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Aggravating mechanisms from COVID-19

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: the pyrin domain (PYD), the nucleotide-binding domain, and 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

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]

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

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

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

References

  1. Kakavandi S, et al. Structural and non-structural proteins in SARS-CoV-2: potential aspects to COVID-19 treatment or prevention of progression of related diseases. Cell Commun Signal. 2023;21:110. https://doi.org/10.1186/s12964-023-01104-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Choudhury A, Mukherjee G, Mukherjee S. Chemotherapy vs. Immunotherapy in combating nCOVID19: an update. Hum Immunol. 2021;82:649–58. https://doi.org/10.1016/j.humimm.2021.05.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lucas C, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020;584:463–9. https://doi.org/10.1038/s41586-020-2588-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McElvaney OJ, et al. Characterization of the inflammatory response to severe COVID-19 illness. Am J Respir Crit Care Med. 2020;202:812–21. https://doi.org/10.1164/rccm.202005-1583OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vabret N, et al. Immunology of COVID-19: current state of the science. Immunity. 2020;52:910–41. https://doi.org/10.1016/j.immuni.2020.05.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Thwaites RS, et al. Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19. Sci Immunol. 2021;6:eabg9873. https://doi.org/10.1126/sciimmunol.abg9873.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Jarczak D, Nierhaus A. Cytokine Storm—definition, causes, and implications. Int J Mol Sci. 2022;23:11740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pan P, et al. SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. Nat Commun. 2021;12:4664. https://doi.org/10.1038/s41467-021-25015-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ren X, et al. Caspase-1-responsive fluorescence biosensors for monitoring endogenous inflammasome activation. Biosens Bioelectron. 2023;219:114812. https://doi.org/10.1016/j.bios.2022.114812.

    Article  CAS  PubMed  Google Scholar 

  10. Domizio JD, et al. The cGAS–STING pathway drives type I IFN immunopathology in COVID-19. Nature. 2022;603:145–51. https://doi.org/10.1038/s41586-022-04421-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen C, Xu P. Cellular functions of cGAS–STING signaling. Trends Cell Biol. 2023;33:630–48. https://doi.org/10.1016/j.tcb.2022.11.001.

    Article  CAS  PubMed  Google Scholar 

  12. Liu X, et al. SARS-CoV-2 spike protein-induced cell fusion activates the cGAS–STING pathway and the interferon response. Sci Signal. 2022;15:eabg8744. https://doi.org/10.1126/scisignal.abg8744.

    Article  PubMed  Google Scholar 

  13. Coquel F, et al. SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature. 2018;557:57–61.

    Article  CAS  PubMed  Google Scholar 

  14. Rice GI, et al. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009;41:829–32. https://doi.org/10.1038/ng.373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Crow YJ, Manel N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15:429–40. https://doi.org/10.1038/nri3850.

    Article  CAS  PubMed  Google Scholar 

  16. Lee D, et al. Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children. Science. 2023;379:eabo3627. https://doi.org/10.1126/science.abo3627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Stillman B. Deoxynucleoside triphosphate (dNTP) synthesis and destruction regulate the replication of both cell and virus genomes. Proc Natl Acad Sci. 2013;110:14120–1. https://doi.org/10.1073/pnas.1312901110.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rodrigues TS, et al. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. J Exp Med. 2020. https://doi.org/10.1084/jem.20201707.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Rodrigues TS, Zamboni DS. Inflammasome activation by SARS-CoV-2 and its participation in COVID-19 exacerbation. Curr Opin Immunol. 2023;84:102387. https://doi.org/10.1016/j.coi.2023.102387.

    Article  CAS  PubMed  Google Scholar 

  20. Ichinohe T, Yamazaki T, Koshiba T, Yanagi Y. Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection. Proc Natl Acad Sci U S A. 2013;110:17963–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang YC, et al. SARS-CoV-2 nucleocapsid protein, rather than spike protein, triggers a cytokine storm originating from lung epithelial cells in patients with COVID-19. Infection. 2023. https://doi.org/10.1007/s15010-023-02142-4.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu M-H, Lin X-L, Xiao L-L. SARS-CoV-2 nucleocapsid protein promotes TMAO-induced NLRP3 inflammasome activation by SCAP–SREBP signaling pathway. Tissue Cell. 2024;86:102276. https://doi.org/10.1016/j.tice.2023.102276.

    Article  CAS  PubMed  Google Scholar 

  23. Villacampa A, et al. SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells. Cell Commun Signal. 2024;22:38. https://doi.org/10.1186/s12964-023-01397-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dardalhon V, Korn T, Kuchroo VK, Anderson AC. Role of Th1 and Th17 cells in organ-specific autoimmunity. J Autoimmun. 2008;31:252–6. https://doi.org/10.1016/j.jaut.2008.04.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vargas-Rojas MI, et al. Increase of Th17 cells in peripheral blood of patients with chronic obstructive pulmonary disease. Respir Med. 2011;105:1648–54. https://doi.org/10.1016/j.rmed.2011.05.017.

    Article  PubMed  Google Scholar 

  26. Ferreira AC, et al. SARS-CoV-2 engages inflammasome and pyroptosis in human primary monocytes. Cell Death Discovery. 2021;7:43. https://doi.org/10.1038/s41420-021-00428-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Park S, et al. The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J Immunol. 2013;191:4358–66. https://doi.org/10.4049/jimmunol.1301170.

