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1.
PLoS One ; 15(12): e0243270, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33301474

RESUMO

The SARS-CoV-2 (COVID-19) pandemic is a global crisis that threatens our way of life. As of November 18, 2020, SARS-CoV-2 has claimed more than 1,342,709 lives, with a global mortality rate of ~2.4% and a recovery rate of ~69.6%. Understanding the interaction of cellular targets with the SARS-CoV-2 infection is crucial for therapeutic development. Therefore, the aim of this study was to perform a comparative analysis of transcriptomic signatures of infection of SARS-CoV-2 compared to other respiratory viruses (EBOV, H1N1, MERS-CoV, and SARS-CoV), to determine a unique anti-SARS-CoV-2 gene signature. We identified for the first time that molecular pathways for heparin-binding, RAGE, miRNA, and PLA2 inhibitors were associated with SARS-CoV-2 infection. The NRCAM and SAA2 genes, which are involved in severe inflammatory responses, and the FGF1 and FOXO1 genes, which are associated with immune regulation, were found to be associated with the cellular gene response to SARS-CoV-2 infection. Moreover, several cytokines, most significantly IL-8 and IL-6, demonstrated key associations with SARS-CoV-2 infection. Interestingly, the only response gene that was shared among the five viral infections was SERPINB1. The protein-protein interaction (PPI) analysis shed light on genes with high interaction activity that SARS-CoV-2 shares with other viral infections. The findings showed that the genetic pathways associated with rheumatoid arthritis, the AGE-RAGE signaling system, malaria, hepatitis B, and influenza A were of high significance. We found that the virogenomic transcriptome of infection, gene modulation of host antiviral responses, and GO terms of SARS-CoV-2 and EBOV were more similar than to SARS, H1N1, and MERS. This work compares the virogenomic signatures of highly pathogenic viruses and provides valid targets for potential therapy against SARS-CoV-2.


Assuntos
/genética , Transcriptoma , /metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Ebolavirus/fisiologia , Perfilação da Expressão Gênica , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/genética , Influenza Humana/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Mapas de Interação de Proteínas , Vírus da SARS/fisiologia
2.
Am J Chin Med ; 48(7): 1539-1552, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33202150

RESUMO

The SARS-CoV-2 outbreak in 2019 highlighted the fact that no specific medications providing effective treatment have been identified and approved. We explored the possibilities for COVID-19 by systematically reviewing evidence on the efficacy and safety of glycyrrhizin preparations for SARS and MERS. Electronic databases were systematically searched from inception to February 2020 for eligible studies that evaluated the efficacy and safety of glycyrrhizin preparations for SARS and MERS. A quantitative analysis or descriptive analysis was applied. Five retrospective cohort studies were included, and NOS scores ranged from 5-7 points. The clinical symptoms of dry cough, chest distress and dyspnoea improved quickly, and elevated serum levels of aminotransferase decreased after compound glycyrrhizin treatment. The SARS-CoV antibody appeared earlier in the treated group than in the control group ([Formula: see text][Formula: see text]d). Compared to that with conventional medications, the average period from peak to 50% improvement of lesions, in terms of X-ray manifestations, was shorter with compound glycyrrhizin treatment ([Formula: see text]2.1[Formula: see text]d), and treatment reduced the dosage ([Formula: see text][Formula: see text]mg/d) and duration of the corticosteroids used, without other serious adverse reactions. Based on the available evidence regarding glycyrrhizin preparations for treating SARS and MERS, we infer that compound glycyrrhizin could be an optional therapeutic strategy for SARS-CoV-2 infections, especially those complicated with liver damage. Further research using well-designed randomized clinical trials (RCTs) is warranted to determine the dosage and duration of use of compound glycyrrhizin and to monitor its specific adverse effects.


