key: cord-0907466-af9jjipz
authors: Das, Ananya; Roy, Sraddhya; Swarnakar, Snehasikta; Chatterjee, Nabanita
title: Understanding the immunological aspects of SARS-CoV-2 causing COVID-19 pandemic: A therapeutic approach
date: 2021-07-23
journal: Clin Immunol
DOI: 10.1016/j.clim.2021.108804
sha: 27308f7e9ec8d2f8793c864de871a6426042c493
doc_id: 907466
cord_uid: af9jjipz

In December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a novel variant of coronavirus has recently emerged from Wuhan in China and has created havoc impulses across the world for a larger number of fatalities. At the same time studies are going on to discover vaccine against it or repurposing of approved drugs is widely adopted are under trial to eradicate the SARS-CoV-2 causing COVID-19. Reports have also shown that there are asymptomatic carriers of COVID-19 disease who can transmit the disease to others too. But the first line defense of the viral attack is body's strong and well-coordinated immune response producing excessive inflammatory innate reaction and impaired adaptive host immune defense may leading death upon the misfunctioning. Considerable works are going on to establish the relation between immune parameters and viral entry that might alter both the innate and adaptive immune system COVID patient by up riding a massive cytokines and chemokines secretion. This review mainly gives an account on how SARS-CoV-2 interact with our immune system and how does our immune system respond to it and along with that drugs which are being used or can be used in fighting the disease and curative therapies as treatment for it has also been addressed.

cell RNA sequencing (scRNAseq) of pulmonary tissues of Covid-19 patients. In added, the activation of interferon (IFN) signaling and monocytes recruitment decreases the alveolar potency and aids ARDS progression [38] . S protein on SARS-CoV-2 binds with greater affinity to host ACE2 receptors in comparison to SARS-CoV-1 [39] . Apart from ACE2 + cells, another study has focused on TMPRSS2, a cellular protease, which is required by the virus for entering into the cell as it helps the S protein on the virus surface to bind to the host ACE2 receptor, specially alveolar type-2 cells (AT2 cells) which express TMPRSS2 in large amount [40, 41] whereas, the affinity towards the cadherin related family member 3 (CDHR3), a rhinovirus-C receptor at ciliated epithelial cells of the upper airway is still not cleared [42] . COVID-19 results into the inflammation in the lung tissues due to less frequent exchange between oxygen and carbondioxide upon decrease in haemoglobin. This occurs due to the role of open reading frames (ORF1ab, ORF3a, ORF10), which attacks the 1-beta chain of haemoglobin into porphyrin ORF8 and surface glycoproteins attaches. This mechanism can be treated with drugs like chloroquine, favipiravir [43] . Transcriptomic study revealed that the genome of the virus is highly complicated and undergoes innumerable transcription events that in turn contributes to the production of unknown ORFs harboring mutations and undergoes recombination event. Rapid evolution of the virus, aids the virus to be drug resistant, frequently altered host specificity, thereby contributing to the virulence of the virus [44] .

Whenever a pathogen enters into our body, it is recognized as antigen and presented through antigen presenting cells (APCs) via major histocompatibility complex (MHC) molecules present on their surface. The exact mechanism of presentation of coronavirus is not fully known. According to the researches on SARS-CoV, MHC I molecule mediates the antigen presentation of the virus [45] and sometimes MHC II also participates in the process [46] . Previous data has shown a variety of polymorphisms such as human leukocyte antigen J o u r n a l P r e -p r o o f Journal Pre-proof (HLA)-DR, B1*1202, HLA-B*4601, HLA-B*0703aand HLA-Cw*0801 and correlates to the infection susceptibility of SARs virus [46, 47] . The protective alleles of HLAs mainly HLA-A*0201, HLA-DR0301 and HLA-Cw1502 [48] . Similarly, polymorphism like HLA-DRB1*11:01 and HLA-DQB1*02:0 in MHC II molecules elevates the risk for developing MERS-CoV infection. Moreover, mannose binding lectin (MBL) also present SARS-CoV to the immune cells [49] . The exact MHC type for the antigen presentation of COVID-19 disease is undeciphered but available data may shed some light in conducting further researches. The prospects that needed experimental focus is exact which type of MHC molecule are involved in the antigen presentation of SARS-CoV2?

