoV-2 encounters a response that requires the strong induction of a subclass of cytokines, including IFN-I, IFN-III, and a few chemokines ⁸⁰. The SAMHD1 tetramer structure could provide a mechanistic understanding of its rapid function in SARS-CoV-2 pathogenesis. SANHD1-deficient cells detect and activate IFN-I-mediated antiviral gene expression in HIV-1 cells via cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS–STING) ⁷⁹. cGAS–STING is decreased during radiotherapy in cancer patients but promptly recovers after radiotherapy. SAMHD1, which suppresses viral replication and viral response genes, occurs more frequently in severe ventilation-associated COVID-19 patients than in nonventilated patients, and we observed important treatment-related alterations, specifically IFN-I responses. ⁸¹. The degradation of SAMHD1 in human primary-activated/dividing CD4+ T cells, the increase in cellular dNTP levels, and the loss of dNTPase activity contribute to the increase in commonly observed dNTP levels ⁶⁴. SARS-CoV-2 aggravates a reaction in which SAMHD1 controls the innate immune response ⁶⁵. SAMHD1 in cells inhibits NF-κB activation and IFN-I induction ⁸². Therefore, low levels of IFN-I could drive more severe SARS‐CoV‐2 infection ⁸³.

4. Inflammasome activation pathway

The NLRP3 inflammasome contains NLRP3 as a sensor protein, ASC as an adaptor protein, and caspase-1 as an effector protein. 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 apoptosis-associated speck-like protein with the caspase recruitment domain (ASC) PYD and subsequently promotes ASC oligomer formation. The ASC platform induces caspase-1 activation, which catalyzes the conversion of pro-IL-1β to mature IL-1β. NLRP3 deubiquitination and self-aggregation occur after ASC recruitment and oligomerization. Active caspase-1 cleaves pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18, respectively. 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. IFN-α, IFN-β, IL-6, tumor necrosis factor (TNF), and TGFβ1 can lead to cytokine storms. The SARS-CoV-2 genome is enclosed by a nucleocapsid (N) protein in phospholipid bilayers. The membrane and envelope proteins are located among the SPs in the virus envelope. There are four main types of inflammasomes, NLRP1, NLRP3, NLRC4, and 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.) ⁸⁴.

Active the NLRP3 inflammasome were found in tissues and peripheral blood mononuclear cells (PBMCs) from postmortem patients with moderate or severe COVID-19. The serum levels of IL-6, LDH, caspase-1, caspase-4/11, and IL-18 are correlated with disease severity. Moreover, higher Caspase-1, Caspase-4/11, and IL-18 levels are associated with poor clinical outcomes ⁸⁵.

SARS-CoV-2 causes pyroptosis in human monocytes. Pyroptosis is associated with caspase-1, caspase-4/11, interleukin 1β (IL-1β), and gasdermin D expression and cytokine levels in primary monocytes ⁸⁶ ⁸⁷. SARS-CoV-2 engages in Caspase 4/11-mediated noncanonical activation of NLRP3 and contributes to COVID-19 exacerbation ⁸⁷. When recombinant baculoviruses displaying SP or nucleocapsid (N) protein were constructed and transfected into lung epithelial A549 cells and a spontaneously immortalized monocyte-like cell line (THP-1)-derived macrophages, the N protein triggered A549 cells to release more serum cytokines than did the SP ⁸⁸.

Blocking the NLRP3 inflammasome reduces the cytokine storms and lung injury caused by SARS-CoV-2 infection. 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 the NLRP3 inflammasome ⁸⁹.

The SARS-CoV-2 ORF10 targets STING, attenuates the STING-TBK1 association, and impairs STING oligomerization, aggregation, and autophagy (Fig. 4). It impairs cGAS–STING-TBK1 signaling and antagonizes STING-dependent IFN activation and autophagy ⁹⁰. ORF9b and nonstructural protein 7 (NSP7) antagonize the production of type I and III IFNs by targeting the retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5), TLR3-TIR-domain-containing adapter-inducing interferon-β (TRIF), and cGAS-STING signaling pathways ⁹¹ ⁹². The expression of NSP7 blocks innate immune activation and facilitates virus replication ⁹³.

The detection of cytosolic DNA (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 ⁹⁴. Microglial NLRP3 inflammasome activation is a major driver of neurodegeneration ⁹⁵ ⁹⁶ ⁹⁷^,, and purified SP activated the NLRP3 inflammasome in LPS-primed microglia in an ACE2-dependent manner ⁹⁸. In addition, mitochondrial antiviral signaling protein (MAVS) connects with NLRP3 and controls its inflammasome activity ⁹⁹.

5. cGAS–STING signaling pathway

SARS-CoV-2, an RNA virus, activates the cDNA sensor cGAS–STING signaling in endothelial cells. The cGAS-STING pathway controls immunity to cDNA and drives aberrant IFN-I responses in patients with COVID-19 ¹⁰⁰. Mitochondrial DNA is released and leads to IFN-I production. Blocking STING reduces severe lung inflammation, but a STING agonist also protects against SARS-CoV-2 infection¹⁰⁰ ¹⁰¹. cGAS catalyzes the conversion of cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) to cDNA. It triggers STING–tank-binding kinase 1 (TBK1)–interferon regulatory factor 3 (IRF3) signaling ¹⁰². cGAS also appears in the nucleus, where cGAS in an inactive state is isolated from chromatin. Nuclear cGAS recruits protein arginine methyltransferase 5 (PRMT5) upon viral infection. In innate immunity, nucleus-localized cGAS interacts with PRMT5 to catalyze the symmetric dimethylation of histone H3 arginine 2 at IRF3-responsive genes, such as interferon beta 1 (IFNβ1) and interferon alpha 4 (IFNα4). As a result, PRMT5 facilitates IRF3 access ¹⁰³. 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 ¹⁰⁴ ¹⁰⁵.

Severe COVID-19-related inflammation is associated with excessive lung tissue damage and syncytial pneumocyte formation. Cultured epithelial cells expressing ACE2 and 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 ¹⁰⁶. 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 ¹⁰⁷. Activated STING triggers membrane permeabilization and thus lysosomal cell death. cGAS–STING–lysosomal cell death combined with NLRP3 ameliorates the pathology of inflammatory conditions through cytosolic DNA sensing ⁹⁴ (Fig. 5). 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 ¹⁰⁸.

