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1.
Int J Mol Med ; 46(2): 467-488, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-678269

ABSTRACT

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Virus Internalization/drug effects , Angiotensin II Type 1 Receptor Blockers/classification , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Bromhexine/pharmacology , Bromhexine/therapeutic use , Chlorpromazine/pharmacology , Chlorpromazine/therapeutic use , Clinical Trials as Topic/methods , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Diminazene/pharmacology , Diminazene/therapeutic use , Drug Repositioning/methods , Drug Repositioning/standards , Drug Repositioning/trends , Gabexate/analogs & derivatives , Gabexate/pharmacology , Gabexate/therapeutic use , Humans , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Peptidyl-Dipeptidase A/therapeutic use , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Receptor, Angiotensin, Type 1/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/therapeutic use , Signal Transduction/drug effects
2.
Int J Oncol ; 57(2): 533-539, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-667782

ABSTRACT

Severe acute respiratory syndrome (SARS) coronavirus­2 (SARS­CoV2) is the cause of a new disease (COVID­19) which has evolved into a pandemic during the first half of 2020. Older age, male sex and certain underlying diseases, including cancer, appear to significantly increase the risk for severe COVID­19. SARS­CoV­2 infection of host cells is facilitated by the angiotensin­converting enzyme 2 (ACE­2), and by transmembrane protease serine 2 (TMPRSS2) and other host cell proteases such as cathepsin L (CTSL). With the exception of ACE­2, a systematic analysis of these two other SARS­CoV2 infection mediators in malignancies is lacking. Here, we analysed genetic alteration, RNA expression, and DNA methylation of TMPRSS2 and CTSL across a wide spectrum of tumors and controls. TMPRSS2 was overexpressed in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), uterine corpus endometrial carcinoma and uterine carcinosarcoma, with PRAD and READ exhibiting the highest expression of all cancers. CTSL was upregulated in lymphoid neoplasm diffuse large B­cell lymphoma, oesophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, lower grade glioma, pancreatic adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, and thymoma. Hypo­methylation of both genes was evident in most cases where they have been highly upregulated. We have expanded on our observations by including data relating to mutations and copy number alterations at pan­cancer level. The novel hypotheses that are stemming out of these data need to be further investigated and validated in large clinical studies.


Subject(s)
Betacoronavirus/pathogenicity , Biomarkers, Tumor/genetics , Cathepsin L/genetics , Coronavirus Infections/virology , Neoplasms/genetics , Opportunistic Infections/virology , Pneumonia, Viral/virology , Serine Endopeptidases/genetics , Virus Internalization , Coronavirus Infections/enzymology , Coronavirus Infections/immunology , DNA Methylation , Databases, Genetic , Female , Host-Pathogen Interactions , Humans , Immunocompromised Host , Male , Neoplasms/enzymology , Neoplasms/immunology , Opportunistic Infections/enzymology , Opportunistic Infections/immunology , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/immunology , Risk Factors
3.
Clin Appl Thromb Hemost ; 26: 1076029620936776, 2020.
Article in English | MEDLINE | ID: covidwho-657787

ABSTRACT

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/complications , Pandemics , Pneumonia, Viral/complications , Thrombophilia/etiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Anticoagulants/therapeutic use , Arterial Occlusive Diseases/etiology , Arterial Occlusive Diseases/physiopathology , Arterial Occlusive Diseases/virology , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Catheterization, Swan-Ganz , Combined Modality Therapy , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Fibrinolytic Agents/therapeutic use , Humans , Hyperbaric Oxygenation , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pulmonary Embolism/etiology , Pulmonary Embolism/therapy , Pulmonary Embolism/virology , Respiratory Distress Syndrome, Adult/etiology , Thrombolytic Therapy/instrumentation , Thrombolytic Therapy/methods , Thrombophilia/physiopathology , Thrombophilia/therapy , Venous Thrombosis/etiology , Venous Thrombosis/physiopathology , Venous Thrombosis/virology , Virus Internalization/drug effects
4.
Nat Commun ; 11(1): 3618, 2020 07 17.
Article in English | MEDLINE | ID: covidwho-651635