Assuntos
/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Ácido Glicirrízico/uso terapêutico , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Vírus da SARS/efeitos dos fármacos , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , /virologia , Infecções por Coronavirus/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Pandemias , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/virologia , Resultado do Tratamento
3.
Viruses ; 12(11)2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-33187074

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 are enveloped, positive-sense, single-stranded RNA viruses and causes of epidemic diseases that have resulted in public health emergencies worldwide. Angiotensin-converting enzyme 2 (ACE2) is the receptor that allows the entry of these two viruses into host cells, a key step in the life cycle of the pathogens. The characterization of the interactions of ACE2 with the viral spike glycoproteins and structural studies of the ACE2-binding-induced conformational changes in the viral spike glycoproteins have furthered our understanding of the entry processes of these two viruses, and these studies provide useful information that will facilitate the development of antiviral agents and vaccines to control the diseases.


Assuntos
/metabolismo , Vírus da SARS/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Internalização do Vírus , Anticorpos Neutralizantes/imunologia , Infecções por Coronavirus/virologia , Humanos , Ligação Proteica , Domínios Proteicos , Glicoproteína da Espícula de Coronavírus/genética
4.
Mol Cells ; 43(11): 953-963, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33199671

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an infectious disease with multiple severe symptoms, such as fever over 37.5°C, cough, dyspnea, and pneumonia. In our research, microRNAs (miRNAs) binding to the genome sequences of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory-related coronavirus (MERS-CoV), and SARS-CoV-2 were identified by bioinformatic tools. Five miRNAs (hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-195-5p, hsa-miR-16-5p, and hsa-miR-196a-1-3p) were found to commonly bind to SARS-CoV, MERS-CoV, and SARS-CoV-2. We also identified miRNAs that bind to receptor proteins, such as ACE2, ADAM17, and TMPRSS2, which are important for understanding the infection mechanism of SARS-CoV-2. The expression patterns of those miRNAs were examined in hamster lung samples infected by SARS-CoV-2. Five miRNAs (hsa-miR-15b-5p, hsa-miR-195-5p, hsa-miR-221-3p, hsa-miR-140-3p, and hsa-miR-422a) showed differential expression patterns in lung tissues before and after infection. Especially, hsa-miR-15b-5p and hsa-miR-195-5p showed a large difference in expression, indicating that they may potentially be diagnostic biomarkers for SARS-CoV-2 infection.


Assuntos
/genética , Pulmão/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Vírus da SARS/fisiologia , /fisiologia , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , /metabolismo , Animais , Células Cultivadas , Biologia Computacional , Cricetinae , Regulação da Expressão Gênica , Marcadores Genéticos/genética , Humanos , Pulmão/fisiologia , MicroRNAs/genética , Pandemias , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
5.
Protein J ; 39(6): 644-656, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33106987

RESUMO

Novel coronavirus disease 2019 (COVID-19) has resulted in a global pandemic and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several studies have suggested that a precise disulfide-thiol balance is crucial for viral entry and fusion into the host cell and that oxidative stress generated from free radicals can affect this balance. Here, we reviewed the current knowledge about the role of oxidative stress on SARS-CoV and SARS-CoV-2 infections. We focused on the impact of antioxidants, like NADPH and glutathione, and redox proteins, such as thioredoxin and protein disulfide isomerase, that maintain the disulfide-thiol balance in the cell. The possible influence of these biomolecules on the binding of viral protein with the host cell angiotensin-converting enzyme II receptor protein as well as on the severity of COVID-19 infection was discussed.


Assuntos
/metabolismo , Estresse Oxidativo , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/metabolismo , Acetilcisteína/farmacologia , Animais , Antivirais/farmacologia , Descoberta de Drogas , Humanos , Modelos Moleculares , Estresse Oxidativo/efeitos dos fármacos , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas do Envelope Viral/metabolismo
6.
mBio ; 11(5)2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082259