    Article  CAS  PubMed  Google Scholar 

  28. Vora SM, Lieberman J, Wu H. Inflammasome activation at the crux of severe COVID-19. Nat Rev Immunol. 2021;21:694–703. https://doi.org/10.1038/s41577-021-00588-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ichinohe T, Yamazaki T, Koshiba T, Yanagi Y. Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection. Proc Natl Acad Sci. 2013;110:17963–8. https://doi.org/10.1073/pnas.1312571110.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Schmacke NA, et al. IKKβ primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network. Immunity. 2022. https://doi.org/10.1016/j.immuni.2022.10.021.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Okondo MC, et al. Inhibition of Dpp8/9 activates the Nlrp1b inflammasome. Cell Chem Biol. 2018;25:262-267.e265. https://doi.org/10.1016/j.chembiol.2017.12.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. de Oliveira Mann CC, Hopfner K-P. Nuclear cGAS: guard or prisoner? EMBO J. 2021;40:e108293. https://doi.org/10.15252/embj.2021108293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ren H, et al. Micronucleus production, activation of DNA damage response and cGAS–STING signaling in syncytia induced by SARS-CoV-2 infection. Biol Direct. 2021;16:20. https://doi.org/10.1186/s13062-021-00305-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee JH, et al. COVID-19 molecular pathophysiology: acetylation of repurposing drugs. Int J Mol Sci. 2022;23:13260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Neufeldt CJ, et al. SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS–STING and NF-κB. Commun Biol. 2022;5:45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jiang S, et al. The porcine cyclic GMP-AMP Synthase-STING pathway exerts an unusual antiviral function independent of interferon and autophagy. J Virol. 2022. https://doi.org/10.1128/jvi.01476-22.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Paul BD, Snyder SH, Bohr VA. Signaling by cGAS–STING in neurodegeneration, neuroinflammation, and aging. Trends Neurosci. 2021;44:83–96. https://doi.org/10.1016/j.tins.2020.10.008.

    Article  CAS  PubMed  Google Scholar 

  38. Kanwar B, Lee CJ, Lee J-H. Specific treatment exists for SARS-CoV-2 ARDS. Vaccines. 2021;9:635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ferren M, et al. Hamster organotypic modeling of SARS-CoV-2 lung and brainstem infection. Nat Commun. 2021;12:5809. https://doi.org/10.1038/s41467-021-26096-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chin AC. Neuroinflammation and the cGAS–STING pathway. J Neurophysiol. 2019;121:1087–91. https://doi.org/10.1152/jn.00848.2018.

    Article  CAS  PubMed  Google Scholar 

  41. Gulen MF, et al. cGAS–STING drives ageing-related inflammation and neurodegeneration. Nature. 2023;620:374–80. https://doi.org/10.1038/s41586-023-06373-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tang C, Ji X, Wu L, Xiong Y. Impaired dNTPase activity of SAMHD1 by phosphomimetic mutation of Thr-592. J Biol Chem. 2015;290:26352–9. https://doi.org/10.1074/jbc.M115.677435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Roux A, et al. FOXO1 transcription factor plays a key role in T cell—HIV-1 interaction. PLoS Pathog. 2019;15: e1007669. https://doi.org/10.1371/journal.ppat.1007669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Franzolin E, Salata C, Bianchi V, Rampazzo C. The deoxynucleoside triphosphate triphosphohydrolase activity of SAMHD1 protein contributes to the mitochondrial DNA depletion associated with genetic deficiency of deoxyguanosine kinase *. J Biol Chem. 2015;290:25986–96. https://doi.org/10.1074/jbc.M115.675082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. White TE, et al. The retroviral restriction ability of SAMHD1, but not its deoxynucleotide triphosphohydrolase activity, is regulated by phosphorylation. Cell Host Microbe. 2013;13:441–51. https://doi.org/10.1016/j.chom.2013.03.005.

    Article  CAS  PubMed  Google Scholar 

  46. Wu L. Cellular and biochemical mechanisms of the retroviral restriction factor SAMHD1. Int Sch Res Not. 2013;2013:728392. https://doi.org/10.1155/2013/728392.

    Article  Google Scholar 

  47. Chen S, et al. SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways. Proc Natl Acad Sci. 2018;115:E3798–807.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Cingöz O, Arnow ND, Puig Torrents M, Bannert N. Vpx enhances innate immune responses independently of SAMHD1 during HIV-1 infection. Retrovirology. 2021;18:4. https://doi.org/10.1186/s12977-021-00548-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Su J, et al. HIV-2/SIV Vpx targets a novel functional domain of STING to selectively inhibit cGAS–STING-mediated NF-κB signalling. Nat Microbiol. 2019;4:2552–64. https://doi.org/10.1038/s41564-019-0585-4.

