Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 22
Filter
1.
Biosci Rep ; 41(10)2021 10 29.
Article in English | MEDLINE | ID: covidwho-1510636

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compounds that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2)) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to down-regulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused down-regulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus. However, cell-based antiviral drug screening assay showed 30-60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggest that these two closely related compounds possess multimodal anti-COVID-19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Computational Biology/methods , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/immunology , COVID-19/immunology , Cell Line, Tumor , Drug Evaluation, Preclinical/methods , HSP70 Heat-Shock Proteins/antagonists & inhibitors , Humans , Mitochondrial Proteins/antagonists & inhibitors , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , SARS-CoV-2/immunology , Serine Endopeptidases/immunology , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
2.
Eur J Pharmacol ; 912: 174548, 2021 Dec 05.
Article in English | MEDLINE | ID: covidwho-1446596

ABSTRACT

The importance of sex differences is increasingly acknowledged in the incidence and treatment of disease. Accumulating clinical evidence demonstrates that sex differences are noticeable in COVID-19, and the prevalence, severity, and mortality rate of COVID-19 are higher among males than females. Sex-related genetic and hormonal factors and immunological responses may underlie the sex bias in COVID-19 patients. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2) are essential proteins involved in the cell entry of SARS-CoV-2. Since ACE2 is encoded on the X-chromosome, a double copy of ACE2 in females may compensate for virus-mediated downregulation of ACE2, and thus ACE2-mediated cellular protection is greater in females. The X chromosome also contains the largest immune-related genes leading females to develop more robust immune responses than males. Toll-like receptor-7 (TLR-7), one of the key players in innate immunity, is linked to sex differences in autoimmunity and vaccine efficacy, and its expression is greater in females. Sex steroids also affect immune cell function. Estrogen contributes to higher CD4+ and CD8+ T cell activation levels, and females have more B cells than males. Sex differences not only affect the severity and progression of the disease, but also alter the efficacy of pharmacological treatment and adverse events related to the drugs/vaccines used against COVID-19. Administration of different drugs/vaccines in different doses or intervals may be useful to eliminate sex differences in efficacy and side/adverse effects. It should be noted that studies should include sex-specific analyses to develop further sex-specific treatments for COVID-19.


Subject(s)
COVID-19/etiology , COVID-19/genetics , Genetic Predisposition to Disease/genetics , Adult , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Estrogens/genetics , Estrogens/immunology , Female , Humans , Immunity, Innate/genetics , Immunity, Innate/immunology , Male , Middle Aged , SARS-CoV-2/immunology , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Sex Characteristics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
3.
PLoS One ; 16(9): e0257705, 2021.
Article in English | MEDLINE | ID: covidwho-1416908

ABSTRACT

SARS-CoV-2 enters host cells when the viral spike protein is cleaved by transmembrane protease serine 2 (TMPRSS2) after binding to the host angiotensin-converting enzyme 2 (ACE2). Since ACE2 and TMPRSS2 are expressed in the tongue and gingival mucosa, the oral cavity is a potential entry point for SARS-CoV-2. This study evaluated the inhibitory effects of general ingredients of toothpastes and mouthwashes on the spike protein-ACE2 interaction and the TMPRSS2 protease activity using an in vitro assay. Both assays detected inhibitory effects of sodium tetradecene sulfonate, sodium N-lauroyl-N-methyltaurate, sodium N-lauroylsarcosinate, sodium dodecyl sulfate, and copper gluconate. Molecular docking simulations suggested that these ingredients could bind to inhibitor-binding site of ACE2. Furthermore, tranexamic acid exerted inhibitory effects on TMPRSS2 protease activity. Our findings suggest that these toothpaste and mouthwash ingredients could help prevent SARS-CoV-2 infection.


Subject(s)
COVID-19/prevention & control , Mouthwashes/pharmacology , Oral Hygiene/methods , SARS-CoV-2/drug effects , Toothpastes/pharmacology , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/immunology , Humans , Serine Endopeptidases/immunology , Spike Glycoprotein, Coronavirus/immunology
4.
Int J Mol Sci ; 22(16)2021 Aug 12.
Article in English | MEDLINE | ID: covidwho-1354986