The pathway induces microglial activation to resolve inflammation in the brain. However, excessive engagement can lead to neuroinflammation and neurodegeneration ¹⁰⁹. cGAS–STING signaling is strongly related to the pathogenesis of neuroinflammation-driven disease progression ¹¹⁰. A vast array of germline-encoded innate immune receptors, commonly known as PRRs, facilitate innate immune recognition. Due to cellular senescence, autoimmune disorders, and mitotic stress in cancers, cytosolic DNA levels increase. These events lead to the activation of cGAS–STING and the exacerbation of pathological courses ¹¹⁰.

6. Spike protein pathway

Glycoproteins are required for viral entry and fusion. The SP is a trimeric glycoprotein encoded by ORF2 in the viral genome. The membrane-distal S1 subunit and proximal S2 subunit in the virus envelope form homotrimers ¹¹¹. Glycoproteins derived from SARS-CoV-1, SACR-Co-V-2, human cytomegalovirus, and hepatitis C virus potentially trigger NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages ¹¹² ¹¹³. SP binding to ACE2 induces NF-κB activation and inflammation via ACE2 in endothelial cells ¹¹⁴. The furin cleavage product of SP uses the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 as an entry point ¹¹⁵.

The SARS-CoV-2 SP S1 subunit activated the NF-κB and c-JNK signaling pathways. Furthermore, SP interacts with and activates TLR4 ²⁵ ¹¹⁶. SP induces neuroinflammation in BV-2 microglia, a microglial cell line derived from C57BL/6 mice. Immunofluorescence microscopy revealed increased TLR4 expression in BV-2 microglia when stimulated with S1 ²⁸. After SARS-CoV-2 infection, the augmented immunogenicity of the SP results from macrophage reprogramming. SP-driven IL-1β secretion in macrophages requires nonspecific monocyte preactivation in vivo. Then, macrophages trigger NLRP3 inflammasome signaling ¹¹⁷. The SP drives inflammasome activation in macrophages isolated from convalescent COVID-19 patients, correlating with distinct epigenetic and gene expression signatures ¹¹⁷. The SP is a PAMP that requires macrophage preactivation for NLRP3 inflammasome formation, and vigorous SP-driven inflammasome activity releases IL-1β in the convalescent macrophages of COVID-19 patients ¹¹⁷. However, it is not released in macrophages from healthy SARS-CoV-2-naive patients. SARS-CoV-2 infection causes profound and long-lived reprogramming of macrophages. This results in augmented immunogenicity of the SARS-CoV-2 SP, an effective vaccine antigen, which promotes potent adaptive and innate immune signaling ¹¹⁷.

SARS-CoV-2 infection can lead to syncytium formation within cells. The syncytia express ACE2 and SP, which produce approximately four micronuclei per syncytium. Remarkably, these micronuclei are highly expressed during the DNA damage response or during cGAS–STING signaling, which is associated with cellular devastation and poor immune reactions ¹¹⁸ ¹¹⁹. Pathogenic platelet factor 4 (PF4)-dependent syndrome can occur after ChAdOx1 nCoV-19 vaccination ¹²⁰. Various side effects caused by the vaccine’s SP appear in a real-time setting. The SP has a unique pathological mechanism: there are strange similarities with amyloid disease-associated blood coagulation and fibrinolytic disturbances together with neurologic and cardiac problems. The protease neutrophil elastase (NE) efficiently cleaves SP, exposes amyloidogenic segments, and accumulates the most amyloidogenic synthetic spike peptide, but full-length folded SP does not form amyloid fibrils ¹²¹ ¹²². SARS-CoV-2 SP vaccination establishes long-lived SP–specific plasma cell reservoirs in the bone marrow of nonhuman primates ¹²³. The SP might have induced immune reactions in humans.

Lipid nanoparticles of the formulated nucleoside-modified mRNAs of SPs are stabilized in their prefusion conformation. They induce an immune reaction involving IL-2⁺ CD8⁺ and CD4⁺ T helper type 1 cells or IFNγ+ cells ¹²⁴. Lipid nanoparticles encode the prefusion conformation of SP. General adverse reactions include pain, swelling, redness, muscle pain, headache, fever, and chills after vaccination. Adverse events of special interest (AESI) included anaphylaxis, life-threatening disease, permanent disability/sequelae, and death. The overall seroprevalence of Korean anti-SARS-CoV-2 was very low on September 6, 2021, but the incidence of AESI was very high, as was the case in England during the pandemic. We compared AESI after vaccination in England and South Korea (Fig. 6). These findings suggested that AESI might originate from immune reactions induced by lipid nanoparticles, including the SARS-CoV-2 SP, in mRNA vaccines ¹² ¹¹⁷ ¹²³ ¹²⁴.

Like other RNA viruses, SARS-CoV-2 undergoes genetic evolution and develops mutations over time, resulting in the emergence of multiple variants that may have different characteristics than their ancestral strains ¹²⁵ ¹²⁶. The wild-type/Wuhan variant S1 is highly proinflammatory in zebrafish, but the SP of the SARS-CoV-2 variants of interest shows differential proinflammatory effects ¹²⁷. Moreover, the SP signals through TLR2 and activates NLRP3 in human macrophages from convalescent patients with COVID-19 but not from healthy SARS-CoV-2–naïve individuals ¹¹⁷. SP can prime the NLRP3 inflammasome and enhance caspase-1 activity through NF-κB signaling. S1 interacts with amyloid-beta, prion protein, α-Syn, and tau, presumably through heparin-binding domains, to form homopolymers or heteropolymers resembling amyloid fibrils in the neurodegenerative process of misfolded protein disorders in the brain and increases the protein level of p38 MAPK in BV-2 microglia. S1 also binds to transactive response DNA-binding protein 43 (TDP-43) and RNA-binding motifs (RRMs); TDP-43 RRM is involved in amyotrophic lateral sclerosis (ALS) and AD. The interaction of the SP with the prion protein is more robust than that with amyloid-beta, tau, or α-Syn ²⁸ ⁹⁸ ¹²⁸. The hyperinflammatory state of COVID-19 triggers CNS neuroinflammation by activating astrocytes and microglia. This condition could facilitate prion-like pathology ¹²⁹. Like other prion proteins, the SP contains several prionogenic domains. SP triggers a neurodegenerative condition known as prion-disease-like pathology ¹³⁰. SP can catalyze the aggregation of aggregation-prone proteins in the brain, and spike-derived peptides can act as functional amyloids. Cross-reactive antibodies can originate from many reported complications, such as the worsening of demyelinating diseases, Guillain–Barré syndrome, immune thrombotic thrombocytopenia, and stroke ¹³¹. As a result, rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines develop, such as anaphylaxis, chest pain, chills, flushing, hypertension, and tachycardia ¹² ¹³². In addition, two distinct self-limiting syndromes, myocarditis and pericarditis, occur in only one patient after COVID-19 vaccination. Specifically, myocarditis develops rapidly in younger patients. It occurred mainly after the second vaccination. However, pericarditis, which occurs after receiving mRNA vaccines, affects older people after the first or second vaccination ¹³³.