    Article  CAS  PubMed  Google Scholar 

  50. Olajide OA, Iwuanyanwu VU, Adegbola OD, Al-Hindawi AA. SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia. Mol Neurobiol. 2021. https://doi.org/10.1007/s12035-021-02593-6.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Albornoz EA, et al. SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein. Mol Psychiatry. 2022. https://doi.org/10.1038/s41380-022-01831-0.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Lee J-H, Choi S-H, Lee CJ, Oh S-S. Recovery of dementia syndrome following treatment of brain inflammation. Dement Geriatr Cogn Disord Extra. 2020;10:1–12. https://doi.org/10.1159/000504880.

    Article  Google Scholar 

  53. Lee JH, Lee CJ, Park J, Lee SJ, Choi SH. The neuroinflammasome in Alzheimer’s disease and cerebral stroke. Dement Geriatr Cogn Dis Extra. 2021;11:159–67. https://doi.org/10.1159/000516074.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Beckman D, et al. SARS-CoV-2 infects neurons and induces neuroinflammation in a non-human primate model of COVID-19. Cell Rep. 2022. https://doi.org/10.1016/j.celrep.2022.111573.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Choudhury A, Mukherjee S. In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs. J Med Virol. 2020;92:2105–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Horowitz JE, et al. Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease. Nat Genet. 2022;54:382–92. https://doi.org/10.1038/s41588-021-01006-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kucia M, et al. An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner. Leukemia. 2021. https://doi.org/10.1038/s41375-021-01332-z.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Zeberg H, Pääbo S. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature. 2020;587:610–2. https://doi.org/10.1038/s41586-020-2818-3.

    Article  CAS  PubMed  Google Scholar 

  59. Rannikko EH, Weber SS, Kahle PJ. Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes. BMC Neurosci. 2015;16:57. https://doi.org/10.1186/s12868-015-0192-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Muscat SM, Barrientos RM. The perfect cytokine storm: how peripheral immune challenges impact brain plasticity & memory function in aging. Brain Plasticity. 2021;7:47–60. https://doi.org/10.3233/BPL-210127.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Manik M, Singh RK. Role of toll-like receptors in modulation of cytokine storm signaling in SARS-CoV-2-induced COVID-19. J Med Virol. 2022;94:869–77. https://doi.org/10.1002/jmv.27405.

    Article  CAS  PubMed  Google Scholar 

  62. Frank MG, et al. SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMP-like properties. Brain Behav Immun. 2022;100:267–77. https://doi.org/10.1016/j.bbi.2021.12.007.

    Article  CAS  PubMed  Google Scholar 

  63. Conte C. Possible Link between SARS-CoV-2 Infection and Parkinson’s Disease: The Role of Toll-Like Receptor 4. Int J Mol Sci. 2021;22:7135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jurgens HA, Amancherla K, Johnson RW. Influenza infection induces neuroinflammation, alters hippocampal neuron morphology, and impairs cognition in adult mice. J Neurosci. 2012;32:3958–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tanaka N, Cortese GP, Barrientos RM, Maier SF, Patterson SL. Aging and an immune challenge interact to produce prolonged, but not permanent, reductions in hippocampal L-LTP and mBDNF in a rodent model with features of delirium. Eneuro. 2018. https://doi.org/10.1523/ENEURO.0009-18.2018.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Daly JL, et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science. 2020;370:861–5. https://doi.org/10.1126/science.abd3072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cantuti-Castelvetri L, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 2020;370:856–60. https://doi.org/10.1126/science.abd2985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 Is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998;92:735–45. https://doi.org/10.1016/S0092-8674(00)81402-6.

    Article  CAS  PubMed  Google Scholar 

  69. Rizzolio S, et al. Neuropilin-1–dependent regulation of EGF-receptor signaling. Can Res. 2012;72:5801–11. https://doi.org/10.1158/0008-5472.Can-12-0995.

    Article  CAS  Google Scholar 

  70. Liu W, et al. Upregulation of neuropilin-1 by basic fibroblast growth factor enhances vascular smooth muscle cell migration in response to VEGF. Cytokine. 2005;32:206–12. https://doi.org/10.1016/j.cyto.2005.09.009.

    Article  CAS  PubMed  Google Scholar 

  71. Matsushita A, Gotze T, Korc M. Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res. 2007;67:10309–16. https://doi.org/10.1158/0008-5472.Can-07-3256.

    Article  CAS  PubMed  Google Scholar 

  72. Sulpice E, et al. Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood. 2008;111:2036–45. https://doi.org/10.1182/blood-2007-04-084269.

    Article  CAS  PubMed  Google Scholar 

  73. Slomiany MG, Black LA, Kibbey MM, Day TA, Rosenzweig SA. IGF-1 induced vascular endothelial growth factor secretion in head and neck squamous cell carcinoma. Biochem Biophys Res Commun. 2006;342:851–8. https://doi.org/10.1016/j.bbrc.2006.02.043.

    Article  CAS  PubMed  Google Scholar 

  74. Ball SG, Bayley C, Shuttleworth CA, Kielty CM. Neuropilin-1 regulates platelet-derived growth factor receptor signalling in mesenchymal stem cells. Biochem J. 2010;427:29–40. https://doi.org/10.1042/bj20091512.