In SARS-CoV-2, pattern recognition receptors (PRRs) activates the innate immune responses via extracellular and endosomal Toll-like receptors (TLRs) in concert with cytosolic RIG-I like receptors (RLRs) [50] . Following the activation of PRRs, downstream signaling cascades stimulates the cytokines production like Type I/III IFNs as defense against virus, tumor necrosis factor alpha (TNF-α), interleukins (IL-1,IL-6, IL-18) and other proinflammatory cytokines [51] . The complex signaling pathways involving myeloid differentiation primary response 88 (MYD88) produces type I IFNs and activate the transcription factor NF-κB which induces the transcription and production of proinflammatory cytokines [52] . Type-I IFNs activate the downstream signal transducer and activator of transcription (STAT) proteins that catalyses generation of interferon stimulated genes (ISGs) coded antiviral proteins like IFN-induced protein with tetratricopeptide repeats-1. This phenomenon retards the replication of the virus in both neighboring and infected cells by activating an immune response against the virus. So, how COVID-19 can cause severe infection in patients? What are the immune escape strategies that are being nsp1 also inhibit activation of IFN-β promoter which is viral dependent [54] . The induction of IFN is blocked by accessory protein 4a of MERS-CoV upon interaction with double stranded DNA (dsDNA) directly [55] . Furthermore, studies have shown that in MERS-CoV infection ORF4a, ORF4b, ORF5 and membrane (M) proteins blocks transport of IRF3 into the nucleus and also inactivates IFNb promoter [56] . The gene expressions for antigen presentation are also downregulated after MERs-CoV infection. Thus, SARS-CoV and MERS-CoV has modified to escape from host immune surveillance. Efficient data is not available to support the theory that SARS-CoV2 also uses the same mechanism to avoid immune surveillance. Table 2 provides a comparative study on the immunological functions played by structural proteins of the virus.

First line of defense comes from the cells of innate immune system that include residential macrophages, conventional dendritic cells (cDCs), monocytes-derived dendritic cells (moDCs), granulocytes and natural killer cells [74] . In any viral infection, the innate immune system relies on Type I interferon (IFN) responses whose downstream cascade regulate the viral replication and induce adaptive immune responses. However, nCOVID-19 may dampen the IFN Type-1 response to terminate the anti-viral response. According to studies, SARS-CoV directly affect macrophages and T cells [75] . Recent research has shown that SARS-CoV-2 induces CD169 + tissue-resident macrophages to produce IL-6 which results into lymphocyte apoptosis via upregulation of Fas in human spleen and lymphnode [76] . According to the data of scRNAseq of COVID patients, there was expansion of lung macrophages in patients with severe COVID-19 infection may recruit IMs and neutrophils though CCR1 and CXCR2 [79] . According to earlier data, SARS-CoV-1 infection resulted in an diverging phenotype of AM phenotype which limits the trafficking of DC and activation of T cell [80] and YM1 + FIZZ1 + alternatively activated macrophages increased hypersensitivity in airway, thus worsening the fibrosis by SARS-infection [81] .

These mechanisms, in SARS-CoV-2, need more research focus. Recent research revealed that ACE2 and SARS-CoV-2 N protein is also present CD169 + macrophages of spleen and lymph node SARS-CoV-2 patients that are involved in production of IL-6 [82] . As mentioned earlier, SARS-CoV-2 undergoes the process of causing infection via ACE2 receptors but very low macrophage percentage in lungs express ACE2 receptors. So, the question arises that is there any other receptor present through which SARS-CoV-2 is infecting immune cells?