ABSTRACT

Global emergencies caused by the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle-East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2 significantly endanger human health. The spike (S) glycoprotein is the key antigen and its conserved S2 subunit contributes to viral entry by mediating host-viral membrane fusion. However, structural information of the post-fusion S2 from these highly pathogenic human-infecting coronaviruses is still lacking. We used single-particle cryo-electron microscopy to show that the post-fusion SARS-CoV S2 forms a further rotated HR1-HR2 six-helix bundle and a tightly bound linker region upstream of the HR2 motif. The structures of pre- and post-fusion SARS-CoV S glycoprotein dramatically differ, resembling that of the Mouse hepatitis virus (MHV) and other class I viral fusion proteins. This structure suggests potential targets for the development of vaccines and therapies against a wide range of SARS-like coronaviruses.


Subject(s)
Betacoronavirus/chemistry , Betacoronavirus/physiology , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Motifs , Coronavirus/chemistry , Coronavirus/classification , Coronavirus Infections/virology , Cryoelectron Microscopy , Humans , Membrane Fusion , Models, Molecular , Pandemics , Pneumonia, Viral/virology , Protein Conformation , Protein Multimerization , Virus Internalization
5.
Elife ; 92020 07 14.
Article in English | MEDLINE | ID: covidwho-646829

ABSTRACT

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 10 million people, including pregnant women. To date, no consistent evidence for the vertical transmission of SARS-CoV-2 exists. The novel coronavirus canonically utilizes the angiotensin-converting enzyme 2 (ACE2) receptor and the serine protease TMPRSS2 for cell entry. Herein, building upon our previous single-cell study (Pique-Regi et al., 2019), another study, and new single-cell/nuclei RNA-sequencing data, we investigated the expression of ACE2 and TMPRSS2 throughout pregnancy in the placenta as well as in third-trimester chorioamniotic membranes. We report that co-transcription of ACE2 and TMPRSS2 is negligible in the placenta, thus not a likely path of vertical transmission for SARS-CoV-2. By contrast, receptors for Zika virus and cytomegalovirus, which cause congenital infections, are highly expressed by placental cell types. These data show that the placenta minimally expresses the canonical cell-entry mediators for SARS-CoV-2.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Placenta/metabolism , Placenta/virology , Pneumonia, Viral/transmission , Receptors, Virus/metabolism , Serine Endopeptidases/metabolism , Virus Internalization , Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Coronavirus Infections/transmission , Female , Humans , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Pregnancy , Receptors, Virus/genetics , Serine Endopeptidases/genetics , Zika Virus , Zika Virus Infection
6.
Int J Mol Sci ; 21(14)2020 Jul 11.
Article in English | MEDLINE | ID: covidwho-646205

ABSTRACT

Recently, the world has been dealing with a devastating global pandemic coronavirus infection, with more than 12 million infected worldwide and over 300,000 deaths as of May 15th 2020, related to a novel coronavirus (2019-nCoV), characterized by a spherical morphology and identified through next-generation sequencing. Although the respiratory tract is the primary portal of entry of SARS-CoV-2, gastrointestinal involvement associated with nausea, vomiting and diarrhoea may also occur. No drug or vaccine has been approved due to the absence of evidence deriving from rigorous clinical trials. Increasing interest has been highlighted on the possible preventative role and adjunct treatment of lactoferrin, glycoprotein of human secretions part of a non-specific defensive system, known to play a crucial role against microbial and viral infections and exerting anti-inflammatory effects on different mucosal surfaces and able to regulate iron metabolism. In this review, analysing lactoferrin properties, we propose designing a clinical trial to evaluate and verify its effect using a dual combination treatment with local, solubilized intranasal spray formulation and oral administration. Lactoferrin could counteract the coronavirus infection and inflammation, acting either as natural barrier of both respiratory and intestinal mucosa or reverting the iron disorders related to the viral colonization.