RESUMO

The emergence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the 2019 coronavirus disease (COVID-19), has erupted into a global pandemic that has led to tens of millions of infections and hundreds of thousands of deaths worldwide. The development of therapeutics to treat infection or as prophylactics to halt viral transmission and spread is urgently needed. SARS-CoV-2 relies on structural rearrangements within a spike (S) glycoprotein to mediate fusion of the viral and host cell membranes. Here, we describe the development of a lipopeptide that is derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibits infection by SARS-CoV-2. The lipopeptide inhibits cell-cell fusion mediated by SARS-CoV-2 S and blocks infection by live SARS-CoV-2 in Vero E6 cell monolayers more effectively than previously described lipopeptides. The SARS-CoV-2 lipopeptide exhibits broad-spectrum activity by inhibiting cell-cell fusion mediated by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) and blocking infection by live MERS-CoV in cell monolayers. We also show that the SARS-CoV-2 HRC-derived lipopeptide potently blocks the spread of SARS-CoV-2 in human airway epithelial (HAE) cultures, an ex vivo model designed to mimic respiratory viral propagation in humans. While viral spread of SARS-CoV-2 infection was widespread in untreated airways, those treated with SARS-CoV-2 HRC lipopeptide showed no detectable evidence of viral spread. These data provide a framework for the development of peptide therapeutics for the treatment of or prophylaxis against SARS-CoV-2 as well as other coronaviruses.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, continues to spread globally, placing strain on health care systems and resulting in rapidly increasing numbers of cases and mortalities. Despite the growing need for medical intervention, no FDA-approved vaccines are yet available, and treatment has been limited to supportive therapy for the alleviation of symptoms. Entry inhibitors could fill the important role of preventing initial infection and preventing spread. Here, we describe the design, synthesis, and evaluation of a lipopeptide that is derived from the HRC domain of the SARS-CoV-2 S glycoprotein that potently inhibits fusion mediated by SARS-CoV-2 S glycoprotein and blocks infection by live SARS-CoV-2 in both cell monolayers (in vitro) and human airway tissues (ex vivo). Our results highlight the SARS-CoV-2 HRC-derived lipopeptide as a promising therapeutic candidate for SARS-CoV-2 infections.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Lipopeptídeos/farmacologia , Glicoproteína da Espícula de Coronavírus/química , Internalização do Vírus/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Antivirais/química , Betacoronavirus/química , Betacoronavirus/fisiologia , Chlorocebus aethiops , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Células HEK293 , Humanos , Lipopeptídeos/química , Fusão de Membrana/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/química , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Domínios Proteicos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/virologia , Vírus da SARS/química , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/fisiologia , Células Vero
7.
Viruses ; 12(10)2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003587

RESUMO

Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is responsible for the current global coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The viral entry of SARS-CoV-2 depends on an interaction between the receptor-binding domain of its trimeric spike glycoprotein and the human angiotensin-converting enzyme 2 (ACE2) receptor. A better understanding of the spike/ACE2 interaction is still required to design anti-SARS-CoV-2 therapeutics. Here, we investigated the degree of cooperativity of ACE2 within both the SARS-CoV-2 and the closely related SARS-CoV-1 membrane-bound S glycoproteins. We show that there exist differential inter-protomer conformational transitions between both spike trimers. Interestingly, the SARS-CoV-2 spike exhibits a positive cooperativity for monomeric soluble ACE2 binding when compared to the SARS-CoV-1 spike, which might have more structural restraints. Our findings can be of importance in the development of therapeutics that block the spike/ACE2 interaction.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Betacoronavirus/metabolismo , Proteínas de Transporte , Infecções por Coronavirus/virologia , Microscopia Crioeletrônica , Células HEK293 , Humanos , Pandemias , Pneumonia Viral/virologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Vírus da SARS/metabolismo , Síndrome Respiratória Aguda Grave/virologia , Internalização do Vírus
8.
BMC Infect Dis ; 20(1): 805, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126857