Evidences revealed reduced number of natural killer (NK) cells, in peripheral blood are positively correlated with COVID severity [83] [84] [85] . In influenza infection, CXCR3 mediated NK cell infiltration [86] . In vitro study shows increased level of CXCR3 ligand (CXCL9- 11) in SARS-CoV-2 infected tissue of human lung along with expanded monocyte level stimulated by CXCR3 ligand in SARS-coV-2 infection [38] . These studies suggest that the CXCR3 pathway recruits NK cell in SARS-coV-2 infected patient the lungs from peripheral blood. Recent studies have shown that peripheral blood NK cells of SARS-coV-2 patients with deceased expression of enzymes such as granzyme B, granulysin and also reduced surface markers CD107a, Ksp37, and an impaired chemokine production of TNF-α and IFN-ɣ that suggest an impaired cytotoxicity [84, 87] . Moreover, SARS-CoV-2 infection has shown less number of CD16 + KIR + peripheral blood NK cells [88] . The expression of immune checkpoint NK group 2 member 2A (NKG2A) is increased with the upregulation of genes

Antigen presentation by APCs to other immune cells subsequently activates pathogen [90] . SARS-CoV-2 specific IgG of S protein was found in the serum of patient even after 60 days of symptom onset, which decreased within 8 weeks of onset of post symptom [51] . Further studies are needed on the existence of viral specific IgG + memory cells in recovered COVID patients.

Latest data has shown that in COVID-19 patients the peripheral count of CD4 + and CD8 + T cells have been greatly reduced but they were hyperactive in status. Additionally, a hike in highly proinflammatory CCR4 + CCR6 + CD4 + T cells (Th17 cells) producing IL-17 and granulysin expressing Tc cells were observed in patients with severe immune injury [91] .

Moreover, the cytotoxic Tc cells (CD8 + T cells) were much higher in number e.g. 31.6% cells were perforin positive, 64.2% cells were granulysin positive and 30.5% cells were double positive for both perforin and granulysin [91] . These results implicated that the high number of Th17 and CD8 + T cells and their hyperactive function is responsible for severe immune inflammation in patients and produces low IFN-γ and TNF-α in CD4 + T cells and high granzyme B and perforin in CD8 + T cells in COVID-19 infected patients [92] . It has been reported that CD8 + T cells, developed during SARS-CoV infection, are specifically produced for the antigen S, M, E and N proteins. In SARS-CoV infection, CD8 + T cells have been J o u r n a l P r e -p r o o f Journal Pre-proof observed to differentiate into CD45ROˉCCR7ˉCD62Lˉ effector memory cells while CD4 + T cells express CD45 + CCR7 + CD62Lˉ central memory T cells [93] . Th1 cells which was hyperactivated releases granulocyte-monocyte colony stimulating factors (GM-CSF) and

IFNγ. This recruits increased numbers of CD14 + CD16 + monocytes that are inflammatory, stimulated by Il-6 [94] . In moderately infected lung macrophages produced increased chemokines, that will attract T cells, via ethe engagement of CXCR3 and CXCR6 . Moreover, experimental analysis suggests that these memory cells lasts for 3-4 years after the infection has been cured and slowly diminishes in the absence of antigen after 4 years [93] . Moreover, all the subtypes of T cells found in SARS-CoV-2 infection, shows higher expression of negative immune checkpoint markers and exhaustion markers that is correlated with severe immune pathogenicity. The study of 10 patients group revealed increased levels of PD-1 in CD8 + T cells and Tim3 in CD4 + T cell were observed in three patients of both prodromal and symptomatic stages of SARS-CoV-2 infection [96] . Furthermore, several other investigations reported increase in the expression of both co-stimulatory and inhibitory molecules such as OX-40 and CD137 [94] , CTLA-4 and T cell immunoreceptor with Ig and ITIM domains (TIGIT) [92] and NKG2A [84] , were found in T cells which suppressed cytotoxic activity. Till now there is no potent evidence of any memory cells developed in cured COVID-19 patients against SARS-CoV-2.