7. Immunological memory engram pathway

A single or double layer of invaginated pia forms an interstitial fluid-filled space in the perivascular space in the brain. The space represents an extension of the extracellular fluid space around the intracranial vessels that descend into the brain parenchyma ¹³⁴. Human sensory stimuli and abnormal muscular sensations affect breathing via the cerebral cortex and hypothalamus¹³⁵ ¹³⁶. The substrate of information is stored in cells termed engram cells ¹³⁷. The brain can trigger immune reactions in patients with COVID-19. The subsequent reactivation of the engram stimulates memory retrieval of immune-related information in the insular cortex ¹³⁸. Chemogenetic reactivation reflects the inflammatory conditions described in the insular cortex ¹³⁹. The immunological memory engram pathway can restore the initial disease state during COVID-19 pathogenesis ¹⁴⁰. SARS-CoV-2 infection during the fetal period may alter the normal functioning of the brain region where memory engrams are generated and affect neuronal progenitor cells ¹⁴¹. The massive infection rate in young people leads to the possibility of an increase in the incidence of congenital infections and originating cognitive alterations in terms of new variants; consequently, neuronal circuit anomalies may indicate vulnerability to mental problems throughout life ¹⁴¹ ¹⁴² ¹⁴³ (Fig. 7).

SARS-CoV-2 may disrupt BBB dysfunction by damaging the choroid plexus epithelium through cytokine, chemokine, and adhesion molecule storms ¹⁴⁴ ¹⁴⁵. The neuropathology of COVID-19 brains was significantly greater than the microgliosis and T-cell infiltration in COVID-19-free patients. Altered brain T-cell-microglia interactions are linked to profound neuroinflammation ¹⁴⁶. This might trigger inflammasomes and pyroptosis in the CNS. Brainstem involvement could explain sudden deaths by respiratory failure ¹⁴⁷ ¹⁴⁸ ¹⁴⁹. COVID-19 is characterized by the rapid development of acute lung injury, ARDS, death due to dysregulated cytokine release, disseminated intravascular coagulation (DIC), multisystem failure, and pneumonia. However, COVID-19 causes unique type L or H phenotype lung injury and requires different ventilatory approaches, depending on the underlying physiology ⁵⁴. Often, preexisting neurological disease may become clinically evident or worsen to immune suppression or modulation ¹⁵⁰. ACE2 expression in the lungs is modest compared to that in other organs, such as the heart, kidneys, and small intestines. However, TLR4 is expressed intracellularly on the whole body's dendritic, epithelial, and endothelial cells ¹⁵¹ ¹⁵². Conventional dendritic cells are highly specialized antigen-presenting cells that are key initiators and regulators of T-cell-mediated immunity, and their absence in a murine line lacking conventional dendritic cells results in consequent impaired CD8+ T-cell responses and subsequently in a significant increase in the SARS-CoV-2 viral load in the lungs ¹⁵³. Microglia and astrocytes participate in immune-to-brain communication during immune activation. Glia, microglia, and astrocytes propagate inflammatory signals and influence physiological responses in the body ¹⁵⁴. Janus kinase (JAK)1-dependent type 2 cytokines promote atopic dermatitis and asthma, and human JAK1 gain-of function variant (JAK1^GoF) leads to the development of spotanous atopic dermatitis and staggering of JAK1 in the vagus nerve to induce lung inflammation. Subsequent genetic expression suppresses group 2 ILC function and allergic airway inflammation. ¹⁵⁵ ACE2 is localized to the cytoplasm, and its expression appears to be highly regulated by other renin-angiotensin system components. In transgenic mouse brains, ACE2 is present in the cytoplasm of neuronal cell bodies but not in glial cells. ACE2 in transgenic mice was significantly increased in an area lacking the blood‒brain barrier and sensitive to blood-borne angiotensin II ¹⁵⁶. Activating the peripheral immune system via the immunologically coordinated engram pathway elicits exaggerated COVID-19 symptoms. This immunological memory engram pathway is activated during COVID-19 pathogenesis.

8. Excess acetylcholine pathway activity in dementia patients with anti-Alzheimer’s disease

SARS-CoV-2 was shown to trigger neuroinflammation in the olfactory mucosa in AD patients ¹⁵⁷, and an analgesic agent against neuroinflammation was shown to prevent and treat AD exacerbation ¹⁵⁸.

8.1 More details on rationale

We observed the effects of excess acetylcholine in combination with the drug Alzheimer’s disease (AD) (AAD) on the sustained viral RNA interferon response. VRDs cause lung inflammation and inflammatory cytokine production. Participants were randomized to VRDs after prescribing dapsone as a standard treatment or AADs as AD symptom treatments from 2005 to 2019 in an RCT. The incidence of endemic diseases on Sorok Island, South Korea, sharply increased from 2008 to 2009; that of chronic obstructive pulmonary disease (COPD) increased rapidly in 2012 and 2013; that of acute bronchitis increased from 2012 to 2014; and that of pneumonia increased in 2013 compared to earlier years. The equation for the use of dapsone in combination with acetylation as a preventive treatment for VRDs and excess ACh in AADs (AA equation) was strongly negatively correlated with the incidence of bronchitis and COPD. Excess ACh produced by AADs exacerbates bronchitis and COPD ¹⁵⁹.