ABSTRACT

Human ACE2 and the serine protease TMPRSS2 of novel SARS-CoV-2 are primary entry receptors in host cells. Expression of these genes at the transcriptional level has not been much discussed in detail. The ISRE elements of the ACE2 promoter are a binding site for the ISGF3 complex of the JAK/STAT signaling pathway. TMPRSS2, including IFNß, STAT1, and STAT2, has the PARP1 binding site near to TSS either up or downstream promoter region. It is well documented that PARP1 regulates gene expression at the transcription level. Therefore, to curb virus infection, both promoting type I IFN signaling to boost innate immunity and prevention of virus entry by inhibiting PARP1, ACE2 or TMPRSS2 are safe options. Most importantly, our aim is to attract the attention of the global scientific community towards the codon 72 Single Nucleotide Polymorphism (SNP) of p53 and its underneath role in the innate immune response against SARS-CoV-2. Here, we discuss codon 72 SNP of human p53's role in the different innate immune response to restrict virus-mediated mortality rate only in specific parts of the world. In addition, we discuss potential targets and emerging therapies using bioengineered bacteriophage, anti-sense, or CRISPR strategies.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , COVID-19/immunology , SARS-CoV-2/genetics , Serine Endopeptidases/genetics , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/immunology , Binding Sites , COVID-19/virology , Humans , Immunity, Innate , Poly (ADP-Ribose) Polymerase-1/chemistry , Poly (ADP-Ribose) Polymerase-1/genetics , Poly (ADP-Ribose) Polymerase-1/immunology , Poly (ADP-Ribose) Polymerase-1/metabolism , Polymorphism, Single Nucleotide , SARS-CoV-2/physiology , Serine Endopeptidases/chemistry , Serine Endopeptidases/immunology , Vaccination , Virus Internalization
5.
EBioMedicine ; 70: 103500, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1322074

ABSTRACT

BACKGROUND: The outbreak of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has become a global health emergency. We aim to decipher SARS-CoV-2 infected cell types, the consequent host immune response and their interplay in lung of COVID-19 patients. METHODS: We analyzed single-cell RNA sequencing (scRNA-seq) data of bronchoalveolar lavage fluid (BALF) samples from 10 healthy donors, 6 severe COVID-19 patients and 3 mild recovered patients. The expressions of SARS-CoV-2 receptors (ACE2 and TMPRSS2) were examined among different cell types. The immune cells infiltration patterns, their expression profiles, and interplays between immune cells and SARS-CoV-2 target cells were further investigated. FINDINGS: Compared to healthy controls, ACE2 and TMPRSS2 expressions were significantly higher in lung epithelial cells of COVID-19 patients, in particular club and ciliated cells. SARS-CoV-2 activated pro-inflammatory genes and interferon/cytokine signaling in these cells. In severe COVID-19 patients, significantly higher neutrophil, but lower macrophage in lung was observed along with markedly increased cytokines expression compared with healthy controls and mild patients. By contrast, neutrophil and macrophage returned to normal level whilst more T and NK cells accumulation were observed in mild patients. Moreover, SARS-CoV-2 infection altered the community interplays of lung epithelial and immune cells: interactions between the club and immune cells were higher in COVID-19 patients compared to healthy donors; on the other hand, immune-immune cells interactions appeared the strongest in mild patients. INTERPRETATION: SARS-CoV-2 could infect lung epithelium, alter communication patterns between lung epithelial cells and immune system, and drive dysregulated host immune response in COVID-19 patients. FUNDING: This project was supported by National Key R&D Program of China (No. 2018YFC1315000/2018YFC1315004), Science and Technology Program Grant Shenzhen (JCYJ20170413161534162), HMRF Hong Kong (17160862), RGC-CRF Hong Kong (C4039-19G), RGC-GRF Hong Kong (14163817), Vice-Chancellor's Discretionary Fund CUHK and CUHK direct grant, Shenzhen Virtual University Park Support Scheme to CUHK Shenzhen Research Institute.


Subject(s)
COVID-19/immunology , Epithelial Cells/immunology , Inflammation/immunology , Lung/immunology , SARS-CoV-2/immunology , Signal Transduction/immunology , A549 Cells , Angiotensin-Converting Enzyme 2/immunology , COVID-19/virology , Case-Control Studies , Cell Line , Cell Line, Tumor , Cytokines/immunology , Humans , Inflammation/virology , Killer Cells, Natural/immunology , Lung/virology , Macrophages/immunology , Neutrophils/immunology , Respiratory Mucosa/immunology , Respiratory Mucosa/virology , Serine Endopeptidases/immunology , T-Lymphocytes/immunology
6.
Eur J Med Genet ; 64(6): 104227, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1188514