    Article  CAS  PubMed  Google Scholar 

  75. Sherafat A, Pfeiffer F, Reiss AM, Wood WM, Nishiyama A. Microglial neuropilin-1 promotes oligodendrocyte expansion during development and remyelination by trans-activating platelet-derived growth factor receptor. Nat Commun. 2021;12:2265. https://doi.org/10.1038/s41467-021-22532-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Glinka Y, Prud’homme GJ. Neuropilin-1 is a receptor for transforming growth factor β-1, activates its latent form, and promotes regulatory T cell activity. J Leukocyte Biol. 2008;84:302–10. https://doi.org/10.1189/jlb.0208090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang Q, et al. Environmentally-induced <i>mdig</i> contributes to the severity of COVID-19 through fostering expression of SARS-CoV-2 receptor NRPs and glycan metabolism. Theranostics. 2021;11:7970–83. https://doi.org/10.7150/thno.62138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kofler N, Simons M. The expanding role of neuropilin: regulation of transforming growth factor-β and platelet-derived growth factor signaling in the vasculature. Curr Opin Hematol. 2016;23:260–7. https://doi.org/10.1097/moh.0000000000000233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Theobald SJ, et al. Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19. EMBO Mol Med. 2021;13:e14150. https://doi.org/10.15252/emmm.202114150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Eisfeld HS, et al. Viral glycoproteins induce NLRP3 inflammasome activation and pyroptosis in macrophages. Viruses. 2021;13:2076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Diaz GA, et al. Myocarditis and pericarditis after vaccination for COVID-19. JAMA. 2021;326:1210–2. https://doi.org/10.1001/jama.2021.13443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ratajczak MZ, et al. SARS-CoV-2 entry receptor ACE2 Is expressed on very small CD45—precursors of hematopoietic and endothelial cells and in response to virus spike protein activates the NLRP3 inflammasome. Stem Cell Reviews and Reports. 2021;17:266–77. https://doi.org/10.1007/s12015-020-10010-z.

    Article  CAS  PubMed  Google Scholar 

  83. Scully M, et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384:2202–11. https://doi.org/10.1056/NEJMoa2105385.

    Article  CAS  PubMed  Google Scholar 

  84. Chakrabarti SS, et al. Rapidly progressive dementia with asymmetric rigidity following ChAdOx1 nCoV-19 vaccination. Aging Dis. 2021. https://doi.org/10.14336/ad.2021.1102.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Schultz NH, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384:2124–30.

    Article  CAS  PubMed  Google Scholar 

  86. Fernandes-Alnemri T, Yu J-W, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458:509–13. https://doi.org/10.1038/nature07710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gaidt, M. M. et al. The DNA inflammasome in human myeloid cells is initiated by a STING-Cell death program upstream of NLRP3. Cell 171, 1110–1124.e1118 (2017). https://doi.org/10.1016/j.cell.2017.09.039

  88. Fengjuan Li NWYZYLYZ. cGAS- stimulator of interferon genes signaling in central nervous system disorders. Aging Dis. 2021;12:1658–74.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Han L, et al. SARS-CoV-2 ORF10 antagonizes STING-dependent interferon activation and autophagy. J Med Viro. 2022;94:5174–88. https://doi.org/10.1002/jmv.27965.

    Article  CAS  Google Scholar 

  90. Yum S, Li M, Fang Y, Chen ZJ. TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections. Proc Natl Acad Sci. 2021;118:e2100225118. https://doi.org/10.1073/pnas.2100225118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cui S, et al. Nuclear cGAS functions non-canonically to enhance antiviral immunity via recruiting methyltransferase Prmt5. Cell Rep. 2020;33:108490. https://doi.org/10.1016/j.celrep.2020.108490.

    Article  CAS  PubMed  Google Scholar 

  92. Cao D, et al. The SARS-CoV-2 papain-like protease suppresses type I interferon responses by deubiquitinating STING. Sci Signal. 2023;16:eadd0082. https://doi.org/10.1126/scisignal.add0082.

    Article  CAS  PubMed  Google Scholar 

  93. Su J, et al. SARS-CoV-2 ORF3a inhibits cGAS–STING-mediated autophagy flux and antiviral function. J Med Virol. 2023;95:e28175.

    Article  CAS  PubMed  Google Scholar 

  94. Jiao P, et al. SARS-CoV-2 nonstructural protein 6 triggers endoplasmic reticulum stress-induced autophagy to degrade STING1. Autophagy. 2023;19:3113–31. https://doi.org/10.1080/15548627.2023.2238579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Han L, et al. SARS-CoV-2 ORF9b antagonizes type I and III interferons by targeting multiple components of the RIG-I/MDA-5–MAVS, TLR3–TRIF, and cGAS–STING signaling pathways. J Med Virol. 2021;93:5376–89. https://doi.org/10.1002/jmv.27050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rui Y, et al. Unique and complementary suppression of cGAS–STING and RNA sensing-triggered innate immune responses by SARS-CoV-2 proteins. Signal Transduct Target Ther. 2021;6:123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Deng J, et al. SARS-CoV-2 NSP7 inhibits type I and III IFN production by targeting the RIG-I/MDA5, TRIF, and STING signaling pathways. J Med Virol. 2023;95:e28561. https://doi.org/10.1002/jmv.28561.