The muscarinic (M) and nicotinic ACh receptors play life-threatening roles in regulating immune function. Viral infection and interferon treatment cause the release of IFN-γ, decrease M2 receptor gene expression at parasympathetic nerve endings, and ultimately inhibit M2 receptor gene expression ⁵⁹ ⁶¹. COVID-19 is regarded as a hyperinflammatory disease characterized by cytokine release by harmful immune cells. However, the plasma concentrations of these viruses are close to those provoked by classical viral respiratory infections (VRDs), such as influenza ¹⁶⁰ ¹⁶¹. VRDs and IFN-1 induce the loss of inhibitory M2 receptor function and gene expression in cultured airway parasympathetic neurons. Moreover, the excess ACh produced by AADs appears to inhibit the production of the ACh receptor, which prevents virus invasion ¹⁵⁹ (Fig. 8). The cohort study indicated another exacerbating factor related to the viral diseases on Sorok Island.

8.2 Supporting evidences

As of April 17, 2022, there were 55,841 cases of COVID-19 reinfection in South Korea, for an incidence rate of 0.35%. Ninety days after the initial diagnosis, there were 53,301 cases of reinfection, which accounted for 95.5% of the total cases. A total of 99.0% of reinfection cases occurred during the period when the omicorn virus was dominant. There were 72 patients with exacerbated COVID-19; 70 (97.2%) patients had exacerbated disease after 50 years of age, and 52 (100%) patients died after 50 years of age ¹⁶². Sixty-seven of the 72 cases (93.1%) occurred in nursing hospitals and homes. Patients in nursing hospitals and homes take the following AD drugs: donepezil, choline alfoscerate, rivastigmine, galantamine, and memantine ¹⁶³. We compared higher risk subjects who had elapsed since receiving the third vaccination because the fourth COVID-19 vaccine dose was first released from February 16 to April 30, 2022. We analyzed the data of 1,509,970 participants in the high-risk groups, namely, residents of patients in elderly care hospitals and facilities (E1) and immunocompromised individuals (E2). Standardizing per 100,000, infection after the third vaccine was 71.7% (E1) and 28.3%, and severity was 89.4% (E1) and 10.6% (E2), death was 92.0% (E1) and 8.0% (E2), and infection after the fourth vaccine was 74.2% (E1) and 25.8% (E2). The severity of infection was 91.5% (E1) and 8.5% (E2), and the mortality rates were 93.8% (E1) and 6.2% (E2) ¹⁶⁴. One major factor is that, compared with E2, E1 has excess ACh, which increases susceptibility to infection and exacerbates severity and mortality. Excess ACh appears to inhibit ACh receptors to promote IFN production during viral invasion ¹⁵⁹ ¹⁶⁵. Excess ACh related to AD and related dementias is an underlying or contributing cause of excess mortality in nursing homes, long-term care settings, homes, and medical facilities ¹⁶⁶ ¹⁶⁷.

8.3 Limitations

A wide variety of factors simultaneously act as aggravating factors. Increased levels of oxidative stress, desensitized inflammation, and immune responses, and alterations to genes associated with olfaction were shown in the transcriptomic signatures of olfactory mucosa cells at the air-liquid interface from individuals with AD ¹⁵⁷. Gut microbiota imbalances can trigger several immune disorders through the activity of T cells, both near and distant from the site of induction ¹⁶⁸. The gut microbiota drives systemic antiviral immunity via IFN-I priming, and microbiota-driven IFN-I priming involves the cGAS–STING axis ¹⁶⁹. Nevertheless, the nucleotide-binding oligomerization domain containing 2 (NOD2) in the hypothalamus recognizes neuropeptides and fragments of bacterial cell walls, which change temperature regulation and feeding behavior in mice, particularly older female mice ¹⁷⁰. These findings explain the multidimensional roles of human IFN in regulating senescence, autophagy, apoptosis, antitumor effects, and cell metabolism ¹⁷¹.

Perspective on implications and limitations

ILC3s are essential for host defense against infection and tissue homeostasis. ILC3s depend on the transcription factor retinoic acid-related orphan receptor-gamma γt (RORγt). It plays a role in angiogenesis, initiating ectopic pulmonary lymphoid aggregates ⁴⁸. In addition, ILC3s harboring NRP1 (NRP1⁺ ILC3s) are found in ectopic lymphoid aggregates in patients with chronic lung disease. NRP1⁺ ILC3s also potentially contribute to inflammation and vascularization ⁴⁶. NRP1⁺ ILC3s are present in the lymphoid tissues and lung tissues of smokers and COPD patients. NRP1⁺ ILC3s produce more cytokines than ILC3s without NRP1 (NRP1^- ILC3s) ⁴⁸. The gut microbiota with acetate modulates ILC3 immunity ¹⁷². The gut microbiota drives systemic antiviral immunity. T and B cells in the mucosa play pivotal roles in maintaining immune homeostasis by suppressing responses to harmless antigens and ensuring the integrity of the barrier functions of the gut mucosa ¹⁶⁸. The microbiota mediates systemic IFN-I priming via DNA-containing membrane vesicles ¹⁶⁹. The prevention of microbiota-driven IFN-I involves the cDNA sensor cGAS–STING axis ¹⁶⁹.The microbiota influences position-specific phenotypes and functions ¹⁷¹. Moreover, ACh excess by AADs might inhibit ACh receptors for IFN production and exacerbate COVID-19 ¹⁵⁹ ¹⁶² ¹⁶⁴.

COVID-19 induces an immune response in CD8+ T cells, in which feedback activates the NLRP3 inflammasome in an antigen-dependent manner to promote IL-1β maturation on APCs ¹⁷³ ¹⁷⁴ ¹⁷⁵. CD8+ T cells might originate from T-cell activation caused by HLA polymorphisms ¹⁷⁶. T cells from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQ13:01KLIANQF ¹⁷⁷. At least 20% of individuals with an HLA-B*15:01 status are asymptomatic ¹⁷⁸ ¹⁷⁹. The weak binding affinity of HLA polymorphisms might contribute to SARS-CoV-2 Omicron’s immune evasion ¹⁸⁰.

In viral diseases, excessive production or decreased production of IFN may be an important factor in ultimately worsening pathology. However, in the eight studies in this study, too many complex and diverse pathways are involved in IFN, making it difficult to find treatments that can effectively and efficiently manage it.