ABSTRACT

The identification of high-risk factors for the infection by SARS-CoV-2 and the negative outcome of COVID-19 is crucial. The genetic background of the host might account for individual responses to SARS-CoV-2 infection besides age and comorbidities. A list of candidate polymorphisms is needed to drive targeted screens, given the existence of frequent polymorphisms in the general population. We carried out text mining in the scientific literature to draw up a list of genes referable to the term "SARS-CoV*". We looked for frequent mutations that are likely to affect protein function in these genes. Ten genes, mostly involved in innate immunity, and thirteen common variants were identified, for some of these the involvement in COVID-19 is supported by publicly available epidemiological data. We looked for available data on the population distribution of these variants and we demonstrated that the prevalence of five of them, Arg52Cys (rs5030737), Gly54Asp (rs1800450) and Gly57Glu (rs1800451) in MBL2, Ala59Thr (rs25680) in CD27, and Val197Met (rs12329760) in TMPRSS2, correlates with the number of cases and/or deaths of COVID-19 observed in different countries. The association of the TMPRSS2 variant provides epidemiological evidence of the usefulness of transmembrane protease serine 2 inhibitors for the cure of COVID-19. The identified genetic variants represent a basis for the design of a cost-effective assay for population screening of genetic risk factors in the COVID-19 pandemic.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Genetic Predisposition to Disease , Immunity, Innate , SARS-CoV-2/pathogenicity , Data Mining , Gene Frequency , Genetic Variation , Host Microbial Interactions , Humans , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/immunology , Polymorphism, Single Nucleotide , Risk Factors , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology
7.
Infect Genet Evol ; 91: 104832, 2021 07.
Article in English | MEDLINE | ID: covidwho-1164210

ABSTRACT

MicroRNAs are gene expression regulators, associated with several human pathologies, including the ones caused by virus infections. Although their role in infection diseases is not completely known, they can exert double functions in the infected cell, by mediating the virus infection and/or regulating the immunity-related gene targets through complex networks of virus-host cell interactions. In this systematic review, the Pubmed, EMBASE, Scopus, Lilacs, Scielo, and EBSCO databases were searched for research articles published until October 22nd, 2020 that focused on describing the role, function, and/or association of miRNAs in SARS-CoV-2 human infection and COVID-19. Following the PRISMA 2009 protocol, 29 original research articles were selected. Most of the studies reported miRNA data based on the genome sequencing of SARS-CoV-2 isolates and computational prediction analysis. The latter predicted, by at least one independent study, 1266 host miRNAs to target the viral genome. Thirteen miRNAs were identified by four independent studies to target SARS-CoV-2 specific genes, suggested to act by interfering with their cleavage and/or translation process. The studies selected also reported on viral and host miRNAs that targeted host genes, on the expression levels of miRNAs in biological specimens of COVID-19 patients, and on the impact of viral genome mutations on miRNA function. Also, miRNAs that regulate the expression levels of the ACE2 and TMPRSS2 proteins, which are critical for the virus entrance in the host cells, were reported. In conclusion, despite the limited number of studies identified, based on the search terms and eligibility criteria applied, this systematic review provides evidence on the impact of miRNAs on SARS-CoV-2 infection and COVID-19. Although most of the reported viral/host miRNAs interactions were based on in silico prediction analysis, they demonstrate the relevance of the viral/host miRNA interaction for viral activity and host responses. In addition, the identified studies highlight the potential use of miRNAs as therapeutic targets against COVID-19, and other viral human diseases (This review was registered at the International Prospective Register of Systematic Reviews (PROSPERO) database (#CRD42020199290).


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Genome, Viral , MicroRNAs/genetics , SARS-CoV-2/genetics , Serine Endopeptidases/genetics , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/immunology , COVID-19/immunology , COVID-19/pathology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , MicroRNAs/classification , MicroRNAs/immunology , Mutation , Protein Binding , Receptors, Virus/genetics , Receptors, Virus/immunology , SARS-CoV-2/immunology , Serine Endopeptidases/immunology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology
8.
Rev Med Virol ; 31(6): e2227, 2021 11.
Article in English | MEDLINE | ID: covidwho-1148855