Subject(s)
Coronavirus Infections/prevention & control , Lactoferrin/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Inflammation , Intestinal Mucosa/drug effects , Intestinal Mucosa/virology , Iron/metabolism , Lactoferrin/pharmacology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiratory Mucosa/drug effects , Respiratory Mucosa/virology , Virus Internalization/drug effects
7.
Int J Mol Sci ; 21(14)2020 Jul 13.
Article in English | MEDLINE | ID: covidwho-646168

ABSTRACT

In line with SARS and MERS, the SARS-CoV-2/COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide. SARS-CoV-2 infection/COVID-19 provides numerous therapeutic targets, each of them promising, but not leading to the success of therapy to date. Neither an antiviral nor an immunomodulatory therapy in patients with SARS-CoV-2 infection/COVID-19 or pre-exposure prophylaxis against SARS-CoV-2 has proved to be effective. In this review, we try to close the gap and point out the likely relationships among lysosomotropism, increasing lysosomal pH, SARS-CoV-2 infection, and disease process, and we deduce an approach for the treatment and prophylaxis of COVID-19, and cytokine release syndrome (CRS)/cytokine storm triggered by bacteria or viruses. Lysosomotropic compounds affect prominent inflammatory messengers (e.g., IL-1B, CCL4, CCL20, and IL-6), cathepsin-L-dependent viral entry of host cells, and products of lysosomal enzymes that promote endothelial stress response in systemic inflammation. As supported by recent clinical data, patients who have already taken lysosomotropic drugs for other pre-existing conditions likely benefit from this treatment in the COVID-19 pandemic. The early administration of a combination of antivirals such as remdesivir and lysosomotropic drugs, such as the antibiotics teicoplanin or dalbavancin, seems to be able to prevent SARS-CoV-2 infection and transition to COVID-19.


Subject(s)
Coronavirus Infections/pathology , Lysosomes/metabolism , Pneumonia, Viral/pathology , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/pathology , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Virus Internalization/drug effects
8.
Nat Med ; 26(7): 1017-1032, 2020 07.
Article in English | MEDLINE | ID: covidwho-639177

ABSTRACT

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Organ Specificity , Pneumonia, Viral/pathology , Adaptive Immunity/physiology , Betacoronavirus/physiology , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Disease Progression , Endothelium, Vascular/pathology , Endothelium, Vascular/virology , Humans , Inflammation/etiology , Inflammation/pathology , Inflammation/virology , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/therapy , Renin-Angiotensin System/physiology , Thrombosis/etiology , Thrombosis/pathology , Thrombosis/virology , Virus Internalization
9.
Signal Transduct Target Ther ; 5(1): 121, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-640304
10.
Commun Biol ; 3(1): 374, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-640282

ABSTRACT

The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , Prostatic Neoplasms/epidemiology , Sex Distribution , Antineoplastic Agents, Hormonal/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/physiology , Betacoronavirus/ultrastructure , Comorbidity , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Disease Susceptibility , Drug Repositioning , Female , Forecasting , Gonadal Steroid Hormones/physiology , Humans , Male , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/physiology , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Protease Inhibitors/therapeutic use , Receptors, Virus/drug effects , Receptors, Virus/physiology , Risk Factors , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/physiology , United States/epidemiology , Virus Internalization
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.
Int J Mol Sci ; 21(13)2020 Jun 30.
Article in English | MEDLINE | ID: covidwho-635461

ABSTRACT

By attaching to the angiotensin converting enzyme 2 (ACE2) protein on lung and intestinal cells, Sudden Acute Respiratory Syndrome (SARS-CoV-2) can cause respiratory and homeostatic difficulties leading to sepsis. The progression from acute respiratory failure to sepsis has been correlated with the release of high-mobility group box 1 protein (HMGB1). Lack of effective conventional treatment of this septic state has spiked an interest in alternative medicine. This review of herbal extracts has identified multiple candidates which can target the release of HMGB1 and potentially reduce mortality by preventing progression from respiratory distress to sepsis. Some of the identified mixtures have also been shown to interfere with viral attachment. Due to the wide variability in chemical superstructure of the components of assorted herbal extracts, common motifs have been identified. Looking at the most active compounds in each extract it becomes evident that as a group, phenolic compounds have a broad enzyme inhibiting function. They have been shown to act against the priming of SARS-CoV-2 attachment proteins by host and viral enzymes, and the release of HMGB1 by host immune cells. An argument for the value in a nonspecific inhibitory action has been drawn. Hopefully these findings can drive future drug development and clinical procedures.


