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1.
Zhonghua Gan Zang Bing Za Zhi ; 28(2): 100-106, 2020 Feb 20.
Article in Chinese | MEDLINE | ID: covidwho-686167

ABSTRACT

Objective: To explore and analyze the possible mechanism of liver injury in patients with coronavirus disease 2019 (novel coronavirus pneumonia, NCP). Methods: The correlation between ALT, AST and other liver enzyme changes condition and NCP patients' disease status reported in the literature was comprehensively analyzed. ACE2 expression in liver tissue for novel coronavirus was analyzed based on single cell sequencing (GSE115469) data. RNA-Seq method was used to analyze Ace2 expression and transcription factors related to its expression in liver tissues at various time-points after hepatectomy in mouse model of acute liver injury with partial hepatectomy. t-test or Spearman rank correlation analysis was used for statistical analysis. Results: ALT and AST were abnormally elevated in some patients with novel coronavirus infection, and the rate and extent of ALT and AST elevation in severe NCP patients were higher than those in non-severe patients. Liver tissue results of single cell sequencing and immunohistochemistry showed that ACE2 was only expressed in bile duct epithelial cells of normal liver tissues, and very low in hepatocytes. In a mouse model of acute liver injury with partial hepatectomy, Ace2 expression was down-regulated on the first day, but it was elevated up to twice of the normal level on the third day, and returned to normal level on seventh day when the liver recovered and hepatocyte proliferation stopped. Whether this phenomenon suggests that the bile duct epithelial cells with positive expression of Ace2 participate in the process of liver regeneration after partial hepatectomy deserves further study. In RNA-Seq data, 77 transcription factors were positively correlated with the expression of Ace2 (r > 0.2, FDR < 0.05), which were mainly enriched in the development, differentiation, morphogenesis and cell proliferation of glandular epithelial cells. Conclusion: We assumed that in addition to the over activated inflammatory response in patients with NCP, the up-regulation of ACE2 expression in liver tissue caused by compensatory proliferation of hepatocytes derived from bile duct epithelial cells may also be the possible mechanism of liver tissue injury caused by 2019 novel coronavirus infection.


Subject(s)
Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , Animals , Humans , Liver , Mice , Peptidyl-Dipeptidase A
2.
Diabetes Metab Syndr ; 14(4): 303-310, 2020.
Article in English | MEDLINE | ID: covidwho-676723

ABSTRACT

BACKGROUND AND AIMS: High prevalence of diabetes makes it an important comorbidity in patients with COVID-19. We sought to review and analyze the data regarding the association between diabetes and COVID-19, pathophysiology of the disease in diabetes and management of patients with diabetes who develop COVID-19 infection. METHODS: PubMed database and Google Scholar were searched using the key terms 'COVID-19', 'SARS-CoV-2', 'diabetes', 'antidiabetic therapy' up to April 2, 2020. Full texts of the retrieved articles were accessed. RESULTS: There is evidence of increased incidence and severity of COVID-19 in patients with diabetes. COVID-19 could have effect on the pathophysiology of diabetes. Blood glucose control is important not only for patients who are infected with COVID-19, but also for those without the disease. Innovations like telemedicine are useful to treat patients with diabetes in today's times.


Subject(s)
Betacoronavirus , Comorbidity , Coronavirus Infections/epidemiology , Diabetes Mellitus/epidemiology , Pneumonia, Viral/epidemiology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Blood Glucose/analysis , Blood Glucose/metabolism , Coronavirus Infections/mortality , Diabetes Mellitus/physiopathology , Diabetes Mellitus/therapy , Dipeptidyl Peptidase 4 , Humans , Hypoglycemic Agents/therapeutic use , Interleukin-6 , Mice , Pandemics , Peptidyl-Dipeptidase A , Pneumonia, Viral/mortality , Prognosis , PubMed , Risk Factors , Telemedicine
3.
F1000Res ; 9: 345, 2020.
Article in English | MEDLINE | ID: covidwho-676603