ABSTRACT

Severe acute respiratory syndrome related coronavirus-2 (SARS-CoV-2) is the cause of Covid-19 which was classified as a global pandemic in March 2020. The increasing global health and economic burden of SARS-CoV-2 has necessitated urgent investigations into the pathogenesis of disease and development of therapeutic and vaccination regimens. Human trials of vaccine and antiviral candidates have been undertaken, but basic pathogenetic studies are still required to inform these trials. Gaps in understanding of cellular infection by, and immunity to, SARS-CoV-2 mean additional models are required to assist in improved design of these therapeutics. Human organoids are three-dimensional models that contain multiple cell types and mimic human organs in ex vivo culture conditions. The SARS-CoV-2 virus has been implicated in causing not only respiratory injury but also injury to other organs such as the brain, liver and kidneys. Consequently, a variety of different organoid models have been employed to investigate the pathogenic mechanisms of disease due to SARS-CoV-2. Data on these models have not been systematically assembled. In this review, we highlight key findings from studies that have utilised different human organoid types to investigate the expression of SARS-CoV-2 receptors, permissiveness, immune response, dysregulation of cellular functions, and potential antiviral therapeutics.


Subject(s)
Host-Pathogen Interactions/immunology , Models, Biological , Organoids/immunology , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Antiviral Agents/pharmacology , Brain/drug effects , Brain/immunology , Brain/virology , COVID-19/drug therapy , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cell Culture Techniques , Colon/drug effects , Colon/immunology , Colon/virology , Cytokines/genetics , Cytokines/immunology , Host-Pathogen Interactions/drug effects , Humans , Liver/drug effects , Liver/immunology , Liver/virology , Lung/drug effects , Lung/immunology , Lung/virology , Organoids/drug effects , Organoids/virology , Receptors, Virus/genetics , Receptors, Virus/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
9.
Rev Med Virol ; 31(6): e2226, 2021 11.
Article in English | MEDLINE | ID: covidwho-1107716

ABSTRACT

The coronavirus disease 2019 (Covid-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that clinically affects multiple organs of the human body. Cells in the oral cavity express viral entry receptor angiotensin-converting enzyme 2 that allows viral replication and may cause tissue inflammation and destruction. Recent studies have reported that Covid-19 patients present oral manifestations with multiple clinical aspects. In this review, we aim to summarise main signs and symptoms of Covid-19 in the oral cavity, its possible association with oral diseases, and the plausible underlying mechanisms of hyperinflammation reflecting crosstalk between Covid-19 and oral diseases. Ulcers, blisters, necrotising gingivitis, opportunistic coinfections, salivary gland alterations, white and erythematous plaques and gustatory dysfunction were the most reported clinical oral manifestations in patients with Covid-19. In general, the lesions appear concomitant with the loss of smell and taste. Multiple reports show evidences of necrotic/ulcerative gingiva, oral blisters and hypergrowth of opportunistic oral pathogens. SARS-CoV-2 exhibits tropism for endothelial cells and Covid-19-mediated endotheliitis can not only promote inflammation in oral tissues but can also facilitate virus spread. In addition, elevated levels of proinflammatory mediators in patients with Covid-19 and oral infectious disease can impair tissue homeostasis and cause delayed disease resolution. This suggests potential crosstalk of immune-mediated pathways underlying pathogenesis. Interestingly, few reports suggest recurrent herpetic lesions and higher bacterial growth in Covid-19 subjects, indicating SARS-CoV-2 and oral virus/bacteria interaction. Larger cohort studies comparing SARS-CoV-2 negative and positive subjects will reveal oral manifestation of the virus on oral health and its role in exacerbating oral infection.


Subject(s)
COVID-19/complications , Gingivitis, Necrotizing Ulcerative/complications , Herpesviridae Infections/complications , Oral Ulcer/complications , Periodontal Diseases/complications , Sialadenitis/complications , Stomatitis, Aphthous/complications , Xerostomia/complications , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Anosmia/complications , Anosmia/immunology , Anosmia/pathology , Anosmia/virology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Dysgeusia/complications , Dysgeusia/immunology , Dysgeusia/pathology , Dysgeusia/virology , Gene Expression , Gingivitis, Necrotizing Ulcerative/immunology , Gingivitis, Necrotizing Ulcerative/pathology , Gingivitis, Necrotizing Ulcerative/virology , Herpesviridae Infections/immunology , Herpesviridae Infections/pathology , Herpesviridae Infections/virology , Humans , Mouth/immunology , Mouth/pathology , Mouth/virology , Oral Ulcer/immunology , Oral Ulcer/pathology , Oral Ulcer/virology , Periodontal Diseases/immunology , Periodontal Diseases/pathology , Periodontal Diseases/virology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Sialadenitis/immunology , Sialadenitis/pathology , Sialadenitis/virology , Stomatitis, Aphthous/immunology , Stomatitis, Aphthous/pathology , Stomatitis, Aphthous/virology , Xerostomia/immunology , Xerostomia/pathology , Xerostomia/virology
10.
Sci Rep ; 11(1): 4533, 2021 02 25.
Article in English | MEDLINE | ID: covidwho-1104538