Subject(s)
Betacoronavirus/physiology , HMGB1 Protein/metabolism , Respiratory Insufficiency/pathology , Sepsis/pathology , HMGB1 Protein/antagonists & inhibitors , Humans , Macrophages/cytology , Macrophages/metabolism , Macrophages/virology , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Plant Exudates/chemistry , Plant Exudates/pharmacology , Plants, Medicinal/chemistry , Plants, Medicinal/metabolism , Respiratory Insufficiency/metabolism , Respiratory Insufficiency/prevention & control , Sepsis/metabolism , Sepsis/prevention & control , Virus Internalization/drug effects
13.
Fertil Steril ; 114(1): 33-43, 2020 07.
Article in English | MEDLINE | ID: covidwho-634346

ABSTRACT

OBJECTIVE: To identify cell types in the male and female reproductive systems at risk for SARS-CoV-2 infection because of the expression of host genes and proteins used by the virus for cell entry. DESIGN: Descriptive analysis of transcriptomic and proteomic data. SETTING: Academic research department and clinical diagnostic laboratory. PATIENT(S): Not applicable (focus was on previously generated gene and protein expression data). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Identification of cell types coexpressing the key angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) genes and proteins as well as other candidates potentially involved in SARS-CoV-2 cell entry. RESULT(S): On the basis of single-cell RNA sequencing data, coexpression of ACE2 and TMPRSS2 was not detected in testicular cells, including sperm. A subpopulation of oocytes in nonhuman primate ovarian tissue was found to express ACE2 and TMPRSS2, but coexpression was not observed in ovarian somatic cells. RNA expression of TMPRSS2 in 18 samples of human cumulus cells was shown to be low or absent. There was general agreement between publicly available bulk RNA and protein datasets in terms of ACE2 and TMPRSS2 expression patterns in testis, ovary, endometrial, and placental cells. CONCLUSION(S): These analyses suggest that SARS-CoV-2 infection is unlikely to have long-term effects on male and female reproductive function. Although the results cannot be considered definitive, they imply that procedures in which oocytes are collected and fertilized in vitro are associated with very little risk of viral transmission from gametes to embryos and may indeed have the potential to minimize exposure of susceptible reproductive cell types to infection in comparison with natural conception.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Fertility/physiology , Gene Expression Regulation, Viral/physiology , Pneumonia, Viral/metabolism , Reproduction/physiology , Virus Internalization , Adolescent , Adult , Animals , Betacoronavirus/genetics , Cell Line , Coronavirus Infections/genetics , Female , Humans , Macaca fascicularis , Male , Ovary/cytology , Ovary/metabolism , Ovary/virology , Pandemics , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Pregnancy , Proteomics/methods , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Testis/cytology , Testis/metabolism , Testis/virology , Transcriptome/physiology , Young Adult
14.
Int J Mol Sci ; 21(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-627906