An outlook on important questions remaining and directions for future investigations

Activating cytokines or PAMPs leads to the transcriptional upregulation of canonical and noncanonical inflammasome components ¹⁸¹. IFN-I-activated microglia and other brain cells arise and expand in amyloidosis, and IFN-I signaling promotes plaque accumulation in neural cells ¹⁸². Manry et al. reported that circulating autoantibodies neutralizing IFN-α, IFN-ω, and IFN-β increased fatality in 1,261 patients who died and 34,159 individuals from the general population ¹⁸³. Among the COVID-19-positive veterans who were in the Armed Forces, a previous aspirin prescription was clinically significantly associated with a decrease in overall mortality at 14 days (OR, 0.38) and 30 days (OR, 0.38) ¹⁸⁴. Sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase (MPO)-DNA complexes, and citrullinated histone H3. The levels of cell-free DNA and MPO-DNA were high in hospitalized patients receiving mechanical ventilation or breathing room air ¹⁸⁵. Dexamethasone administered at a cumulative dose between 60 and 150 mg was associated with reduced mortality only in patients requiring respiratory support ¹⁸⁶. In COVID-19 and other ARDS cases, a high neutrophil-to-lymphocyte ratio (NLR) is associated with increased myeloid-derived suppressor cells (MDSCs) ¹⁸⁷ ¹⁸⁸. An elevated NLR and typical bone marrow emergency granulopoiesis in COVID-19 patients are related to increased MDSC numbers ¹⁸⁹ ¹⁹⁰. MDSCs increase immunosuppressive activity and are critical during severe COVID-19 ¹⁹¹. According to an RCT, the incidence of VRDs associated with dapsone was lower than that associated with VRDs without dapsone ¹⁵⁹. Dapsone treatment was associated with a lower NLR in the ICU ⁵⁷ ¹⁵⁸ ¹⁹² ¹⁹³. The HLA polymorphisms might be associated with Omicron evasion ¹⁸⁰ and dapsone hypersensitivity is susceptible to the expression of HLA-B*13:01 ¹⁹⁴ ¹⁹⁵. It relates the treatment asymptomatic with an HLA-B*15:01 status ¹⁷⁸ ¹⁷⁹. Anticatalysis might be used as an asymptomatic treatment for COVID-19, as in asymptomatic individuals carrying HLA-B*15:01. We explored immune strategies for preventing COVID-19-related exacerbation of pathophysiology (Table 2).

COVID-19 is exacerbated via seven pathways. COVID-19 is exacerbated by ACE2-TLR4, NRP1, SAMHD1, inflammasome, cGAS–STING, SP, and immunologic engram. Moreover, excess ACh during SARS-CoV-2 variant invasion might inhibit ACh receptors to promote IFN production, but the excess ACh pathway requires further validation. The first-line anti-catalytic triad needs to prevent and block pathological processes, mutations, and deterioration.

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).

In 2021, as external activities were difficult during the pandemic era, we analyzed SCI journals according to L. Wittgenstein's Tractatus Logico-Philosophicus ¹⁹⁶. We investigated and pictured the SARS-CoV-2 penetration route with seven deductions. When these are called basic propositions, the proposition must be the truth function of the basic proposition. If If it is a tautology of (p, q) (T T T T), then p is p (p ⸧ p) and q is q (q ⸧ q). An easy way to prove these is to observe whether the experimental results found are repeated over a period of 1-2 years.

Inclusion criteria. Through information search, key words were connected based on the research results. The order is as follows: 1) the angiotensin-converting enzyme 2 (ACE2) and Toll-like receptor (TLR), 2) the neuropilin (NRP), 3) the sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) tetramerization, 4) the inflammasome activation, 5) the cytosolic DNA sensor cyclic-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS–STING) signaling, 6) the spike protein with vaccines, and 7) the immunological memory engram.

Exclusion criteria: If experimental data was not repeated SCI journals, those were excluded.

We published a preprint (related material) on January 14, 2022.

Preprint: Lee, J. (2022, January 14). Pathology and Anticatalysis treatment of exacerbated COVID-19. https://doi.org/10.31219/osf.io/t9wjz (version 1. 01/14/2022 09:27:40) (Supplement 2)

The preprint was exposed to Views: 617/Downloads: 274. This preprint has been updated to the final version 18 (September 30, 2023) for the support of related information. This study is not a simple retrieval of systemic reviews but rather a prediction of seven pathways using picture theory for the real world during the pandemic ¹⁹⁶. We analyzed the final results on December 3, 2023.

In addition, we conducted the data analysis to find new paths. According to the Korea Drug Code of Medicine, the ADs for symptomatic relief are donepezil hydrochloride, rivastigmine, galantamine, and memantine. The ADs used for psychological symptoms were haloperidol, risperidone, quetiapine, olanzapine, aripiprazole, oxcarbazepine, fluvoxamine, escitalopram, trazodone, sertraline, escitalopram, and fluoxetine. The cumulative number of confirmed cases of coronavirus disease 2019 (COVID-19) was 16,130,920 from January 2020 to April 16, 2022. Based on the status of confirmed cases up to April 16, 2022, in the COVID-19 information management system of the Korea Centers for Disease Control and Prevention, a survey of total cases of COVID-19 reinfection was conducted ¹⁶² ¹⁶⁴. Per the Information Disclosure Act, we obtained relevant information of registration number 9318128 from the Korea Disease Control and Prevention Agency (Supplement 3). A reinfection was defined as a case in which a positive polymerase chain reaction (PCR) or professional rapid antigen test (RAT) result was confirmed 45 days after the first confirmation, regardless of the presence or absence of symptoms.

Ethical Approval

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).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors affirm that the human research participants provided informed consent for the publication of the manuscript results.

Competing interests

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.

Authors' contributions

All the authors listed have made substantial, direct, and intellectual contributions to the work and approved it for publication.

J.L. designed this study and the methodology and wrote this manuscript; S.C. and K.L. introduced dexamethasone use at O2 2L/min states and proved its safety and effectiveness; C.S., E.L.A. and M.D.C. reviewed the manuscript; M.D.C. examined dexamethasone use.

