- Review
- Open access
- Published:
Aggravating mechanisms from COVID-19
Virology Journal volume 21, Article number: 228 (2024)
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.
The NLRP3 protein has three domains: ① the pyrin domain (PYD), ② the nucleotide-binding domain, and ③ the leucine-rich repeat domain. PYD interacts with ASC [8].
-
2.
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.
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).
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).
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).
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).
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
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.
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.
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.
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.
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.
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.
Jarczak D, Nierhaus A. Cytokine Storm—definition, causes, and implications. Int J Mol Sci. 2022;23:11740.
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.
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.
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.
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.
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.
Coquel F, et al. SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature. 2018;557:57–61.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
de Oliveira Mann CC, Hopfner K-P. Nuclear cGAS: guard or prisoner? EMBO J. 2021;40:e108293. https://doi.org/10.15252/embj.2021108293.
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.
Lee JH, et al. COVID-19 molecular pathophysiology: acetylation of repurposing drugs. Int J Mol Sci. 2022;23:13260.
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.
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.
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.
Kanwar B, Lee CJ, Lee J-H. Specific treatment exists for SARS-CoV-2 ARDS. Vaccines. 2021;9:635.
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.
Chin AC. Neuroinflammation and the cGAS–STING pathway. J Neurophysiol. 2019;121:1087–91. https://doi.org/10.1152/jn.00848.2018.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Eisfeld HS, et al. Viral glycoproteins induce NLRP3 inflammasome activation and pyroptosis in macrophages. Viruses. 2021;13:2076.
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.
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.
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.
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.
Schultz NH, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384:2124–30.
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.
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
Fengjuan Li NWYZYLYZ. cGAS- stimulator of interferon genes signaling in central nervous system disorders. Aging Dis. 2021;12:1658–74.
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.
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.
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.
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.
Su J, et al. SARS-CoV-2 ORF3a inhibits cGAS–STING-mediated autophagy flux and antiviral function. J Med Virol. 2023;95:e28175.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Yong SJ. Persistent brainstem dysfunction in long-COVID: a hypothesis. ACS Chem Neurosci. 2021;12:573–80. https://doi.org/10.1021/acschemneuro.0c00793.
Group, S. C.-G. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med. 2020;383:1522–34.
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.
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.
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.
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.
Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020;323:2329–30. https://doi.org/10.1001/jama.2020.6825.
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.
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.
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.
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.
Kawano T, et al. T cell infiltration into the brain triggers pulmonary dysfunction in murine Cryptococcus-associated IRIS. Nat Commun. 2023;14:3831.
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.
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.
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.
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.
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.
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.
Tao K, et al. The biological and clinical significance of emerging SARS-CoV-2 variants. Nat Rev Genet. 2021;22:757–73.
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.
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.
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.
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.
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.
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.
Yao L, et al. Omicron subvariants escape antibodies elicited by vaccination and BA. 2.2 infection. Lancet Infect Dis. 2022;22:1116–7.
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.
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.
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.
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.
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.
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.
Josselyn SA, Tonegawa S. Memory engrams: recalling the past and imagining the future. Science. 2020. https://doi.org/10.1126/science.aaw4325.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gabanyi I, et al. Bacterial sensing via neuronal Nod2 regulates appetite and body temperature. Science. 2022;376:eabj3986.
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.
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.
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.
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.
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.
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.
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.
Lee, J. h. et al. (Research Square, 2024).
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.
Funding
No funding.
Author information
Authors and Affiliations
Contributions
Jong Hoon Lee: Conceptualisation, Methodology, Software, Data curation, Visualization, Investigation, Writing- Original draft preparation. Consolato Sergi: Data curation, Writing—Reviewing and Editing. Richard E. Kast: Investigation, Writing- Reviewing and Editing. Badar A. Kanwar: Investigation,Writing—Reviewing and Editing. Jean Bourbeau: Writing- Reviewing and Editing. Sangsuk Oh: Investigation, Writing- Reviewing and Editing. Mun-Gi Sohn: Investigation, Chul Joong Lee: Writing- Reviewing and Editing, Michael D. Coleman: Supervision, Writing—Reviewing and Editing.
Corresponding authors
Ethics declarations
Ethics approval and consent to participate
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 for publication
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.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
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
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12985-024-02506-8