ABSTRACT

The recently emerged SARS-CoV-2 is the cause of the global health crisis of the coronavirus disease 2019 (COVID-19) pandemic. No evidence is yet available for CoV infection into hosts upon zoonotic disease outbreak, although the CoV epidemy resembles influenza viruses, which use sialic acid (SA). Currently, information on SARS-CoV-2 and its receptors is limited. O-acetylated SAs interact with the lectin-like spike glycoprotein of SARS CoV-2 for the initial attachment of viruses to enter into the host cells. SARS-CoV-2 hemagglutinin-esterase (HE) acts as the classical glycan-binding lectin and receptor-degrading enzyme. Most ß-CoVs recognize 9-O-acetyl-SAs but switched to recognizing the 4-O-acetyl-SA form during evolution of CoVs. Type I HE is specific for the 9-O-Ac-SAs and type II HE is specific for 4-O-Ac-SAs. The SA-binding shift proceeds through quasi-synchronous adaptations of the SA-recognition sites of the lectin and esterase domains. The molecular switching of HE acquisition of 4-O-acetyl binding from 9-O-acetyl SA binding is caused by protein-carbohydrate interaction (PCI) or lectin-carbohydrate interaction (LCI). The HE gene was transmitted to a ß-CoV lineage A progenitor by horizontal gene transfer from a 9-O-Ac-SA-specific HEF, as in influenza virus C/D. HE acquisition, and expansion takes place by cross-species transmission over HE evolution. This reflects viral evolutionary adaptation to host SA-containing glycans. Therefore, CoV HE receptor switching precedes virus evolution driven by the SA-glycan diversity of the hosts. The PCI or LCI stereochemistry potentiates the SA-ligand switch by a simple conformational shift of the lectin and esterase domains. Therefore, examination of new emerging viruses can lead to better understanding of virus evolution toward transitional host tropism. A clear example of HE gene transfer is found in the BCoV HE, which prefers 7,9-di-O-Ac-SAs, which is also known to be a target of the bovine torovirus HE. A more exciting case of such a switching event occurs in the murine CoVs, with the example of the ß-CoV lineage A type binding with two different subtypes of the typical 9-O-Ac-SA (type I) and the exclusive 4-O-Ac-SA (type II) attachment factors. The protein structure data for type II HE also imply the virus switching to binding 4-O acetyl SA from 9-O acetyl SA. Principles of the protein-glycan interaction and PCI stereochemistry potentiate the SA-ligand switch via simple conformational shifts of the lectin and esterase domains. Thus, our understanding of natural adaptation can be specified to how carbohydrate/glycan-recognizing proteins/molecules contribute to virus evolution toward host tropism. Under the current circumstances where reliable antiviral therapeutics or vaccination tools are lacking, several trials are underway to examine viral agents. As expected, structural and non-structural proteins of SARS-CoV-2 are currently being targeted for viral therapeutic designation and development. However, the modern global society needs SARS-CoV-2 preventive and therapeutic drugs for infected patients. In this review, the structure and sialobiology of SARS-CoV-2 are discussed in order to encourage and activate public research on glycan-specific interaction-based drug creation in the near future.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/virology , Evolution, Molecular , Host Microbial Interactions/physiology , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Virus Internalization , Acetylesterase/metabolism , Animals , Betacoronavirus/genetics , Binding Sites , Cell Line , Coronavirus/genetics , Esterases , Gene Transfer, Horizontal , Glycosaminoglycans/metabolism , Hemagglutinins, Viral/genetics , Humans , Lectins/metabolism , Pandemics , Polysaccharides , Receptors, Virus/chemistry , Sialic Acids/chemistry , Sialic Acids/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/physiology , Torovirus , Viral Fusion Proteins/genetics
15.
Am J Physiol Cell Physiol ; 319(2): C244-C249, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-624886

ABSTRACT

The outbreak of COVID-19 pneumonia caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) is posing a global health emergency and has led to more than 380,000 deaths worldwide. The cell entry of SARS-CoV-2 depends on two host proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). There is currently no vaccine available and also no effective drug for the treatment of COVID-19. Hydrogen sulfide (H2S) as a novel gasotransmitter has been shown to protect against lung damage via its anti-inflammation, antioxidative stress, antiviral, prosurvival, and antiaging effects. In light of the research advances on H2S signaling in biology and medicine, this review proposed H2S as a potential defense against COVID-19. It is suggested that H2S may block SARS-CoV-2 entry into host cells by interfering with ACE2 and TMPRSS2, inhibit SARS-CoV-2 replication by attenuating virus assembly/release, and protect SARS-CoV-2-induced lung damage by suppressing immune response and inflammation development. Preclinical studies and clinical trials with slow-releasing H2S donor(s) or the activators of endogenous H2S-generating enzymes should be considered as a preventative treatment or therapy for COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Hydrogen Sulfide/therapeutic use , Pneumonia, Viral/drug therapy , Virus Internalization/drug effects , Virus Replication/drug effects , Animals , Betacoronavirus/pathogenicity , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Hydrogen Sulfide/metabolism , Lung/drug effects , Lung/metabolism , Lung/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Serine Endopeptidases/metabolism , Signal Transduction
16.
Emerg Microbes Infect ; 9(1): 1567-1579, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-622041