    Article  CAS  PubMed  Google Scholar 

  98. Deng J, et al. SARS-CoV-2 NSP8 suppresses type I and III IFN responses by modulating the RIG-I/MDA5, TRIF, and STING signaling pathways. J Med Virol. 2023;95:e28680. https://doi.org/10.1002/jmv.28680.

    Article  CAS  PubMed  Google Scholar 

  99. Humphries F, et al. A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection. Sci Immunol. 2021;6:eabi9002. https://doi.org/10.1126/sciimmunol.abi9002.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Ji X, et al. Mechanism of allosteric activation of SAMHD1 by dGTP. Nat Struct Mol Biol. 2013;20:1304–9. https://doi.org/10.1038/nsmb.2692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yan Y, Tang Y-D, Zheng C. When cyclin-dependent kinases meet viral infections, including SARS-CoV-2. J Med Virol. 2022;94:2962–8. https://doi.org/10.1002/jmv.27719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Gupta RK, Mlcochova P. Cyclin D3 restricts SARS-CoV-2 envelope incorporation into virions and interferes with viral spread. EMBO J. 2022;41:e111653. https://doi.org/10.15252/embj.2022111653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Khan A, Sergi C. SAMHD1 as the potential link between SARS-CoV-2 infection and neurological complications. Front Neurol. 2020;11:562913. https://doi.org/10.3389/fneur.2020.562913.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Bowen NE, et al. Structural and functional characterization explains loss of dNTPase activity of the cancer-specific R366C/H mutant SAMHD1 proteins. J Biol Chem. 2021. https://doi.org/10.1016/j.jbc.2021.101170.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Yu CH, et al. Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification. Nat Commun. 2021;12:731. https://doi.org/10.1038/s41467-021-21023-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Maelfait J, Bridgeman A, Benlahrech A, Cursi C, Rehwinkel J. Restriction by SAMHD1 limits cGAS/STING-dependent innate and adaptive immune responses to HIV-1. Cell Rep. 2016;16:1492–501. https://doi.org/10.1016/j.celrep.2016.07.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Martinez-Lopez A, et al. SAMHD1 deficient human monocytes autonomously trigger type I interferon. Mol Immunol. 2018;101:450–60. https://doi.org/10.1016/j.molimm.2018.08.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Espada CE, et al. SAMHD1 impairs type I interferon induction through the MAVS, IKKε, and IRF7 signaling axis during viral infection. J Biol Chem. 2023;299:104925. https://doi.org/10.1016/j.jbc.2023.104925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Oo A, et al. Elimination of Aicardi–Goutières syndrome protein SAMHD1 activates cellular innate immunity and suppresses SARS-CoV-2 replication. J Biol Chem. 2022. https://doi.org/10.1016/j.jbc.2022.101635.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Berri F, et al. Early plasma interferon-β levels as a predictive marker of COVID-19 severe clinical events in adult patients. J Med Virol. 2023;95: e28361. https://doi.org/10.1002/jmv.28361.

    Article  CAS  PubMed  Google Scholar 

  111. Kwan JYY, et al. Elevation in viral entry genes and innate immunity compromise underlying increased infectivity and severity of COVID-19 in cancer patients. Sci Rep. 2021;11:4533. https://doi.org/10.1038/s41598-021-83366-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Lee JH. Treatment mechanism of immune triad from the repurposing drug against COVID-19. Trans Med Aging. 2023;7:33–45. https://doi.org/10.1016/j.tma.2023.06.005.

    Article  CAS  Google Scholar 

  113. Devaux CA, Rolain JM, Raoult D. ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. J Microbiol Immunol Infect. 2020;53:425–35. https://doi.org/10.1016/j.jmii.2020.04.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kumar S, et al. Racial health disparity and COVID-19. J Neuroimmune Pharmacol. 2021;16:729–42. https://doi.org/10.1007/s11481-021-10014-7.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Chlamydas S, Papavassiliou AG, Piperi C. Epigenetic mechanisms regulating COVID-19 infection. Epigenetics. 2021;16:263–70. https://doi.org/10.1080/15592294.2020.1796896.

    Article  PubMed  Google Scholar 

  116. Lei Y, et al. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2. Circ Res. 2021;128:1323–6. https://doi.org/10.1161/CIRCRESAHA.121.318902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Choudhury A, Das NC, Patra R, Mukherjee S. In silico analyses on the comparative sensing of SARS-CoV-2 mRNA by the intracellular TLRs of humans. J Med Virol. 2021;93:2476–86. https://doi.org/10.1002/jmv.26776.

    Article  CAS  PubMed  Google Scholar 

  118. Patra R, Chandra Das N, Mukherjee S. Targeting human TLRs to combat COVID-19: A solution? J Med Virol. 2021;93:615–7. https://doi.org/10.1002/jmv.26387.

    Article  CAS  PubMed  Google Scholar 

  119. Zhao Y, et al. SARS-CoV-2 spike protein interacts with and activates TLR41. Cell Res. 2021;31:818–20. https://doi.org/10.1038/s41422-021-00495-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Shirvaliloo M. The unfavorable clinical outcome of COVID-19 in smokers is mediated by H3K4me3, H3K9me3 and H3K27me3 histone marks. Epigenomics. 2022;14:153–62. https://doi.org/10.2217/epi-2021-0476.