Funding

No funding

Availability of data and materials

No data associated with the manuscript

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
AMI	Acute myocardial infarction
AMI I/R injury	AMI ischemia–reperfusion injury
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
BiPAP	Bilevel positive airway pressure
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
HAART	Highly active antiretroviral therapy
HIV	Human Immunodeficiency Virus
HLA	Human leukocyte antigen
HLA-DRB1	Major histocompatibility complex, class II, DR beta 1
HSPC ICU	hematopoietic stem/progenitor cell 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
JNK	Jun N-terminal kinases
LDH	Lactate dehydrogenase
LDL	Low-density lipoprotein
LL	Lepromatous leprosy
LPS	Lipopolysaccharide
LTP	Long-term potentiation
M receptor	Muscarinic receptor
MADDS	Monoacetyldapsone
MAPK	Mitogen-activated protein kinase
MCI	Mild cognitive impairment
MDIG	Mineral dust-induced gene
MHC	Major histocompatibility complex
MIS-C/A	Multisystem inflammation syndrome in children and adults
MPO	Myeloperoxidase
N receptor	Nicotinic receptor
NOD2	Nucleotide-binding oligomerization domain containing 2
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
PAI-1	Plasminogen activator inhibitor-1
PAMPs	Pathogen-associated molecular patterns
PBMCs	Human peripheral blood mononuclear cells
PD	Parkinson’s disease
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
PTM	Multiple posttranslational modification
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
SCLS	Systemic capillary leak syndrome
RCT	Randomized controlled trial
SOD	Superoxide dismutase
TGFβ	Transforming growth factor-beta
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

Table 1 COVID-19 picture on the basis of the real world

The 1st version 2022-01-14

The last in 2024-01-04

^*1Original Preprint

^*2Matched

2020-2021

2022-2024

1. ACE2 and TLRs pathways

(25) (Vaduganathan et al, 2020 ^*3)

(26) (Kucia et al, 2021)

(27,28) (Choudhury & Mukherjee, 2020)

(29) (Olajide et al, 2021)

(30) (Rannikko et al, 2015)^*4

(31) (Conte, 2021)

(32) (Jurgens et al, 2012)

(33) (Tanaka et al, 2018)

(34) (Sparkman et al, 2019)

(35) (Muscat & Barrientos, 2021)

(36) (Boldrini et al, 2021)

(37,38) (Zeberg & Pääbo, 2020)

~~¹⁹⁷~~ ~~(Vaduganathan et al, 2020)~~ ^*5

¹⁸ (Kucia et al, 2021) ^*6

²⁰ (Choudhury & Mukherjee, 2020)

²⁸ (Olajide et al, 2021)

²⁹ (Rannikko et al, 2015)

³⁰ (Conte, 2021)

¹⁹⁸ (Jurgens et al, 2012)

¹⁹⁹ (Tanaka et al, 2018)

²⁰⁰ (Sparkman et al, 2019)

~~²⁰¹~~ ~~(Muscat & Barrientos, 2021)~~

~~²⁰²~~ ~~(Boldrini et al, 2021)~~

³¹ (Zeberg & Pääbo, 2020)

¹¹ (Devaux et al, 2020)

¹³ (Kumar et al, 2021)

¹⁵ (Chlamydas et al, 2021)

¹⁶ (Ratajczak et al, 2021)

¹⁷ (Lei et al, 2021)

¹⁸ (Kucia et al. 2021)

²⁰ (Choudhury and Mukherjee 2020)

²¹ (Choudhury et al. 2021)

²² (Patra et al, 2021)

²⁵ (Zhao et al, 2021)

²⁸ (Olajide et al, 2021)

³⁰ (Conte, 2021)

³¹ (Zeberg & Pääbo, 2020)

¹² (Lee, 2023) ^*7

¹⁴ (Shirvaliloo, 2022)

¹⁹ (Kronstein-Wiedemann et al. 2022)

²⁴ (Gonzalez et al, 2023)

²⁶ (Manik & Singh, 2022)

²⁷ (Frank et al, 2022)

2. Neuropilin‑1 Pathway

(39,40) (Cantuti-Castelvetri et al, 2020; Daly et al, 2020)

(41) (Kyrou et al, 2021)

(42) (Khan et al, 2021)

(43) (Davies et al, 2020)

(44) (Zhang et al, 2021)

(45) (Zeberg & Pääbo, 2020)^*8

(46) (Zeberg & Pääbo, 2021)

^32,33 (Cantuti-Castelvetri et al, 2020; Daly et al, 2020)

³⁶ (Kyrou et al, 2021)

⁵⁰ (Khan et al, 2021)

⁴⁹ (Davies et al, 2020)

⁴² (Zhang et al, 2021)

⁴¹ (Zeberg & Pääbo, 2021)

³² (Daly et al. 2020)

³³ (Cantuti-Castelvetri et al. 2020)

³⁴ (Hoffmann et al. 2020)

³⁵ (Mollica, Rizzo, and Massari 2020)

³⁶ (Kyrou et al. 2021)

⁴⁹ (Davies et al. 2020)

⁵⁰ (Khan et al. 2021)

⁵¹ (Yong 2021)

³⁸ (Group 2020)

³⁹ (Li et al. 2020)

⁴¹ (Zeberg and Pääbo 2021)

⁴² (Zhang, Wadgaonkar, et al. 2021)

⁴⁴ (Clottu et al, 2021)

⁴⁶ (Meininger et al, 2020)

⁵⁴ (Marini & Gattinoni, 2020)

⁵⁷ (Kanwar et al, 2021)

⁵⁸ (Ferren et al, 2021)

⁵³ (Lee et al. 2022)

⁵² (Lucchese et al. 2022)

⁴⁰ (Kerner and Quintana-Murci 2022)

⁴³ (Zhang et al, 2022)

⁴⁵ (Spits & Mjösberg, 2022)

⁵⁵ (Kawano et al, 2023)

⁵⁶ (Dangarembizi & Drummond, 2023)

3. SAMHD1 tetramerization pathway

(54) (Coquel et al, 2018)

(55) (White et al, 2013)

(56) (Tang et al, 2015)

(57) (Franzolin et al, 2015)

(58) (Ji et al, 2013)

(59) (Yu et al, 2021)

(60) (Khan & Sergi, 2020)

(61) (Maelfait et al, 2016)

(62) (Crow & Manel, 2015)