ABSTRACT

Multiple studies have reported a doubling in risk of Coronavirus Disease-2019 (COVID-19) among cancer patients. Here, we examine the potential biological rationale behind this recurrent epidemiological observation. By leveraging large-scale genome-wide transcriptional data of normal and malignant tissues from adults and children, we found evidence of increased expression of SARS-CoV-2 viral entry genes in the cancer state, particularly in respiratory, gastrointestinal, and genitourinary tract tissues, with decreased expression in pediatric vs. adult samples. Additionally, by interrogating the temporal effects of radiotherapy on human peripheral blood mononuclear and mucosal cells, we observed important treatment-related alterations in host innate immunity, specifically type I interferon responses. Overall, cancers enhance expression of critical viral entry genes, and innate viral defenses can be dysregulated transiently during radiation treatments. These factors may contribute to the observed increased susceptibility to SARS-CoV-2 entry and severity of COVID-19 in cancer patients.


Subject(s)
COVID-19/complications , Immunity, Innate , Neoplasms/complications , SARS-CoV-2/physiology , Virus Internalization , Adult , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , COVID-19/genetics , COVID-19/immunology , Cathepsin L/genetics , Cathepsin L/immunology , Child , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/radiotherapy , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Severity of Illness Index
11.
Trends Immunol ; 42(1): 31-44, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065238

ABSTRACT

The majority of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals remain paucisymptomatic, contrasting with a minority of infected individuals in danger of death. Here, we speculate that the robust disease resistance of most individuals is due to a swift production of type I interferon (IFNα/ß), presumably sufficient to lower the viremia. A minority of infected individuals with a preexisting chronic inflammatory state fail to mount this early efficient response, leading to a delayed harmful inflammatory response. To improve the epidemiological scenario, we propose combining: (i) the development of efficient antivirals administered early enough to assist in the production of endogenous IFNα/ß; (ii) potentiating early IFN responses; (iii) administering anti-inflammatory treatments when needed, but not too early to interfere with endogenous antiviral responses.


Subject(s)
Antiviral Agents/immunology , COVID-19/immunology , Immunologic Factors/immunology , Interferon Type I/immunology , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Immunologic Factors/metabolism , Immunologic Factors/therapeutic use , Interferon Type I/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Serine Endopeptidases/immunology , Serine Endopeptidases/metabolism , Virus Replication/drug effects , Virus Replication/immunology
12.
Curr Opin Allergy Clin Immunol ; 21(3): 252-260, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1066415

ABSTRACT

PURPOSE OF REVIEW: Asthma patients are typically at increased risk for severe outcomes from viral respiratory infections. However, asthma and atopy do not appear to be overrepresented comorbidities in COVID-19 patients, and hypotheses attempt to explain this observation. As COVID-19 continues to spread globally, it is imperative to understand how disease outcomes may be influenced in this population to guide patient care. RECENT FINDINGS: Angiotensin converting enzyme 2 (ACE2) is the principal host cell receptor for SARS-CoV-2 entry and Transmembrane Protease Serine 2 (TMRSS2) is the main priming protease. Models have linked atopic endotypes to reductions in ACE2 and increases in TMRSS2 on respiratory epithelia. Epidemiologic and experimental findings imply alterations in ACE2 expression correlate with clinical COVID-19 disease, but limitations restrict the ability to draw direct conclusions. SUMMARY: There is reasonable evidence to assert atopic endotypes modulate COVID-19 susceptibility, but it remains premature to classify this association as protective or deleterious. Asthma is a heterogeneous disease and epidemiologic studies should focus on investigating COVID-19 outcomes by underlying endotype. Direct experimental and clinical evidence is needed to draw definitive conclusions on how the complex interplay of ACE2 and TMRSS2 affect viral entry. VIDEO ABSTRACT: https://www.dropbox.com/sh/9sfwqhz2h78sio3/AAB0JYd4MFzM5JjDFcYwz4CXa?dl=0.