ABSTRACT

As the coronavirus disease 2019 (COVID-19) pandemic grows throughout the world, it is imperative that all approaches to ameliorating its effects be investigated, including repurposing drugs that show promise in other diseases. We have been investigating an approach to multiple disorders that involves recruiting the innate immune system to aid the body's healing and regenerative mechanism(s). In the case of West Nile Virus encephalitis and potentially COVID-19, the proposed intervention to stimulate the innate immune system may give the adaptive immune response the necessary time to develop, finish clearing the virus, and provide future immunity. Furthermore, we have found that GM-CSF-induced recruitment of the innate immune system is also able to reverse brain pathology, neuroinflammation and cognitive deficits in mouse models of Alzheimer's disease and Down syndrome, as well as improving cognition in normal aging and in human patients with cognitive deficits due to chemotherapy, both of which exhibit neuroinflammation. Others have shown that GM-CSF is an effective treatment for both bacterial and viral pneumonias, and their associated inflammation, in animals and that it has successfully treated pneumonia-associated Acute Respiratory Distress Syndrome in humans. These and other data strongly suggest that GM-CSF may be an effective treatment for many viral infections, including COVID-19.


Subject(s)
Coronavirus Infections/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Immune System , Pneumonia, Viral/immunology , West Nile Fever/immunology , Animals , Betacoronavirus , Coronavirus Infections/therapy , Encephalitis/therapy , Encephalitis/virology , Humans , Mice , Pandemics , Pneumonia, Viral/therapy , West Nile Fever/therapy
4.
Science ; 369(6499): 77-81, 2020 07 03.
Article in English | MEDLINE | ID: covidwho-667322

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. Because of the novelty of the virus, there are currently no SARS-CoV-2-specific treatments or vaccines available. Therefore, rapid development of effective vaccines against SARS-CoV-2 are urgently needed. Here, we developed a pilot-scale production of PiCoVacc, a purified inactivated SARS-CoV-2 virus vaccine candidate, which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats, and nonhuman primates. These antibodies neutralized 10 representative SARS-CoV-2 strains, suggesting a possible broader neutralizing ability against other strains. Three immunizations using two different doses, 3 or 6 micrograms per dose, provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without observable antibody-dependent enhancement of infection. These data support the clinical development and testing of PiCoVacc for use in humans.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines , Animals , Antibodies, Neutralizing/biosynthesis , Antibodies, Neutralizing/immunology , Antibodies, Viral/biosynthesis , Antibodies, Viral/immunology , Betacoronavirus/isolation & purification , Chlorocebus aethiops , Coronavirus Infections/immunology , Coronavirus Infections/virology , Dose-Response Relationship, Immunologic , Female , Immunogenicity, Vaccine , Immunoglobulin G/biosynthesis , Immunoglobulin G/blood , Immunoglobulin G/immunology , Macaca mulatta , Male , Mice , Mice, Inbred BALB C , Pilot Projects , Pneumonia, Viral/virology , Rats , Rats, Wistar , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/adverse effects , Vaccines, Inactivated/immunology , Vero Cells , Viral Load , Viral Vaccines/administration & dosage , Viral Vaccines/adverse effects , Viral Vaccines/immunology
7.
Front Immunol ; 11: 1518, 2020.
Article in English | MEDLINE | ID: covidwho-644235

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1ß. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Inflammasomes/antagonists & inhibitors , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pneumonia, Viral/metabolism , Animals , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/metabolism , Heterocyclic Compounds, 4 or More Rings/pharmacology , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Immunity, Innate , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/metabolism , Mice , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Pyroptosis/drug effects , Respiratory Distress Syndrome, Adult/drug therapy , Respiratory Distress Syndrome, Adult/etiology , Respiratory Distress Syndrome, Adult/metabolism , Sesquiterpenes, Guaiane/pharmacology , Sesquiterpenes, Guaiane/therapeutic use , Sulfones/pharmacology , Sulfones/therapeutic use
8.
Front Immunol ; 11: 1512, 2020.
Article in English | MEDLINE | ID: covidwho-642764

ABSTRACT

Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.