Till now according to the reports, the main cause of death due to COVID-19 is severe -inflammatory cytokines such as IL2, IL7, IL10, G-CSF, IP10, MCP1, MIP1α, and TNFα, which are positively correlated with disease severity [26] . In a report from Wuhan where 99 cases had been studied, an increase in total neutrophils, decrease in total lymphocytes and increased in serum IL-6 has been observed. A delayed IFN-I signaling was observed which accumulate inflammatory monocyte-macrophages (IMMs).This resulted in high levels of cytokine and chemokine in lung, vascular leakage, and impaired the response of viral-specific T cell [98] . In SARS infected patients, an elevated level of IL-6, IL-8 and inducible protein 10 (IP-10) has been found in lung tissue [99] . Increased levels of proinflammatory cytokines is mainly responsible for severe lung injury, leading to demise of nCovid victims [91] . High levels of IP10 was related with immune mediated severe lung injury and apoptosis of lymphocytes in SARS [99] . Together with the cytokines, certain chemokines such as CXCL10, IP10,CCL2, CCL3, CCL5, CXCL8, CXCL9 support the impaired systemic inflammatory response in SARS-CoV-2 [100] . In comparison with SARS-CoV, SARS-CoV-2 upregulated five chemokines namely CXCL1, CXCL5, CXCL10, CCL2 and IL-6 [101] . SARS-CoV-2 patients with more severe pneumonia and pulmonary syndrome showed correlated higher expression of GM-CSF + and IL-6 + CD4 + T cells, higher coexpression of IFN-γ and GM-CSF in pathogenic Th1 cells, much higher expression of CD14 + CD16 + monocyte [94] . In a nutshell, high infiltration of all type of immune cells such as T cells, monocytes, macrophages, NK cells, DCs, and secretion of their proinflammatory cytokines into lung cause severe ARDS leading to death in the patients.

Currently there is no clinically approved antiviral vaccine for the treating SARS-CoV-2. All patients are treated with supportive treatment strategies targeted to culminate the patients' symptoms (like pneumonia, fever, breathing problems) and often supported with combination of drugs. However, these strategies cannot be implemented for a long time. As per data, there are 11 phase 4, 36 phase 2 and 4 phase 1 trails [102] . Table 3 encloses a list of commonly used combinational drugs for the treatment of COVID-19.

As it has been an absolute outbreak and pandemic disease declared by WHO, a specific cure has to be found out to cure the disease completely. According to the genomic and structural analysis of SARS-CoV-2, there are a number of therapeutic targets which are under clinical trials in different laboratories across the whole world.

The Washington Department of Health Administration has first introduced remdesivir which inhibit RNA dependent RNA polymerase activity intravenously and found that it has a potential to protect from SARS-CoV-2 infection. The combination of remdesivir and choloroquine has shown to prevent SARS-CoV-2 infection invitro. Therefore, other nucleotide analogue such as favipiravir, ribavirin can also be administered as potential inhibitors. There are certain proteases such as 3 chymotrypsin-like protease (CLpro) along with papain like protease (PLpro) that cleave viral polyproteins, can be the noble drug targets for the treatment. These also affects the replication of virus and antagonize IFN, IL-6. As SARS-CoV-2 binds with the ACE2 receptors of host cell, therefore targeting the S protein on the surface of the virus or the binding of the S protein and ACE2 can be a potential therapeutic target to combat COVID-19 infection. Fig 2 points out the role of various drugs in distinctive stages of SARS-CoV-2 replication process.

According to studies the development of recombinant monoclonal antibody (mAb) J o u r n a l P r e -p r o o f Journal Pre-proof can be a noble way to neutralize SARS-CoV-2. For example, CR3022, a SARS specific human mAb, can bind with the RBD of SARS-CoV-2and can be used as candidate vaccine for SARS-CoV-2. Other mAbs, such as m396, CR3014, can be alternative against SARS-CoV-2. Recently, a recombinant mAb named tocilizumab has come into application that can bind to IL-6 receptor, thereby terminating its signal transduction but its efficiency is still under study [29] . In addition to it, virus neutralizing antibody isolated from convalescent serum of COVID-19 patients, who has recovered from the infection, is also administered in susceptible individuals as it proved to be promising treatment approach during the previous corona outbreaks. It can impose immediate immune response in the unaffected susceptible individuals [109] . The generation of antibodies against the S proteins of the virus is being followed by Moderna Inc., MA, USA. There is also hope for development of new mAbs, which may take less time to be available to the doctors due to their speedy trials and their high specificity.