Subject(s)
Asthma/immunology , COVID-19/immunology , Models, Immunological , SARS-CoV-2/immunology , Virus Internalization , Angiotensin-Converting Enzyme 2/immunology , Humans , Risk Factors , Serine Endopeptidases/immunology
13.
JBRA Assist Reprod ; 25(2): 310-313, 2021 04 27.
Article in English | MEDLINE | ID: covidwho-1052536

ABSTRACT

The COVID-19 pandemic is an unexpected worldwide situation, and all countries have implemented their own policies to curb the spread of the virus. The pathophysiology of COVID-19 has opened numerous hypotheses of functional alterations in different physiological aspects. The direct impact of SARS-CoV-2 on the urogenital organs of males and females is still to be assessed. Nevertheless, based on biological similarities between SARS-CoV and SARS-CoV-2, several hypotheses have been proposed. In this study, we will discuss the possible mechanism of action, and potential effects on the male/female reproductive system and fertility.


Subject(s)
COVID-19 , Fertility , Reproduction , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Genitalia/immunology , Genitalia/metabolism , Genitalia/virology , Humans , Serine Endopeptidases/immunology , Serine Endopeptidases/metabolism
14.
Int J Lab Hematol ; 43(2): 160-168, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-954105

ABSTRACT

In December 2019, a new type of coronavirus was detected for the first time in Wuhan, Hubei Province, China. According to the reported data, the emerging coronavirus has spread worldwide, infecting more than fifty-seven million individuals, leading to more than one million deaths. The current study aimed to review and discuss the hematological findings of COVID-19. Laboratory changes and hematologic abnormalities have been reported repeatedly in COVID-19 patients. WBC count and peripheral blood lymphocytes are normal or slightly reduced while these indicators may change with the progression of the disease. In addition, several studies demonstrated that decreased hemoglobin levels in COVID-19 patients were associated with the severity of the disease. Moreover, thrombocytopenia, which is reported in 5%-40% of patients, is known to be associated with poor prognosis of the disease. COVID-19 can present with various hematologic manifestations. In this regard, accurate evaluation of laboratory indicators at the beginning and during COVID-19 can help physicians to adjust appropriate treatment and provide special and prompt care for those in need.


Subject(s)
COVID-19/blood , COVID-19/epidemiology , Hematology/methods , Pandemics , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Biomarkers/blood , Blood Platelets/immunology , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/pathology , COVID-19/virology , China/epidemiology , Erythrocytes/immunology , Erythrocytes/pathology , Erythrocytes/virology , Hematology/instrumentation , Humans , Laboratories , Leukocytes/immunology , Leukocytes/pathology , Leukocytes/virology , Receptors, Virus/genetics , Receptors, Virus/immunology , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Virus Internalization
15.
Stem Cells Transl Med ; 10(4): 636-642, 2021 04.
Article in English | MEDLINE | ID: covidwho-921740

ABSTRACT

Anti-inflammatory and immune-modulatory therapies have been proposed for the treatment of COVID-19 and its most serious complications. Among others, the use of mesenchymal stromal cells (MSCs) is under investigation given their well-documented anti-inflammatory and immunomodulatory properties. However, some critical issues regarding the possibility that MSCs could be infected by the virus have been raised. Angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2) are the main host cell factors for the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), entry, but so far it is unclear if human MSCs do or do not express these two proteins. To elucidate these important aspects, we evaluated if human MSCs from both fetal and adult tissues constitutively express ACE2 and TMPRSS2 and, most importantly, if they can be infected by SARS-CoV-2. We evaluated human MSCs derived from amnios, cord blood, cord tissue, adipose tissue, and bone marrow. ACE2 and TMPRSS2 were expressed by the SARS-CoV-2-permissive human pulmonary Calu-3 cell line but not by all the MSCs tested. MSCs were then exposed to SARS-CoV-2 wild strain without evidence of cytopathic effect. Moreover, we also excluded that the MSCs could be infected without showing lytic effects since their conditioned medium after SARS-CoV-2 exposure did not contain viral particles. Our data, demonstrating that MSCs derived from different human tissues are not permissive to SARS-CoV-2 infection, support the safety of MSCs as potential therapy for COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , COVID-19/immunology , Gene Expression Regulation/immunology , Mesenchymal Stem Cells/immunology , SARS-CoV-2/immunology , Serine Endopeptidases/immunology , Cells, Cultured , Humans
16.
Front Immunol ; 11: 552925, 2020.
Article in English | MEDLINE | ID: covidwho-843107