Subject(s)
Adoptive Transfer/methods , Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Killer Cells, Natural/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Adrenal Cortex Hormones/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Ascorbic Acid/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/mortality , Coronavirus Infections/virology , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Disease Susceptibility/immunology , Humans , Immunity, Innate/drug effects , Immunity, Innate/immunology , Immunologic Memory , Interferon Type I/metabolism , Interferon Type I/therapeutic use , Killer Cells, Natural/drug effects , Mice , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/virology
10.
Nat Commun ; 11(1): 3523, 2020 07 09.
Article in English | MEDLINE | ID: covidwho-640262

ABSTRACT

The spread of the SARS-CoV-2 into a global pandemic within a few months of onset motivates the development of a rapidly scalable vaccine. Here, we present a self-amplifying RNA encoding the SARS-CoV-2 spike protein encapsulated within a lipid nanoparticle (LNP) as a vaccine. We observe remarkably high and dose-dependent SARS-CoV-2 specific antibody titers in mouse sera, as well as robust neutralization of both a pseudo-virus and wild-type virus. Upon further characterization we find that the neutralization is proportional to the quantity of specific IgG and of higher magnitude than recovered COVID-19 patients. saRNA LNP immunizations induce a Th1-biased response in mice, and there is no antibody-dependent enhancement (ADE) observed. Finally, we observe high cellular responses, as characterized by IFN-γ production, upon re-stimulation with SARS-CoV-2 peptides. These data provide insight into the vaccine design and evaluation of immunogenicity to enable rapid translation to the clinic.


Subject(s)
Antibodies, Neutralizing/immunology , Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Nanoparticles/chemistry , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Animals , Antibodies, Viral/blood , Antibodies, Viral/metabolism , Antibody-Dependent Enhancement/immunology , Betacoronavirus/genetics , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/immunology , Disease Models, Animal , Humans , Immunity, Cellular , Immunoglobulin G/blood , Mice , Mice, Inbred BALB C , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , RNA, Viral/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/chemistry , Vaccines, Synthetic/immunology , Viral Vaccines/chemistry
11.
Theranostics ; 10(16): 7448-7464, 2020.
Article in English | MEDLINE | ID: covidwho-640241

ABSTRACT

The COVID-19 pandemic is an emerging threat to global public health. While our current understanding of COVID-19 pathogenesis is limited, a better understanding will help us develop efficacious treatment and prevention strategies for COVID-19. One potential therapeutic target is angiotensin converting enzyme 2 (ACE2). ACE2 primarily catalyzes the conversion of angiotensin I (Ang I) to a nonapeptide angiotensin or the conversion of angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and has direct effects on cardiac function and multiple organs via counter-regulation of the renin-angiotensin system (RAS). Significant to COVID-19, ACE2 is postulated to serve as a major entry receptor for SARS-CoV-2 in human cells, as it does for SARS-CoV. Many infected individuals develop COVID-19 with fever, cough, and shortness of breath that can progress to pneumonia. Disease progression promotes the activation of immune cells, platelets, and coagulation pathways that can lead to multiple organ failure and death. ACE2 is expressed by epithelial cells of the lungs at high level, a major target of the disease, as seen in post-mortem lung tissue of patients who died with COVID-19, which reveals diffuse alveolar damage with cellular fibromyxoid exudates bilaterally. Comparatively, ACE2 is expressed at low level by vascular endothelial cells of the heart and kidney but may also be targeted by the virus in severe COVID-19 cases. Interestingly, SARS-CoV-2 infection downregulates ACE2 expression, which may also play a critical pathogenic role in COVID-19. Importantly, targeting ACE2/Ang 1-7 axis and blocking ACE2 interaction with the S protein of SARS-CoV-2 to curtail SARS-CoV-2 infection are becoming very attractive therapeutics potential for treatment and prevention of COVID-19. Here, we will discuss the following subtopics: 1) ACE2 as a receptor of SARS-CoV-2; 2) clinical and pathological features of COVID-19; 3) role of ACE2 in the infection and pathogenesis of SARS; 4) potential pathogenic role of ACE2 in COVID-19; 5) animal models for pathological studies and therapeutics; and 6) therapeutics development for COVID-19.


