Essay: Understanding COVID-19: From Virus Structure to Potential Treatments

Coronavirus 2019(COVID-19) is an infectious disease which is caused by a newly identified coronavirus with the name of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2).Members of the coronaviridae family are enveloped single-stranded RNA, positive-sense, viruses (2). Researchers called this family as a coronavirus because of virus surface is surrounded by a ring of projections (3). The new coronavirus is widespread, because of easily and quickly transmitting of this virus through discharge from the nose or droplets of saliva which can be spread by sneeze or cough of a person who is infected with this virus.some different complications from this virus are cough,fever,fatigue,headache,hemtopoysis and diarrhea.(4)
The procedure of viral infection, including intracellular transport of virions, proliferation and assembling of virions in infected cells can significantly influenced by structural protein such as E protein (small membrane protein), M protein (the membrane protein), and S proein (spike protein) whhich can be seen on memberane of virus . Another regulators are functional proteins and some proteases .functional proteins are
Helicase, RdRp protein (RNA-dependent RNA polymerase), 3-CLpro protein (3-chymotrypsin-like protease), and PLpro protein (papain-like protease) which play a crucial role in infection of covid 19.(5) Attachment of spikes of covid-19strongly to a cell protein with name of ACE2, which is identify on the surface of humman cells, is the first step of viral pathogen and likely is very vital in transmission of this virus from one person to another.(6)
ACE2 expressing target cells (such as alveolar type 2 cells) are the aim of This virus and leads to infection. anti-viral IFN responses may fade the virus which is result . Overproduction of pro-inflammatory cytokines happen after neutrophils and monocytes/macrophages influx and leads to cytokine storm which can leads to severe damage on lungs. Th1/Th17 cells response may be activated and contributes to exacerbate inflammatory responses in host.(7-10).
In lung, ACE2 can be expressed by Type 2 alveolar cells and monocytes/macrophages . In the situation of ACE2 is minimally expressed in the potential target immune cells, the existence of some other receptor is probable, or other some other cellular entry such as antibody-dependent enhancement. Innate immune system cells identify the virus’s influx by PAMPs (pathogen associated molecular patterns). TLR3, TLR7, endosomal RNA receptors, and RIG-I/MDA5 (the cytosolic RNA sensor) can recognize PAMPs in the form of viral genomic RNA or the intermediates during viral replication .
This diagnosed cascade can active the down-stream signaling cascade, i.e. NF-κB and IRF3, accompanied by their nuclear translocation. these transcription agents promote expression of some pro inflammatory cytokines immune system such as type I interferon and this initial responses contain the first step of defense in front of COVID-19 (7, 27). Type I interferon, can regulate the JAK-STAT pathway, this pathway can phosphorylate STAT1 and STAT2. STAT1/2 make a complex with IRF9, and this complex move to nucleus to initiate the intracellular expression .It also recommended that IFN can have a good effect if it utilize at the first step of diseases. (7, 28, 29). cute Lung Injury and Acute Respiratory Distress Syndrome
During acute lung injury (ALI), capillaries of the lung become permeable and led to inflammation. This condition could occur due to endotoxemia(1). The severe ALI condition also called acute respiratory distress syndrome (ARDS), happened in a condition of endotoxin shock(2). In both of these conditions, over-activation of the immune system increased proinflammatory mediators; thus, anti-inflammatory therapy is particularly essential (3).
Nuclear factor kappa-light-chain-enhancer of activated B cells Pathway
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF- kappa B) is a nuclear transcriptional factor and comprised of several structurally related proteins that form both homo- and heterodimers. The most common Rel/NFkB dimer in mammals comprises p50-RelA (p65)(4). NF- kappa B was linked in the cytoplasm with its inhibitory subunit, inhibitory kappa B (IκB), which prevented it from translocating into the nucleus, when LPS exposed to NF-kappa B/IκBs complexes through phosphorylation and degradation of IκB, release NF-kappa B and enabling it to translocate in the nucleus for transcription. NF-kappa B has a potential role in regulating many effector genes, including those encoding cytokines and adhesion molecules. Also, it is an upstream regulator of the TNF-α, IL-6, IL-8, matrix metalloproteinase (MMP)-9, and intracellular adhesion molecule-1 (ICAM-1)(5, 6).
Several cascades have been reported for the activation of NF- kappa B. once is the binding TNF-α to its receptors TNFR1 or TNFR2(7, 8), which after trimerization requits TRAF2, RIP, and NIK(9). NIK then phosphorylates and activates IkB kinase (IKK)(10), which subsequently targets IkBa for ubiquitination and degradation by the proteasome. Another cascade is through activation of phosphatidylinositol 3-kinase (PI3K) by TNFR1 and its downstream target, Akt kinase, which mediate TNF-α promoted NF-kB activation by phosphorylation of threonine 23 in IKKa(11). It is also noted that TLR4 was recruited to MyD88 and TAK1 after being stimulated by LPS, and after that, it detached from the receptor presumably to bifurcate the NF-κB-dependent cascade. Thus MyD88 and TAK1 act as specific targets for TLR4-induced inflammatory responses(12).
High-mobility group box 1 (HMGB1) proteins is a well-known protein in the case of inflammation and cell damage, trough inflammation factors like lipopolysaccharide (LPS) this protein secreted within the cell into the extracellular matrix(13). It could play a role as a damage-associated molecular pattern (DAMP)(14), which could be a part of many clinical diseases, such as ALI/ARDS, sepsis, asthma, and cancer(15, 16). HMGB1 proteins through binding to a receptor for advanced glycation end products (RAGE) and toll-like receptor 2/4 (TLR-2/4), would activate the inflammation-related signaling pathways, including NF-κB and mitogen-activated protein kinase (MAPK) pathways, flourished by the overproduction of the downstream proinflammatory mediators, TNF-α, IL-1β, and IL-8 as well(17).