ABSTRACT

Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) induced Coronavirus Disease - 19 (COVID-19) cases have been increasing at an alarming rate (7.4 million positive cases as on June 11 2020), causing high mortality (4,17,956 deaths as on June 11 2020) and economic loss (a 3.2% shrink in global economy in 2020) across 212 countries globally. The clinical manifestations of this disease are pneumonia, lung injury, inflammation, and severe acute respiratory syndrome (SARS). Currently, there is no vaccine or effective pharmacological agents available for the prevention/treatment of SARS-CoV2 infections. Moreover, development of a suitable vaccine is a challenging task due to antibody-dependent enhancement (ADE) and Th-2 immunopathology, which aggravates infection with SARS-CoV-2. Furthermore, the emerging SARS-CoV-2 strain exhibits several distinct genomic and structural patterns compared to other coronavirus strains, making the development of a suitable vaccine even more difficult. Therefore, the identification of novel small molecule inhibitors (NSMIs) that can interfere with viral entry or viral propagation is of special interest and is vital in managing already infected cases. SARS-CoV-2 infection is mediated by the binding of viral Spike proteins (S-protein) to human cells through a 2-step process, which involves Angiotensin Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease (TMPRSS)-2. Therefore, the development of novel inhibitors of ACE2/TMPRSS2 is likely to be beneficial in combating SARS-CoV-2 infections. However, the usage of ACE-2 inhibitors to block the SARS-CoV-2 viral entry requires additional studies as there are conflicting findings and severe health complications reported for these inhibitors in patients. Hence, the current interest is shifted toward the development of NSMIs, which includes natural antiviral phytochemicals and Nrf-2 activators to manage a SARS-CoV-2 infection. It is imperative to investigate the efficacy of existing antiviral phytochemicals and Nrf-2 activators to mitigate the SARS-CoV-2-mediated oxidative stress. Therefore, in this review, we have reviewed structural features of SARS-CoV-2 with special emphasis on key molecular targets and their known modulators that can be considered for the development of NSMIs.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections , Drug Delivery Systems , Pandemics , Pneumonia, Viral , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Humans , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , SARS-CoV-2 , Serine Endopeptidases/immunology , Serine Proteinase Inhibitors/therapeutic use , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/immunology , Th2 Cells/immunology , Viral Vaccines/immunology , Viral Vaccines/therapeutic use
17.
Rev Med Virol ; 31(3): e2176, 2021 05.
Article in English | MEDLINE | ID: covidwho-815924

ABSTRACT

The novel coronavirus (SARS-CoV-2) has turned into a life-threatening pandemic disease (Covid-19). About 5% of patients with Covid-19 have severe symptoms including septic shock, acute respiratory distress syndrome, and the failure of several organs, while most of them have mild symptoms. Frequently, the kidneys are involved through direct or indirect mechanisms. Kidney involvement mainly manifests itself as proteinuria and acute kidney injury (AKI). The SARS-CoV-2-induced kidney damage is expected to be multifactorial; directly it can infect the kidney podocytes and proximal tubular cells and based on an angiotensin-converting enzyme 2 (ACE2) pathway it can lead to acute tubular necrosis, protein leakage in Bowman's capsule, collapsing glomerulopathy and mitochondrial impairment. The SARS-CoV-2-driven dysregulation of the immune responses including cytokine storm, macrophage activation syndrome, and lymphopenia can be other causes of the AKI. Organ interactions, endothelial dysfunction, hypercoagulability, rhabdomyolysis, and sepsis are other potential mechanisms of AKI. Moreover, lower oxygen delivery to kidney may cause an ischaemic injury. Understanding the fundamental molecular pathways and pathophysiology of kidney injury and AKI in Covid-19 is necessary to develop management strategies and design effective therapies.