ABSTRACT

Diverse SARS-like coronaviruses (SL-CoVs) have been identified from bats and other animal species. Like SARS-CoV, some bat SL-CoVs, such as WIV1, also use angiotensin converting enzyme 2 (ACE2) from human and bat as entry receptor. However, whether these viruses can also use the ACE2 of other animal species as their receptor remains to be determined. We report herein that WIV1 has a broader tropism to ACE2 orthologs than SARS-CoV isolate Tor2. Among the 9 ACE2 orthologs examined, human ACE2 exhibited the highest efficiency to mediate the infection of WIV1 pseudotyped virus. Our findings thus imply that WIV1 has the potential to infect a wide range of wild animals and may directly jump to humans. We also showed that cell entry of WIV1 could be restricted by interferon-induced transmembrane proteins (IFITMs). However, WIV1 could exploit the airway protease TMPRSS2 to partially evade the IFITM3 restriction. Interestingly, we also found that amphotericin B could enhance the infectious entry of SARS-CoVs and SL-CoVs by evading IFITM3-mediated restriction. Collectively, our findings further underscore the risk of exposure to animal SL-CoVs and highlight the vulnerability of patients who take amphotericin B to infection by SL-CoVs, including the most recently emerging (SARS-CoV-2).


Subject(s)
Betacoronavirus/physiology , Chiroptera/virology , Membrane Proteins/metabolism , Peptidyl-Dipeptidase A/metabolism , RNA-Binding Proteins/metabolism , Receptors, Virus/metabolism , Serine Endopeptidases/metabolism , Virus Internalization , Animals , Betacoronavirus/classification , HEK293 Cells , Humans , Rats , SARS Virus/physiology , Viverridae
17.
Front Cell Infect Microbiol ; 10: 317, 2020.
Article in English | MEDLINE | ID: covidwho-615470

ABSTRACT

The rapidly evolving pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection worldwide cost many lives. The angiotensin converting enzyme-2 (ACE-2) has been identified as the receptor for the SARS-CoV-2 viral entry. As such, it is now receiving renewed attention as a potential target for anti-viral therapeutics. We review the physiological functions of ACE2 in the cardiovascular system and the lungs, and how the activation of ACE2/MAS/G protein coupled receptor contributes in reducing acute injury and inhibiting fibrogenesis of the lungs and protecting the cardiovascular system. In this perspective, we predominantly focus on the impact of SARS-CoV-2 infection on ACE2 and dysregulation of the protective effect of ACE2/MAS/G protein pathway vs. the deleterious effect of Renin/Angiotensin/Aldosterone. We discuss the potential effect of invasion of SARS-CoV-2 on the function of ACE2 and the loss of the protective effect of the ACE2/MAS pathway in alveolar epithelial cells and how this may amplify systemic deleterious effect of renin-angiotensin aldosterone system (RAS) in the host. Furthermore, we speculate the potential of exploiting the modulation of ACE2/MAS pathway as a natural protection of lung injury by modulation of ACE2/MAS axis or by developing targeted drugs to inhibit proteases required for viral entry.


Subject(s)
Alveolar Epithelial Cells/metabolism , Betacoronavirus/metabolism , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus/metabolism , Renin-Angiotensin System/physiology , Coronavirus Infections/pathology , Host-Pathogen Interactions/physiology , Humans , Lung/pathology , Lung/virology , Pandemics , Pneumonia, Viral/pathology , Virus Internalization
18.
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
19.
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
20.
Front Cell Infect Microbiol ; 10: 290, 2020.
Article in English | MEDLINE | ID: covidwho-612813

ABSTRACT

The recent pandemic SARS-CoV-2 outbreak affects all kinds of individuals worldwide. The health, social, and economic impacts of the pandemic are dramatic, and vaccines or specific treatment options are not yet available. The only approaches that we currently have available to stop the epidemic are those of classical epidemic control, such as case isolation, contact tracing and quarantine, physical distancing, and hygiene measures. It is therefore essential to find further preventive measures and possible interventions that can slow down the number of infected individuals and decrease the severity of disease when affected by SARS-CoV-2. It seems that epigenetic mechanisms are an important part of the pathophysiology and illness severity of COVID-19. These mechanisms have been identified in SARS-CoV-2 but also in other viral infections. If and when these mechanisms are confirmed, then epigenetic interventions influencing DNA methylation could be indicated as primary and/or secondary preventive options.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/physiology , Coronavirus Infections/virology , DNA Methylation , Epigenesis, Genetic , Lung/virology , Pneumonia, Viral/virology , Virus Internalization , Aging , Cell Fusion , Coronavirus Infections/drug therapy , Disease Susceptibility , Female , Gene Silencing , Humans , Male , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Receptors, Virus/genetics , Receptors, Virus/metabolism
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