    Article  CAS  PubMed  Google Scholar 

  121. Kronstein-Wiedemann R, et al. SARS-CoV-2 infects red blood cell progenitors and dysregulates hemoglobin and iron metabolism. Stem Cell Reviews and Reports. 2022;18:1809–21. https://doi.org/10.1007/s12015-021-10322-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gonzalez JJI, et al. TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascade. eBio. 2023. https://doi.org/10.1128/mbio.00225-23.

    Article  Google Scholar 

  123. Hoffmann M, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–80. https://doi.org/10.1016/j.cell.2020.02.052.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Mollica V, Rizzo A, Massari F. The pivotal role of TMPRSS2 in coronavirus disease 2019 and prostate cancer. Future Oncol. 2020;16:2029–33. https://doi.org/10.2217/fon-2020-0571.

    Article  CAS  PubMed  Google Scholar 

  125. Kyrou I, Randeva HS, Spandidos DA, Karteris E. Not only ACE2—the quest for additional host cell mediators of SARS-CoV-2 infection: Neuropilin-1 (NRP1) as a novel SARS-CoV-2 host cell entry mediator implicated in COVID-19. Signal Transduct Target Ther. 2021;6:21. https://doi.org/10.1038/s41392-020-00460-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Davies J, et al. Neuropilin1 as a new potential SARSCoV2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID19. Mol Med Rep. 2020;22:4221–6. https://doi.org/10.3892/mmr.2020.11510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Khan M, et al. Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb. Cell. 2021;184:5932-5949.e5915. https://doi.org/10.1016/j.cell.2021.10.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Yong SJ. Persistent brainstem dysfunction in long-COVID: a hypothesis. ACS Chem Neurosci. 2021;12:573–80. https://doi.org/10.1021/acschemneuro.0c00793.

    Article  CAS  PubMed  Google Scholar 

  129. Group, S. C.-G. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med. 2020;383:1522–34.

    Article  Google Scholar 

  130. Li Y, et al. The MERS-CoV receptor DPP4 as a candidate binding target of the SARS-CoV-2 spike. iScience. 2020;23:101160. https://doi.org/10.1016/j.isci.2020.101160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zeberg H, Pääbo S. A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. Proc Natl Acad Sci. 2021;118: e2026309118. https://doi.org/10.1073/pnas.2026309118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Clottu AS, Humbel M, Fluder N, Karampetsou MP, Comte D. Innate lymphoid cells in autoimmune diseases. Front Immunol. 2021;12: 789788. https://doi.org/10.3389/fimmu.2021.789788.

    Article  CAS  PubMed  Google Scholar 

  133. Meininger I, et al. Tissue-specific features of innate lymphoid cells. Trends Immunol. 2020;41:902–17. https://doi.org/10.1016/j.it.2020.08.009.

    Article  CAS  PubMed  Google Scholar 

  134. Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020;323:2329–30. https://doi.org/10.1001/jama.2020.6825.

    Article  PubMed  Google Scholar 

  135. Lucchese G, et al. Anti-neuronal antibodies against brainstem antigens are associated with COVID-19. EBioMedicine. 2022;83:104211. https://doi.org/10.1016/j.ebiom.2022.104211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kerner G, Quintana-Murci L. The genetic and evolutionary determinants of COVID-19 susceptibility. Eur J Hum Genet. 2022;30:915–21. https://doi.org/10.1038/s41431-022-01141-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zhang J, et al. Neuropilin-1 mediates lung tissue-specific control of ILC2 function in type 2 immunity. Nat Immunol. 2022;23:237–50. https://doi.org/10.1038/s41590-021-01097-8.

    Article  CAS  PubMed  Google Scholar 

  138. Spits H, Mjösberg J. Heterogeneity of type 2 innate lymphoid cells. Nat Rev Immunol. 2022;22:701–12. https://doi.org/10.1038/s41577-022-00704-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Kawano T, et al. T cell infiltration into the brain triggers pulmonary dysfunction in murine Cryptococcus-associated IRIS. Nat Commun. 2023;14:3831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Dangarembizi R, Drummond R. Immune-related neurodegeneration in the midbrain causes pulmonary dysfunction in murine cryptococcal IRIS. Trends Neurosci. 2023;46:1003–4. https://doi.org/10.1016/j.tins.2023.09.005.

    Article  CAS  PubMed  Google Scholar 

  141. Örd M, Faustova I, Loog M. The sequence at Spike S1/S2 site enables cleavage by furin and phospho-regulation in SARS-CoV2 but not in SARS-CoV1 or MERS-CoV. Sci Rep. 2020;10:16944.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Sergi CM, Chiu B. Targeting NLRP3 inflammasome in an animal model for Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). J Med Virol. 2021;93:669–70. https://doi.org/10.1002/jmv.26461.

    Article  CAS  PubMed  Google Scholar 

  143. Shirato K, Kizaki T. SARS-CoV-2 spike protein S1 subunit induces pro-inflammatory responses via toll-like receptor 4 signaling in murine and human macrophages. Heliyon. 2021;7:e06187. https://doi.org/10.1016/j.heliyon.2021.e06187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Cai Y, et al. Distinct conformational states of SARS-CoV-2 spike protein. Science. 2020;369:1586–92. https://doi.org/10.1126/science.abd4251.