In this pandemic situation, approved vaccines against SARS-CoV-2 are essentially required as soon as possible for decreasing disease severity together with reduced shedding and transmission of virus. Currently, no approved vaccine is available in the market to cure this disease. In the world full of darkness, a keen ray of light has been illuminated by the recent development of a vaccine mRNA1273 by The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). This mRNA1273 is now under phase one trial. The vaccine may be available in the near future, but the time require for this to reach the market depends on the efficacy and success in all three phases of clinical trials.

Significant studies have been focused on identifying various target epitopes mapping on SARS-CoV-2 for development of targeted vaccines. Apart from antibodies J o u r n a l P r e -p r o o f Journal Pre-proof targeting RBD of S proteins, studies have been undertaken to identify additional viral fragments (epitopes). This investigation has utilized the data on genetic differences and similarities among the three strains of coronavirus by utilizing bioinformatics analysis [110, 111] . By implementing immune informatics scientists discovered five cytotoxic T lymphocytes (CTLs) epitopes and eight B-cell epitopes in the viral surface glycoproteins.

Among the B cell epitopes three are sequential and rest five are discontinuous. Furthermore, CTL epitopes are activated as judged by molecular dynamicity that the interaction between the CTL epitopes and HLA chains of MHC-I complexes are mediated by hydrogen (H) bonds and salt bridges, indicating their efficacy to confer immune responses [111] . Another study has identified five linear and two conformational B cell epitopes of SARS-CoV-2 surface proteins [112]. Table 4 .

Another concept of controlling the rapid spread of the virus is to develop herd immunity which is defined as decrease in population of susceptible individuals below the threshold value required for transmission. The contagious state of SARS-CoV-2 (R 0 ) varies between 2%-3%. So, for acquiring herd immunity the threshold value is 67% for this virus.

The current scenario of rapidly spreading and unpredicted infectious nature of SARS- Better studies needed to understand the role of this mutation in viral pathogenecity.

[21] 

Coronavirus disease 2019 (COVID-19): a clinical update

Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies

The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health -The latest 2019 novel coronavirus outbreak in Wuhan, China

Coronaviruses post-SARS: Update on replication and pathogenesis

Human Coronavirus: Host-Pathogen Interaction

Origin and evolution of pathogenic coronaviruses

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World Health Organisaton, COVID-19 Weekly Epidemiological Update Global summary

Spike mutation D614G alters SARS-CoV-2 fitness

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COVID-2019: The role of the nsp2 and nsp3 in its pathogenesis

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Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

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Angiotensin-Converting Enzyme 2 ( ACE2 ) Is a Key Modulator of the Renin Angiotensin System in Health and Disease

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Ultrastructure and Origin of Membrane Vesicles Associated with the

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A guideline for homology modeling of the proteins from newly discovered betacoronavirus

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial

The nsp1, nsp13, and M Proteins Contribute to the Hepatotropism of Murine Coronavirus JHM.WU

Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors

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crossm Binding of the Methyl Donor

The nsp9 Replicase Protein of SARS-Coronavirus, Structure and Functional Insights

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Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites

SARS

SARS-CoV-2 and COVID-19: The most important research questions

MERS-CoV accessory orfs play key role for infection and pathogenesis

Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome

Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections

Immunopathogenesis of coronavirus infections: Implications for SARS

Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

Immune cell pro fi ling of COVID-19 patients in the recovery stage by single-cell sequencing

Brief Report A Dynamic Immune Response Shapes COVID-19 Progression ll ll Brief Report A Dynamic Immune Response Shapes COVID-19 Progression

Evasion by Stealth : Inefficient Immune Activation Underlies Poor T Cell Response and Severe Disease in SARS-CoV-Infected Mice

Induction of Alternatively Activated Macrophages Enhances Pathogenesis during Severe Acute Respiratory Syndrome Coronavirus

The Novel Severe Acute Respiratory Syndrome Coronavirus 2 ( SARS-CoV-2 ) Directly Decimates Human Spleens and Lymph Nodes Running title : SARS-CoV-2 infects human spleens and lymph nodes