Trough the results of some studies, it is concluded that by inhibiting the HMGB1-mediated TLR4/NF-κB signaling pathway, we could get better results in the treatment of LPS-induced ALI/ARDS(18, 19).
Sevoflurane:
Sevoflurane is an inhaled, sweet-smelling, highly fluorinated methyl isopropyl that is widely used in general anesthesia. Inhales effects of this drug have anti-inflammatory and protective effects on inflammatory damages caused by sepsis or ischemia/reperfusion of blood flow in the heart, brain, kidneys, and liver (20, 21). Among the most important effects of his drug are the prevention of acute lung injury (ALI) and liver ischemia/reperfusion (IR) (22, 23). The inhibitory effect of 3% sevoflurane was evaluated in vivo and in vitro on lipopolysaccharides (LPS) positively (22, 24, 25). Sevoflurane improved cytokines storm by lowering serum levels of interleukin (IL)-1 and -6, IFN- γ and tumor necrosis factor (TNF)_B. The results showed that Sevoflurane reduced NF-κB expression by increasing miR-9-5p expression and decreasing p56 factor expression. The result of this process is the protection of the liver from IR damage (23). Western blot analysis showed that sevoflurane could improve the inflammatory response by blocking the miR-27a / TLR4 / MyD88 / NF-κB signaling pathway in airway smooth muscle cells (ASM). As a result, the lungs are protected from ALI (22, 26). It also increases the synthesis of PGE2 by COX-2 in peritoneal macrophages which decreases ALI (21, 27). Due to its anti-inflammatory properties and the effect of this drug on reducing the severity of cytokine storm, sevoflurane is recommended for COVID-19 treatment.
Quercetin:
Quercetin is a plant flavonol from the flavonoid group of polyphenols. Both in vivo and in vitro studies showed quercetin has anti-inflammatory, antiviral, anti-microbial, anti-tumor, antioxidant properties and reduces the risk of cardiovascular disease (28, 29). It has been shown to apply its anti-inflammatory effects through downregulating the NF-κB signaling pathways in vitro (30, 31) and in vivo (32, 33). Quercetin notably barricades LPS- induced NO, IL-1, iNOS, COX-2 (34) and at concentrations up to 50 μM inhibits the production of IL-6, MCP-1, IP-10, RANTES, GM-CSF, G-CSF, TNF-α, LIF, LIX, and VEGF as well as calcium release in dsRNA induced with polyinosinic-polycytidylic acid (35). Quercetin restricts LPS-induced inflammation through blockage of Src- and Syk-mediatedPI3K-(p85) tyrosine phosphorylation and subsequent TLR4/MyD88/PI3K complex formation that de-escalates activation of downstream signaling pathways. It promotes HO-1 induction in a dose- and time-dependent procedure. I-κB-phosphorylation, NF-κB translocation, AP-1, and NF-κB-DNA-binding and reporter gene transcription are suppressed by quercetin (34). The results demonstrate quercetin could dose-dependently decrease the mRNA and protein levels of ICAM-1, and monocyte chemoattractant protein-1 (MCP-1). Reduction of ICAM and MCP-1 by inhibition and blocking of inflammatory pathway signaling pathways such as phosphorylation of mitogen-activated protein kinases (MAPKs), an inhibitor of nuclear factor κ-B kinase (IKK)α/β, c-Jun, cAMP response element-binding protein (CREB), activating transcription factor 2 (ATF2) and nuclear factor (NF)-κB p65 is performed, which results in blocking the transfer of NF-κB p65 to the nucleus (31). Due to its inhibition of inflammatory pathways and suppression of cytokine storm by this substance (36, 37), quercetin can be a suitable option for the treatment of patients with COVID-19.
Resveratrol:
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. It has been found in red grapes (38). Resveratrol has anti-oxidation (39), anti-tumor (40) and anti-inflammation (41) activities. Resveratrol therapy (100 mg / Kg) significantly diminishes the permeability of the pulmonary arteries and cytokine storm caused by staphylococcal enterotoxin B (SEB 50 μg) and the resulting inflammation. This cytokine storm associated with increased caspase-8-dependent apoptosis in SEB activated T cells. Resveratrol treatment significantly regulates myeloid Cd11b and Gr1 suppressor cells (MDSCs), thereby inhibiting the activation of SEB-mediated T cell in laboratory conditions. In addition, resveratrol treatment is associated with SIRT1 regulation and low NF- κB regulation in inflammatory cells in the lungs (42, 43). In another study, treatment with the administration of resveratrol (100 mg/kg) significantly reduced spinal cord injury (SCI)-induced pulmonary edema. Resveratrol also significantly reduces the penetration of neutrophils and the production of inflammatory mediators. Resveratrol treatment was associated with careful regulation of SIRT1 expression and suppression of NF-κB activity in lung tissue. These data suggest that resveratrol may sustain the lungs from SCI-induced inflammatory damage (44). Increased expression of pro-inflammatory cytokines signaling pathways (TNF-α, IL-6, IL-1β, and IL-12p70), nitric oxide (NO), and interleukin-1 receptor-associated kinase 1 (IRAK-1) phosphorylation, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) which have been stimulated with lipopolysaccharide, has been treated by RM (another form of resveratrol) (45). Therefore, according to the above, resveratrol can be effective in treating COVID-19.