Subject(s)
Betacoronavirus , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/chemistry , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Disease Models, Animal , Host Microbial Interactions/physiology , Humans , Mice , Models, Biological , Pandemics , Pneumonia, Viral/therapy , Renin-Angiotensin System/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Theranostic Nanomedicine , Viral Vaccines/isolation & purification , Virus Internalization
12.
Front Immunol ; 11: 1451, 2020.
Article in English | MEDLINE | ID: covidwho-637661

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) represents an emergent global threat which is straining worldwide healthcare capacity. As of May 27th, the disease caused by SARS-CoV-2 (COVID-19) has resulted in more than 340,000 deaths worldwide, with 100,000 deaths in the US alone. It is imperative to study and develop pharmacological treatments suitable for the prevention and treatment of COVID-19. Ascorbic acid is a crucial vitamin necessary for the correct functioning of the immune system. It plays a role in stress response and has shown promising results when administered to the critically ill. Quercetin is a well-known flavonoid whose antiviral properties have been investigated in numerous studies. There is evidence that vitamin C and quercetin co-administration exerts a synergistic antiviral action due to overlapping antiviral and immunomodulatory properties and the capacity of ascorbate to recycle quercetin, increasing its efficacy. Safe, cheap interventions which have a sound biological rationale should be prioritized for experimental use in the current context of a global health pandemic. We present the current evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients as an adjunct to promising pharmacological agents such as Remdesivir or convalescent plasma.


Subject(s)
Antiviral Agents/therapeutic use , Ascorbic Acid/therapeutic use , Betacoronavirus/physiology , Coronavirus Infections/prevention & control , Immunologic Factors/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pre-Exposure Prophylaxis/methods , Quercetin/therapeutic use , Animals , Antiviral Agents/adverse effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Synergism , Drug Therapy, Combination , Humans , Mice , Pneumonia, Viral/virology , Quercetin/adverse effects , Quercetin/chemistry , Quercetin/pharmacokinetics , Virus Replication/drug effects
13.
Mol Med ; 26(1): 69, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-635101

ABSTRACT

BACKGROUND: We previously showed that the autophagy inhibitor chloroquine (CQ) increases inflammatory cleaved caspase-1 activity in myocytes, and that caspase-1/11 is protective in sterile liver injury. However, the role of caspase-1/11 in the recovery of muscle from ischemia caused by peripheral arterial disease is unknown. We hypothesized that caspase-1/11 mediates recovery in muscle via effects on autophagy and this is modulated by CQ. METHODS: C57Bl/6 J (WT) and caspase-1/11 double-knockout (KO) mice underwent femoral artery ligation (a model of hind-limb ischemia) with or without CQ (50 mg/kg IP every 2nd day). CQ effects on autophagosome formation, microtubule associated protein 1A/1B-light chain 3 (LC3), and caspase-1 expression was measured using electron microscopy and immunofluorescence. Laser Doppler perfusion imaging documented perfusion every 7 days. After 21 days, in situ physiologic testing in tibialis anterior muscle assessed peak force contraction, and myocyte size and fibrosis was also measured. Muscle satellite cell (MuSC) oxygen consumption rate (OCR) and extracellular acidification rate was measured. Caspase-1 and glycolytic enzyme expression was detected by Western blot. RESULTS: CQ increased autophagosomes, LC3 consolidation, total caspase-1 expression and cleaved caspase-1 in muscle. Perfusion, fibrosis, myofiber regeneration, muscle contraction, MuSC fusion, OCR, ECAR and glycolytic enzyme expression was variably affected by CQ depending on presence of caspase-1/11. CQ decreased perfusion recovery, fibrosis and myofiber size in WT but not caspase-1/11KO mice. CQ diminished peak force in whole muscle, and myocyte fusion in MuSC and these effects were exacerbated in caspase-1/11KO mice. CQ reductions in maximal respiration and ATP production were reduced in caspase-1/11KO mice. Caspase-1/11KO MuSC had significant increases in protein kinase isoforms and aldolase with decreased ECAR. CONCLUSION: Caspase-1/11 signaling affects the response to ischemia in muscle and effects are variably modulated by CQ. This may be critically important for disease treated with CQ and its derivatives, including novel viral diseases (e.g. COVID-19) that are expected to affect patients with comorbidities like cardiovascular disease.