    Article  CAS  PubMed  Google Scholar 

  145. Sahin U, et al. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature. 2021;595:572–7. https://doi.org/10.1038/s41586-021-03653-6.

    Article  CAS  PubMed  Google Scholar 

  146. Tao K, et al. The biological and clinical significance of emerging SARS-CoV-2 variants. Nat Rev Genet. 2021;22:757–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Idrees D, Kumar V. SARS-CoV-2 spike protein interactions with amyloidogenic proteins: potential clues to neurodegeneration. Biochem Biophys Res Commun. 2021;554:94–8. https://doi.org/10.1016/j.bbrc.2021.03.100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Young MJ, O’Hare M, Matiello M, Schmahmann JD. Creutzfeldt-Jakob disease in a man with COVID-19: SARS-CoV-2-accelerated neurodegeneration? Brain Behav Immun. 2020;89:601–3. https://doi.org/10.1016/j.bbi.2020.07.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Montezano AC, et al. SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication. Sci Rep. 2023;13:14086. https://doi.org/10.1038/s41598-023-41115-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Liu X, et al. SARS-CoV-2 spike protein–induced cell fusion activates the cGAS–STING pathway and the interferon response. Sci Signal. 2022;15:eabg8744.

    Article  PubMed  Google Scholar 

  151. Nyström S, Hammarström P. Amyloidogenesis of SARS-CoV-2 spike protein. J Am Chem Soc. 2022;144:8945–50. https://doi.org/10.1021/jacs.2c03925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Prabhakaran M, et al. Adjuvanted SARS-CoV-2 spike protein vaccination elicits long-lived plasma cells in nonhuman primates. Sci Trans Med. 2024;16:eadd5960. https://doi.org/10.1126/scitranslmed.add5960.

    Article  CAS  Google Scholar 

  153. Yao L, et al. Omicron subvariants escape antibodies elicited by vaccination and BA. 2.2 infection. Lancet Infect Dis. 2022;22:1116–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Tyrkalska SD, et al. Differential proinflammatory activities of Spike proteins of SARS-CoV-2 variants of concern. Sci Adv. 2022;8:eabo0732. https://doi.org/10.1126/sciadv.abo0732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Szebeni J, et al. Applying lessons learned from nanomedicines to understand rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines. Nat Nanotechnol. 2022;17:337–46. https://doi.org/10.1038/s41565-022-01071-x.

    Article  CAS  PubMed  Google Scholar 

  156. Fink DL, et al. HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65. Retrovirology. 2022;19:2. https://doi.org/10.1186/s12977-021-00586-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Troili F, et al. Perivascular unit: this must be the place the anatomical crossroad between the immune, vascular and nervous system. Front Neuroanat. 2020;14:17. https://doi.org/10.3389/fnana.2020.00017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Baig AM. Computing the effects of SARS-CoV-2 on respiration regulatory mechanisms in COVID-19. ACS Chem Neurosci. 2020;11:2416–21. https://doi.org/10.1021/acschemneuro.0c00349.

    Article  CAS  PubMed  Google Scholar 

  159. Dhont S, Derom E, Van Braeckel E, Depuydt P, Lambrecht BN. The pathophysiology of ‘happy’ hypoxemia in COVID-19. Respir Res. 2020;21:198. https://doi.org/10.1186/s12931-020-01462-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Josselyn SA, Tonegawa S. Memory engrams: recalling the past and imagining the future. Science. 2020. https://doi.org/10.1126/science.aaw4325.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Koren T, et al. Insular cortex neurons encode and retrieve specific immune responses. Cell. 2021;184:5902-5915.e5917. https://doi.org/10.1016/j.cell.2021.10.013.

    Article  CAS  PubMed  Google Scholar 

  162. Gogolla N. The brain remembers where and how inflammation struck. Cell. 2021;184:5851–3. https://doi.org/10.1016/j.cell.2021.11.002.

    Article  CAS  PubMed  Google Scholar 

  163. Zhang L, et al. SARS-CoV-2 crosses the blood–brain barrier accompanied with basement membrane disruption without tight junctions alteration. Signal Transduct Target Ther. 2021;6:337. https://doi.org/10.1038/s41392-021-00719-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Schwabenland M, et al. Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions. Immunity. 2021;54:1594-1610.e1511. https://doi.org/10.1016/j.immuni.2021.06.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sepehrinezhad A, Gorji A, Sahab Negah S. SARS-CoV-2 may trigger inflammasome and pyroptosis in the central nervous system: a mechanistic view of neurotropism. Inflammopharmacology. 2021. https://doi.org/10.1007/s10787-021-00845-4.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Lee M-H, et al. Microvascular injury in the brains of patients with Covid-19. N Engl J Med. 2020;384:481–3. https://doi.org/10.1056/nejmc2033369.