(63) (Rice et al, 2009)

⁶² (Coquel et al, 2018)

⁷⁰ (White et al, 2013)

⁷³ (Tang et al, 2015)

²⁰³ (Franzolin et al, 2015)

⁷⁴ (Ji et al, 2013)

⁷⁵ (Yu et al, 2021)

⁸⁰ (Khan & Sergi, 2020)

⁷⁷ (Maelfait et al, 2016)

⁷⁹ (Crow & Manel, 2015)

⁷⁸ (Rice et al, 2009)

⁶⁴ (Bowen et al, 2021)

⁶⁶ (Cingöz et al, 2021)

⁷⁵ (Yu et al. 2021)

⁸⁰ (Khan and Sergi 2020)

⁸¹ (Kwan et al, 2021)

⁷¹ (Yan, Tang, and Zheng 2022)

⁷² (Gupta and Mlcochova 2022)

⁶⁵ (Oo et al. 2022)

⁶⁷ (Lee et al, 2023)

⁶⁹ (Fink et al, 2022)

⁷¹ (Yan et al, 2022)

⁷² (Gupta & Mlcochova, 2022)

4. Inflammasome activation pathway

(47) (Rodrigues et al, 2020)

(48) (Ferreira et al, 2021)

(49) (Pan et al, 2021)

(50) (Theobald et al, 2021)

(51) (Vora et al, 2021)

(52) (Ichinohe et al, 2013)

(53) (Park et al, 2013)

⁸⁵ (Rodrigues et al, 2020)

⁸⁶ (Ferreira et al, 2021)

⁸⁴ (Pan et al, 2021)

¹¹⁷ (Theobald et al, 2021) ^*9

~~²⁰⁴~~ ~~(Vora et al, 2021)~~

⁸⁹ (Ichinohe et al, 2013)

⁹⁹ (Park et al, 2013)

⁸⁵ (Rodrigues et al. 2020)

⁸⁶ (Ferreira et al. 2021)

⁸⁴ (Pan et al. 2021)

⁹¹ (Han et al. 2021)

⁹² (Rui et al. 2021)

⁹⁵ (Lee et al, 2020)

⁹⁶ (Lee et al, 2021)

⁸⁷ (Rodrigues and Zamboni 2023)

⁹⁰ (Han et al. 2022)

⁹³ (Deng et al. 2023)

⁹⁷ (Beckman et al, 2022)

⁹⁸ (Albornoz et al, 2022)

⁸⁸ (Wang et al, 2023)

5. cGAS–STING signaling pathway

(65) (de Oliveira Mann & Hopfner, 2021)

(66) (Paul et al, 2021)

(67) (Fengjuan Li, 2021)

(68) (Ren et al, 2021)

(69) (Gaidt et al, 2017)

(70) (Aarreberg et al, 2019)

(71) (Bolton et al, 2021)

(72) (Hammond & Loghavi, 2021)

¹⁰⁴ (de Oliveira Mann & Hopfner, 2021)

¹⁰⁹ (Paul et al, 2021)

¹¹⁰ (Fengjuan Li, 2021)

¹¹⁹ (Ren et al, 2021)

⁹⁴ (Gaidt et al, 2017)

²⁰⁵ (Aarreberg et al, 2019)

~~²⁰⁶~~ ~~(Bolton et al, 2021)~~

~~²⁰⁷~~ ~~(Hammond & Loghavi, 2021)~~

¹⁰¹ (Humphries et al. 2021)

¹⁰² (Yum et al, 2021)

¹⁰³ (Cui et al. 2020)

¹⁰⁴ (de Oliveira Mann and Hopfner 2021)

¹⁰⁹ (Paul et al, 2021)

¹¹⁰ (Fengjuan Li 2021)

¹⁰⁰ (Domizio et al, 2022)

¹⁰⁵ (Neufeldt et al. 2022)

¹⁰⁸ (Su et al. 2023)

¹⁰⁶ (Liu et al, 2022)

¹⁰⁷ (Chen & Xu, 2023)

6. Spike protein pathway

(73,74) (Bahl et al, 2017; Pardi et al, 2015)

(75) (Sahin et al, 2021)

(76) (Cho et al, 2021)

(77) (Eisfeld et al, 2021)

(78) (Diaz et al, 2021)

(79) (Ratajczak et al, 2021)

(80) (Scully et al, 2021)

(81) (Reuters, 2021)

(82) (Idrees & Kumar, 2021)

(83) (Young et al, 2020)

(84) (Chakrabarti et al, 2021)

(85) (Schultz et al, 2021)

(86) (Vojdani et al, 2021)

(87) (Stillman, 2013)

(88) (Bowen et al, 2021)

(89) (Bowen et al)

(90) (Kwan et al, 2021)

^208,209 (Bahl et al, 2017; Pardi et al, 2015)

~~²¹⁰~~ ~~(Sahin et al, 2021~~

~~²¹¹~~ ~~(Cho et al, 2021)~~

¹¹² (Eisfeld et al, 2021)

¹³³ (Diaz et al, 2021)

¹⁶ (Ratajczak et al, 2021)

¹²⁰ (Scully et al, 2021)

~~²¹²~~ ~~(Reuters, 2021)~~

¹²⁸ (Idrees & Kumar, 2021)

¹²⁹ (Young et al, 2020)

¹³⁰ (Chakrabarti et al, 2021

¹³¹ (Schultz et al, 2021)

~~²¹³~~ ~~(Vojdani et al, 2021)~~

⁶³ (Stillman, 2013)

⁶⁴ (Bowen et al, 2021)

⁸¹ (Kwan et al, 2021)

¹¹¹ (Örd, Faustova, and Loog 2020)

¹¹² (Eisfeld et al. 2021)

¹¹³ (Sergi & Chiu, 2021)

¹¹⁶ (Shirato and Kizaki 2021)

¹¹⁷ (Theobald et al. 2021)

¹¹⁹ (Ren et al. 2021)

¹²⁰ (Scully et al. 2021)

¹²¹ (Cai et al. 2020)

¹²⁴ (Sahin et al. 2021)

¹²⁵ (Tao et al, 2021)

¹²⁸ (Idrees & Kumar, 2021)

¹²⁹ (Young et al, 2020)

¹³⁰ (Chakrabarti et al, 2021)