Subject(s)
Caspase 1/metabolism , Caspases, Initiator/metabolism , Chloroquine/pharmacology , Coronavirus Infections/pathology , Ischemia/pathology , Muscle, Skeletal/pathology , Pneumonia, Viral/pathology , Animals , Autophagosomes/metabolism , Autophagy/drug effects , Betacoronavirus , Coronavirus Infections/drug therapy , Glycolysis/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microtubule-Associated Proteins/metabolism , Muscle Cells/metabolism , Muscle Development , Muscle, Skeletal/metabolism , Neovascularization, Physiologic , Oxidative Phosphorylation , Pandemics , Peripheral Arterial Disease/pathology , Pneumonia, Viral/drug therapy , Regeneration , Signal Transduction
15.
Curr Protoc Microbiol ; 58(1): e108, 2020 09.
Article in English | MEDLINE | ID: covidwho-614201

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the city of Wuhan, Hubei Province, China, in late 2019. Since then, the virus has spread globally and caused a pandemic. Assays that can measure the antiviral activity of antibodies or antiviral compounds are needed for SARS-CoV-2 vaccine and drug development. Here, we describe in detail a microneutralization assay, which can be used to assess in a quantitative manner if antibodies or drugs can block entry and/or replication of SARS-CoV-2 in vitro. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Microneutralization assay to test inhibition of virus by antibodies (purified antibodies or serum/plasma) Basic Protocol 2: Screening of anti-SARS-CoV-2 compounds in vitro Support Protocol: SARS-CoV-2 propagation.


Subject(s)
Antibodies, Viral/immunology , Betacoronavirus/immunology , Drug Evaluation, Preclinical/methods , Neutralization Tests/methods , Animals , Chlorocebus aethiops , Coronavirus Infections/immunology , Coronavirus Infections/virology , Humans , Mice , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Vero Cells , Virus Internalization/drug effects , Virus Replication/drug effects
16.
J Transl Med ; 18(1): 257, 2020 06 25.
Article in English | MEDLINE | ID: covidwho-613899

ABSTRACT

BACKGROUND: The recent global pandemic has placed a high priority on identifying drugs to prevent or lessen clinical infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused by Coronavirus disease-2019 (COVID-19). METHODS: We applied two computational approaches to identify potential therapeutics. First, we sought to identify existing FDA approved drugs that could block coronaviruses from entering cells by binding to ACE2 or TMPRSS2 using a high-throughput AI-based binding affinity prediction platform. Second, we sought to identify FDA approved drugs that could attenuate the gene expression patterns induced by coronaviruses, using our Disease Cancelling Technology (DCT) platform. RESULTS: Top results for ACE2 binding iincluded several ACE inhibitors, a beta-lactam antibiotic, two antiviral agents (Fosamprenavir and Emricasan) and glutathione. The platform also assessed specificity for ACE2 over ACE1, important for avoiding counterregulatory effects. Further studies are needed to weigh the benefit of blocking virus entry against potential counterregulatory effects and possible protective effects of ACE2. However, the data herein suggest readily available drugs that warrant experimental evaluation to assess potential benefit. DCT was run on an animal model of SARS-CoV, and ranked compounds by their ability to induce gene expression signals that counteract disease-associated signals. Top hits included Vitamin E, ruxolitinib, and glutamine. Glutathione and its precursor glutamine were highly ranked by two independent methods, suggesting both warrant further investigation for potential benefit against SARS-CoV-2. CONCLUSIONS: While these findings are not yet ready for clinical translation, this report highlights the potential use of two bioinformatics technologies to rapidly discover existing therapeutic agents that warrant further investigation for established and emerging disease processes.