Subject(s)
Acute Kidney Injury/pathology , COVID-19/physiopathology , Cytokine Release Syndrome/pathology , Disseminated Intravascular Coagulation/pathology , Lymphopenia/pathology , Necrosis/pathology , Proteinuria/pathology , Sepsis/pathology , Acute Kidney Injury/immunology , Acute Kidney Injury/virology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , COVID-19/immunology , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Disseminated Intravascular Coagulation/immunology , Disseminated Intravascular Coagulation/virology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Kidney Tubules, Proximal/immunology , Kidney Tubules, Proximal/physiopathology , Lymphopenia/immunology , Lymphopenia/virology , Necrosis/immunology , Necrosis/virology , Podocytes/immunology , Podocytes/pathology , Proteinuria/immunology , Proteinuria/virology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Sepsis/immunology , Sepsis/virology , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
18.
Rev Med Virol ; 31(3): e2174, 2021 05.
Article in English | MEDLINE | ID: covidwho-784380

ABSTRACT

The current pandemic of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has quickly emerged as a global health concern with government bodies worldwide taking drastic control measures. Understanding the virology of SARS-CoV-2, its molecular mechanisms, and its pathogenesis are required for a targeted therapeutic approach. In this review, we highlight the current molecular and drug advances that target SARS-CoV-2 at the genome level. We also summarize studies that therapeutically target the host angiotensin-converting enzyme 2 and proteases. Finally, we summarize antibody-mediated therapeutic approaches, as well as recent trends in vaccine development. Hence, the purpose of this study is to investigate different molecular targets in SARS-CoV-2 pathogenesis and their usefulness in developing strategies for drug development.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Antibodies, Monoclonal/therapeutic use , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Serine Endopeptidases/genetics , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/immunology , Antibodies, Viral/therapeutic use , Antiviral Agents/chemical synthesis , Antiviral Agents/therapeutic use , COVID-19/immunology , COVID-19/prevention & control , COVID-19/therapy , COVID-19/virology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/metabolism , Drug Approval , Drug Discovery , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunization, Passive/methods , Protease Inhibitors/chemical synthesis , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Serine Endopeptidases/immunology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/immunology , United States , United States Food and Drug Administration
19.
IUBMB Life ; 72(11): 2331-2354, 2020 11.
Article in English | MEDLINE | ID: covidwho-763131

ABSTRACT

The SARS-CoV-2 makes its way into the cell via the ACE2 receptor and the proteolytic action of TMPRSS2. In response to the SARS-CoV-2 infection, the innate immune response is the first line of defense, triggering multiple signaling pathways to produce interferons, pro-inflammatory cytokines and chemokines, and initiating the adaptive immune response against the virus. Unsurprisingly, the virus has developed strategies to evade detection, which can result in delayed, excessive activation of the innate immune system. The response elicited by the host depends on multiple factors, including health status, age, and sex. An overactive innate immune response can lead to a cytokine storm, inflammation, and vascular disruption, leading to the vast array of symptoms exhibited by COVID-19 patients. What is known about the expression and epigenetic regulation of the ACE2 gene and the various players in the host response are explored in this review.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/immunology , Cytokine Release Syndrome/immunology , Epigenesis, Genetic , Host-Pathogen Interactions/immunology , Serine Endopeptidases/genetics , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/immunology , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate , Interferons/genetics , Interferons/immunology , Receptors, Virus/genetics , Receptors, Virus/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Serine Endopeptidases/immunology , Signal Transduction , Spike Glycoprotein, Coronavirus/immunology , Virus Internalization , Virus Replication
20.
Infection ; 48(5): 665-669, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-691043

ABSTRACT

Novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) became pandemic by the end of March 2020. In contrast to the 2002-2003 SARS-CoV outbreak, which had a higher pathogenicity and lead to higher mortality rates, SARSCoV-2 infection appears to be much more contagious. Moreover, many SARS-CoV-2 infected patients are reported to develop low-titer neutralizing antibody and usually suffer prolonged illness, suggesting a more effective SARS-CoV-2 immune surveillance evasion than SARS-CoV. This paper summarizes the current state of art about the differences and similarities between the pathogenesis of the two coronaviruses, focusing on receptor binding domain, host cell entry and protease activation. Such differences may provide insight into possible intervention strategies to fight the pandemic.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , SARS Virus/pathogenicity , Severe Acute Respiratory Syndrome/epidemiology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2 , Antibodies, Viral/biosynthesis , Betacoronavirus/immunology , COVID-19 , Cathepsins/genetics , Cathepsins/immunology , Coronavirus Infections/enzymology , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Enzyme Activation/immunology , Humans , Immune Evasion , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/enzymology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Protein Binding , Protein Domains , SARS Virus/immunology , SARS-CoV-2 , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Severe Acute Respiratory Syndrome/enzymology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/pathology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization , Virus Replication
SELECTION OF CITATIONS
SEARCH DETAIL
...