¹³¹ (Schultz et al, 2021)

¹³³ (Diaz et al. 2021)

¹¹⁴ (Montezano et al. 2023)

¹¹⁸ (Liu et al. 2022)

¹²² (Nyström and Hammarström 2022)

¹²³ (Prabhakaran et al, 2024)

¹²⁶ (Lee, 2023)

¹²⁶ (Yao et al, 2022)

¹²⁷ (Tyrkalska et al, 2022)

¹³² (Szebeni et al, 2022)

7. Immunological memory engram pathway

(91) (Song et al, 2021)

(92) (Schwabenland et al, 2021)

(93) (Sepehrinezhad et al, 2021)

(94,95) (Lee et al, 2020; Yachou et al, 2020)

(96) (Josselyn & Tonegawa, 2020)

(97) (Koren et al, 2021)

(98) (Gogolla, 2021)

(99) (Koike et al, 2021)

(100) (Marini & Gattinoni, 2020)

(101) (Finsterer & Scorza, 2021)

(102) (Fu et al, 2020)

(103) (Ferren et al, 2021)

(104) (Norden et al, 2016)

~~²¹⁴~~ ~~(Song et al, 2021)~~

¹⁴⁶ (Schwabenland et al, 2021)

¹⁴⁷ (Sepehrinezhad et al, 2021)

^148,149 (Lee et al, 2020; Yachou et al, 2020)

¹³⁸ (Josselyn & Tonegawa, 2020)

¹³⁹ (Koren et al, 2021)

¹⁴⁰ (Gogolla, 2021)

~~²¹⁵~~ ~~(Koike et al, 2021)~~

⁵⁴ (Marini & Gattinoni, 2020)

¹⁵⁰ (Finsterer & Scorza, 2021)

¹⁵² (Fu et al, 2020)

⁵⁸ (Ferren et al, 2021)

¹⁵⁴ (Norden et al, 2016)

¹³⁴ (Troili et al. 2020)

¹³⁵ (Baig 2020)

¹³⁶ (Dhont et al. 2020)

¹³⁸ (Josselyn and Tonegawa 2020)

¹³⁹ (Koren et al. 2021)

¹⁴⁰ (Gogolla 2021)

¹⁴⁴ (Zhang, Zhou, et al. 2021)

¹⁴⁶ (Schwabenland et al. 2021)

¹⁴⁷ (Sepehrinezhad, Gorji, and Sahab Negah 2021)

¹⁴⁸ (Lee et al. 2020)

¹⁴⁹ (Yachou et al. 2020)

¹⁵⁰ (Finsterer and Scorza 2021)

¹⁵² (Fu et al. 2020)

¹³⁷ (Ortega-de San Luis et al, 2023)

¹⁴¹ (Hernandez-Lopez et al. 2023)

¹⁴⁵ (Yang et al. 2022)

¹⁵³ (Bar-On et al, 2023)

¹⁵⁵ (Tamari et al, 2024)

8. Excess acetylcholine pathway

¹⁶⁰ (Mudd et al, 2020)

¹⁶¹ (Monneret et al, 2021)

¹⁶⁵ (Horkowitz et al, 2020)

¹⁶⁹ (Erttmann et al, 2022)

¹⁷⁰ (Gabanyi et al, 2022)

¹⁷¹ (Liu et al, 2022)

¹⁵⁷ (Shahbaz et al, 2023)

¹⁵⁸ (Lee et al, 2022)

¹⁵⁹ (Lee et al, 2023)

¹⁶⁴ (Shim, 2023)

¹⁶⁶ (Axenhus et al, 2022)

¹⁶⁷ (Chen et al, 2023)

*1: The original Preprint file (Supplement 2): Lee, J. (2022, January 14). Pathology and Anticatalysis treatment of exacerbated COVID-19. https://doi.org/10.31219/osf.io/t9wjz

*2: Each one was checked and matched with the reference number of this paper.

*3: In parentheses, the author and publication year are described to help distinguish the information in the paper.

*4: Yellow represents papers published before 2020-2021 at the beginning of the pandemic.

*5: The cited paper that used the strikethrough was removed during the 18th update because it did not reflect reality.

*6: The papers in bold black indicate the papers used from the beginning to the end.

*7: Underlined are papers submitted in 2022-2023. There is also a paper published in 2024.

*8: Paper No. 45, 89 in the 1^st version is excluded because it is a preprint.

*9: Italics indicate cases where the cited paper has been moved to explain a different mechanism in reality.

Table 2. The Immune Triad for Anticatalysis Treatment Against Exacerbations of COVID-19

	Acetylation, cGAS-STING axis	Neutrophil, IFN pathways	NETs¹	Inflammasome	ILCs⁴ Cytokine	Clinical results	Ref.
Aspirin	IFN^active(^*↓)				ILC2s (nasal mucosa↑, blood↓)	Mortality (↓)	²¹⁶ ²¹⁷
Dapsone	IFN^active(↓)	IFN^active(↓)	MPO-DNA NETs (↓)	NLRP3³ (↓)	ILCs (↓)	Mortality (↓) NLR ratio (↓) Exacerbation (↓)	¹² ²¹⁸ ²¹⁹ ²²⁰ ²²¹ ²²² ²²³ ²²⁴
Dexamethasone		IFN^active(↓)	immature neutrophils (^**↑)		blood ILC2s (↓)	Mortality (↓) NLR ratio (↓)	²²⁵ ²²⁶ ²²⁷
COVID-19	IFN^active(↑)	IFN^active(↑)	cell-free DNA, MPO²-DNA complexes (↑)	NLRP3 (↑)	CD8+ T cells (↑)		¹⁷³ ¹⁷⁴

¹) Neutrophil extracellular traps, ²⁾myeloperoxidase, ³⁾NLR family pyrin domain-containing 3 (previously known as NACHT, LRR, and PYD domain-containing protein 3 [NALP3] and cryopyrin), ⁴⁾ innate lymphoid cells, ^*)decreased, ^**)increased

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The authors declare no competing interests.

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The picture theory of seven pathways associated with COVID-19 in the real world

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Abstract

Figures

Introduction

Results

Discussion

Conclusion

Methods

Declarations

Abbreviations

Tables

References

Additional Declarations

Supplementary Files

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