Subject(s)
Betacoronavirus/physiology , Computational Biology , Coronavirus Infections/genetics , Coronavirus Infections/therapy , Pneumonia, Viral/genetics , Pneumonia, Viral/therapy , Animals , Betacoronavirus/genetics , Gene Expression Regulation , Glutamine/metabolism , Humans , Mice , Pandemics , Peptidyl-Dipeptidase A/metabolism , Serine Endopeptidases/metabolism
17.
Emerg Microbes Infect ; 9(1): 1523-1533, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-612922

ABSTRACT

With increasing frequency, humans are facing outbreaks of emerging infectious diseases (EIDs) with the potential to cause significant morbidity and mortality. In the most extreme instances, such outbreaks can become pandemics, as we are now witnessing with COVID-19. According to the World Health Organization, this new disease, caused by the novel coronavirus SARS-CoV-2, has already infected more than 10 million people worldwide and led to 499,913 deaths as of 29 June, 2020. How high these numbers will eventually go depends on many factors, including policies on travel and movement, availability of medical support, and, because there is no vaccine or highly effective treatment, the pace of biomedical research. Other than an approved antiviral drug that can be repurposed, monoclonal antibodies (mAbs) hold the most promise for providing a stopgap measure to lessen the impact of an outbreak while vaccines are in development. Technical advances in mAb identification, combined with the flexibility and clinical experience of mAbs in general, make them ideal candidates for rapid deployment. Furthermore, the development of mAb cocktails can provide a faster route to developing a robust medical intervention than searching for a single, outstanding mAb. In addition, mAbs are well-suited for integration into platform technologies for delivery, in which minimal components need to be changed in order to be redirected against a novel pathogen. In particular, utilizing the manufacturing and logistical benefits of DNA-based platform technologies in order to deliver one or more antiviral mAbs has the potential to revolutionize EID responses.


Subject(s)
Antibodies, Viral/therapeutic use , Antiviral Agents/therapeutic use , Biological Products/therapeutic use , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/genetics , Communicable Diseases, Emerging/drug therapy , DNA , Drug Discovery , Humans , Mice , Post-Exposure Prophylaxis , Time Factors
18.
Front Immunol ; 11: 1229, 2020.
Article in English | MEDLINE | ID: covidwho-612918

ABSTRACT

COVID-19 is caused by the Severe Acute Respiratory Syndrome (SARS) coronavirus (Cov)-2, an enveloped virus with a positive-polarity, single-stranded RNA genome. The initial outbreak of the pandemic began in December 2019, and it is affecting the human health of the global community. In common with previous pandemics (Influenza H1N1 and SARS-CoV) and the epidemics of Middle east respiratory syndrome (MERS)-CoV, CoVs target bronchial and alveolar epithelial cells. Virus protein ligands (e.g., haemagglutinin or trimeric spike glycoprotein for Influenza and CoV, respectively) interact with cellular receptors, such as (depending on the virus) either sialic acids, Dipeptidyl peptidase 4 (DPP4), or angiotensin-converting enzyme 2 (ACE2). Host proteases, e.g., cathepsins, furin, or members of the type II transmembrane serine proteases (TTSP) family, such as Transmembrane protease serine 2 (TMPRSS2), are involved in virus entry by proteolytically activating virus ligands. Also involved are Toll Like Receptor (TLR) family members, which upregulate anti-viral and pro-inflammatory mediators [interleukin (IL)-6 and IL-8 and type I and type III Interferons among others], through the activation of Nuclear Factor (NF)-kB. When these events (virus cellular entry and innate immune responses) are uncontrolled, a deleterious systemic response is sometimes encountered in infected patients, leading to the well-described "cytokine storm" and an ensuing multiple organ failure promoted by a downregulation of dendritic cell, macrophage, and T-cell function. We aim to describe how the lung and systemic host innate immune responses affect survival either positively, through downregulating initial viral load, or negatively, by triggering uncontrolled inflammation. An emphasis will be put on host cellular signaling pathways and proteases involved with a view on tackling these therapeutically.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Immunity, Innate , Lung/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Signal Transduction , Animals , Antiviral Agents/therapeutic use , Coronavirus Infections/metabolism , Drug Delivery Systems , Epithelial Cells/virology , Humans , Lung/virology , Mice , Myeloid Cells/virology , Pandemics , Pneumonia, Viral/metabolism , Receptors, Cell Surface/metabolism , Receptors, Virus/metabolism , Serine Proteases/metabolism , Virus Internalization
19.
mBio ; 11(3)2020 06 23.
Article in English | MEDLINE | ID: covidwho-612678