    Article  CAS  PubMed  Google Scholar 

  167. Yachou Y, El Idrissi A, Belapasov V, Ait Benali S. Neuroinvasion, neurotropic, and neuroinflammatory events of SARS-CoV-2: understanding the neurological manifestations in COVID-19 patients. Neurol Sci. 2020;41:2657–69. https://doi.org/10.1007/s10072-020-04575-3.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Finsterer J, Scorza FA. Clinical and pathophysiologic spectrum of neuro-COVID. Mol Neurobiol. 2021;58:3787–91. https://doi.org/10.1007/s12035-021-02383-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Fu J, et al. Expressions and significances of the angiotensin-converting enzyme 2 gene, the receptor of SARS-CoV-2 for COVID-19. Mol Biol Rep. 2020;47(6):4383–92. https://doi.org/10.1007/s11033-020-05478-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Ortega-de San Luis C, Pezzoli M, Urrieta E, Ryan TJ. Engram cell connectivity as a mechanism for information encoding and memory function. Curr Biol. 2023;33:5368–80. https://doi.org/10.1016/j.cub.2023.10.074.

    Article  CAS  PubMed  Google Scholar 

  171. Hernandez-Lopez JM, et al. Neuronal progenitors of the dentate gyrus express the SARS-CoV-2 cell receptor during migration in the developing human hippocampus. Cell Mol Life Sci. 2023;80:140. https://doi.org/10.1007/s00018-023-04787-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Yang R-C, et al. SARS-CoV-2 productively infects human brain microvascular endothelial cells. J Neuroinflammation. 2022;19:149. https://doi.org/10.1186/s12974-022-02514-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Bar-On L, Dekel H, Aftalion M, Chitlaru T, Erez N. Essential role for Batf3-dependent dendritic cells in regulating CD8 T-cell response during SARS-CoV-2 infection. PLoS ONE. 2023;18: e0294176. https://doi.org/10.1371/journal.pone.0294176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Tamari M, et al. Sensory neurons promote immune homeostasis in the lung. Cell. 2024;187:44-61.e17. https://doi.org/10.1016/j.cell.2023.11.027.

    Article  CAS  PubMed  Google Scholar 

  175. Mudd PA, et al. Distinct inflammatory profiles distinguish COVID-19 from influenza with limited contributions from cytokine storm. Sci Adv. 2020;6:eabe3024. https://doi.org/10.1126/sciadv.abe3024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Monneret G, et al. COVID-19: What type of cytokine storm are we dealing with? J Med Virol. 2021;93:197–8. https://doi.org/10.1002/jmv.26317.

    Article  CAS  PubMed  Google Scholar 

  177. Horkowitz AP, et al. Acetylcholine regulates pulmonary pathology during viral infection and recovery. ImmunoTargets and Therapy. 2020;9:333–50. https://doi.org/10.2147/ITT.S279228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Erttmann SF, et al. The gut microbiota prime systemic antiviral immunity via the cGAS–STING-IFN-I axis. Immunity. 2022;55:847-861.e810. https://doi.org/10.1016/j.immuni.2022.04.006.

    Article  CAS  PubMed  Google Scholar 

  179. Gabanyi I, et al. Bacterial sensing via neuronal Nod2 regulates appetite and body temperature. Science. 2022;376:eabj3986.

    Article  CAS  PubMed  Google Scholar 

  180. Liu H, Wang F, Cao Y, Dang Y, Ge B. The multifaceted functions of cGAS. J Mol Cell Biol. 2022. https://doi.org/10.1093/jmcb/mjac031.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Shahbaz MA, et al. Human-derived air–liquid interface cultures decipher Alzheimer’s disease–SARS-CoV-2 crosstalk in the olfactory mucosa. J Neuroinflammation. 2023;20:299. https://doi.org/10.1186/s12974-023-02979-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Lee JH, Kanwar B, Lee CJ, Sergi C, Coleman MD. Dapsone is an anticatalysis for Alzheimer’s disease exacerbation. iScience. 2022. https://doi.org/10.1016/j.isci.2022.104274.

    Article  PubMed  PubMed Central  Google Scholar 

  183. Lee JH, et al. Bronchitis, COPD, and pneumonia after viral endemic of patients with leprosy on Sorok Island in South Korea. Naunyn Schmiedebergs Arch Pharmacol. 2023. https://doi.org/10.1007/s00210-023-02407-7.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Shim J, Park EK, Kim RK, Lee KH, Shin MR, Kwon Dh. the suspected coronavirus disease 2019 reinfection cases and vaccine effectiveness, The Republic of Korea. Public Health Weekly Rep. 2023;16:1504–20. https://doi.org/10.56786/PHWR.2023.16.44.2.

    Article  Google Scholar 

  185. Axenhus M, Frederiksen KS, Zhou RZ, Waldemar G, Winblad B. The impact of the COVID-19 pandemic on mortality in people with dementia without COVID-19: a systematic review and meta-analysis. BMC Geriatr. 2022;22:878. https://doi.org/10.1186/s12877-022-03602-6.

    Article  PubMed  PubMed Central  Google Scholar 

  186. Chen R, et al. Excess mortality with Alzheimer disease and related dementias as an underlying or contributing cause during the COVID-19 pandemic in the US. JAMA Neurol. 2023. https://doi.org/10.1001/jamaneurol.2023.2226.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Lee, J. h. et al. (Research Square, 2024).

  188. Lee JH, et al. Basic implications on three pathways associated with SARS-CoV-2. Biomed J. 2024. https://doi.org/10.1016/j.bj.2024.100766.

    Article  PubMed  Google Scholar 

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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.

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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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