The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

COVID-19 early warning score: a multi-parameter screening Front

Singlecell landscape of bronchoalveolar immune cells in patients with COVID-19

Characteristics of Peripheral Lymphocyte Subset Alteration in COVID-19 Pneumonia

Profile of specific antibodies to the SARS-associated coronavirus

COVID -19 progression linked to B cell activation, medRxiv

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients

Characterization of SARS-CoV-specific memory T cells from recovered individuals 4 years after infection

Pathogenic T-cells and sequencing

Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice

Characterization of cytokine/chemokine profiles of seven acute respiratory syndrome

The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

Molecular immune pathogenesis and diagnosis of COVID-19

Pharmacologic Treatments for

Chloroquine and hydroxychloroquine as available weapons to fight COVID-19

COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Remdesivir as a possible therapeutic option for the COVID-19

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

The convalescent sera option for containing COVID-19

A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV, Science (80-. )

Immunoinformatics-aided identification of T cell and B cell epitopes in the

Mesenchymal stem cells and management of COVID-19 pneumonia

ALBERTA HOPE COVID-19 for the Prevention of Severe COVID19 Disease -Full Text View -ClinicalTrials.gov

Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734 TM ) in Participants With Severe Coronavirus Disease (COVID-19) -Full Text View -ClinicalTrials.gov

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19

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Clinical Study To Evaluate The Performance And Safety Of Favipiravir in COVID-19 -Full Text Ponikowski

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Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19 -Full Text View -ClinicalTrials.gov

The Phase 2 Study to Evaluate the Safety and Efficacy of Clevudine in Patients With Moderate COVID-19 -Full Text View -ClinicalTrials.gov

Study of FT516 for the Treatment of COVID-19 in Hospitalized Patients With Hypoxia -Full Text View -ClinicalTrials.gov

DAS181 for Severe COVID-19: Compassionate Use -Full Text View -ClinicalTrials.gov

Study of Open Label Losartan in COVID-19 -Full Text View -ClinicalTrials.gov

Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo

Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice

Efficacy of Convalescent Plasma Therapy in the Early Care of COVID-19 Patients. -Full Text View -ClinicalTrials.gov

Isotretinoin in Treatment of COVID-19 -Full Text View -ClinicalTrials.gov

Colchicine in COVID-19: a Pilot Study -Full Text View -ClinicalTrials.gov

Ruxolitinib in Covid-19 Patients With Defined Hyperinflammation -Full Text View -ClinicalTrials.gov

Expanded Access Program of Ruxolitinib for the Emergency Treatment of Cytokine Storm From COVID-19 Infection -Full Text View -ClinicalTrials.gov

The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation

A Pilot Study of Sildenafil in COVID-19 -Full Text View -ClinicalTrials.gov

Sirolimus Treatment in Hospitalized Patients With COVID-19 Pneumonia -Full Text View -ClinicalTrials.gov

Single-Blind Study of a Single Dose of Peginterferon Lambda-1a Compared With Placebo in Outpatients With Mild COVID-19 -Full Text View -ClinicalTrials.gov

Rintatolimod and IFN Alpha-2b for the Treatment of Mild or Moderate COVID-19 Infection in Cancer Patients -Full Text View -ClinicalTrials.gov

Administration of Intravenous Vitamin C in Novel Coronavirus Infection (COVID-19) and Decreased Oxygenation -Full Text View -ClinicalTrials.gov

Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19) -Full Text View -ClinicalTrials.gov

An mRNA Vaccine against SARS-CoV-2 -Preliminary Report

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Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

A Study of a Candidate COVID-19 Vaccine (COV001) -Full Text View -ClinicalTrials.gov

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Evaluation of the Safety and Immunogenicity of a SARS-CoV-2 rS (COVID-19) Nanoparticle Vaccine With/Without Matrix-M Adjuvant -Full Text View -ClinicalTrials.gov

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Evaluating the Safety, Tolerability and Immunogenicity of bacTRL-Spike Vaccine for Prevention of COVID-19 -Full Text View -ClinicalTrials.gov