ABSTRACT

It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 "don't eat me" signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions. A CD47 mimic that acts as an essential virulence factor is encoded by all poxviruses, but CD47 expression on infected cells was found to be upregulated even by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that encode no mimic. CD47 upregulation was revealed to be a host response induced by the stimulation of both endosomal and cytosolic pathogen recognition receptors (PRRs). Furthermore, proinflammatory cytokines, including those found in the plasma of hepatitis C patients, upregulated CD47 on uninfected dendritic cells, thereby linking innate modulation with downstream adaptive immune responses. Indeed, results from antibody-mediated CD47 blockade experiments as well as CD47 knockout mice revealed an immunosuppressive role for CD47 during infections with lymphocytic choriomeningitis virus and Mycobacterium tuberculosis Since CD47 blockade operates at the level of pattern recognition receptors rather than at a pathogen or antigen-specific level, these findings identify CD47 as a novel potential immunotherapeutic target for the enhancement of immune responses to a broad range of infectious agents.IMPORTANCE Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile.


Subject(s)
Betacoronavirus/immunology , CD47 Antigen/metabolism , Immunomodulation/immunology , Receptors, Pattern Recognition/immunology , A549 Cells , Adaptive Immunity/immunology , Animals , CD47 Antigen/genetics , Cell Line, Tumor , Cytokines/immunology , Female , Humans , Immunity, Innate/immunology , Lymphocytic choriomeningitis virus/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium tuberculosis/immunology , Up-Regulation/immunology
20.
Vaccine ; 38(35): 5653-5658, 2020 07 31.
Article in English | MEDLINE | ID: covidwho-612504

ABSTRACT

The COVID-19 outbreak has become a global pandemic responsible for over 2,000,000 confirmed cases and over 126,000 deaths worldwide. In this study, we examined the immunogenicity of CHO-expressed recombinant SARS-CoV-2 S1-Fc fusion protein in mice, rabbits, and monkeys as a potential candidate for a COVID-19 vaccine. We demonstrate that the S1-Fc fusion protein is extremely immunogenic, as evidenced by strong antibody titers observed by day 7. Strong virus neutralizing activity was observed on day 14 in rabbits immunized with the S1-Fc fusion protein using a pseudovirus neutralization assay. Most importantly, in <20 days and three injections of the S1-Fc fusion protein, two monkeys developed higher virus neutralizing titers than a recovered COVID-19 patient in a live SARS-CoV-2 infection assay. Our data strongly suggests that the CHO-expressed SARS-CoV-2 S1-Fc recombinant protein could be a strong candidate for vaccine development against COVID-19.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Coronavirus Infections/immunology , Immunoglobulin Fc Fragments/chemistry , Macaca/immunology , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/immunology , Animals , CHO Cells , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Cricetulus , Female , HEK293 Cells , Humans , Immunization, Passive , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Male , Mice , Pandemics , Rabbits
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