RESUMO

BACKGROUND: Both coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are caused by coronaviruses and have infected people in China and worldwide. We aimed to investigate whether COVID-19 and SARS exhibited similar spatial and temporal features at provincial level in mainland China. METHODS: The number of people infected by COVID-19 and SARS were extracted from daily briefings on newly confirmed cases during the epidemics, as of Mar. 4, 2020 and Aug. 3, 2003, respectively. We depicted spatiotemporal patterns of the COVID-19 and SARS epidemics using spatial statistics such as Moran's I and the local indicators of spatial association (LISA). RESULTS: Compared to SARS, COVID-19 had a higher overall incidence. We identified 3 clusters (predominantly located in south-central China; the highest RR = 135.08, 95% CI: 128.36-142.08) for COVID-19 and 4 clusters (mainly in Northern China; the highest RR = 423.51, 95% CI: 240.96-722.32) for SARS. Fewer secondary clusters were identified after the "Wuhan lockdown". The LISA cluster map detected a significantly high-low (Hubei) and low-high spatial clustering (Anhui, Hunan, and Jiangxi, in Central China) for COVID-19. Two significant high-high (Beijing and Tianjin) and low-high (Hebei) clusters were detected for SARS. CONCLUSIONS: COVID-19 and SARS outbreaks exhibited distinct spatiotemporal clustering patterns at the provincial levels in mainland China, which may be attributable to changes in social and demographic factors, local government containment strategies or differences in transmission mechanisms.


Assuntos
Infecções por Coronavirus/epidemiologia , Surtos de Doenças/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Betacoronavirus/fisiologia , China/epidemiologia , Análise por Conglomerados , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Humanos , Incidência , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Síndrome Respiratória Aguda Grave/transmissão , Análise Espaço-Temporal
10.
Placenta ; 101: 13-29, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32911234

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, was first identified after a cluster of cases in Wuhan, China in December 2019. Whether vertical transmission or placental pathology might occur following maternal infection during pregnancy remains unknown. This review aimed to summarise all studies that examined the placenta or neonates following infection with SARS-CoV-2, or closely related highly pathogenic coronavirus (SARS-CoV-1, or the Middle East respiratory syndrome coronavirus (MERS-CoV)). Structured literature searches found 50 studies that met the inclusion criteria. Twenty studies reported placental histopathology findings in third trimester placentas following maternal SARS-CoV-2 infection. Using the Amsterdam Consensus criteria to categorise the histopathology results, evidence of both fetal vascular malperfusion (35.3% of cases; 95% Confidence Interval (CI) 27.7-43.0%) and maternal vascular malperfusion (46% of cases; 95% CI 38.0-54.0%) were reported, along with evidence of inflammation in the placentas (villitis 8.7% cases, intervillositis 5.3% of cases, chorioamnionitis 6% of cases). The placental pathologies observed in SARS-CoV-2 were consistent with findings following maternal SARS-CoV-1 infection. Of those tested, a minority of neonates (2%) and placental samples tested positive for SARS-CoV-2 infection (21%). Limited conclusions can be drawn about the effect of maternal SARS-CoV-2 infection on placental pathology as most lack control groups and the majority of reports followed third trimester infection. Collaboration to maximise the number of samples examined will increase the reliability and generalisability of findings. A better understanding of the association between maternal SARS-CoV-2 infection and placental pathology will inform maternity care during the coronavirus pandemic.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Transmissão Vertical de Doença Infecciosa , Placenta/patologia , Pneumonia Viral/patologia , Complicações Infecciosas na Gravidez/patologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/transmissão , Feminino , Humanos , Recém-Nascido , Pandemias , Placenta/irrigação sanguínea , Placenta/virologia , Circulação Placentária/fisiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/transmissão , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/fisiopatologia , Complicações Infecciosas na Gravidez/virologia , Vírus da SARS/patogenicidade , Vírus da SARS/fisiologia
11.
Virus Res ; 290: 198176, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32987033

RESUMO

We have utilised the transcriptional response of lung epithelial cells following infection by the original Severe Acute Respiratory Syndrome coronavirus (SARS) to identify repurposable drugs for COVID-19. Drugs best able to recapitulate the infection profile are highly enriched for antiviral activity. Nine of these have been tested against SARS-2 and found to potently antagonise SARS-2 infection/replication, with a number now being considered for clinical trials. It is hoped that this approach may serve to broaden the spectrum of approved drugs that should be further assessed as potential anti-COVID-19 agents and may help elucidate how this seemingly disparate collection of drugs are able to inhibit SARS-2 infection/replication.


Assuntos
Antivirais/farmacologia , Reposicionamento de Medicamentos , /efeitos dos fármacos , Antivirais/química , Antivirais/uso terapêutico , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células Epiteliais/virologia , Perfilação da Expressão Gênica , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/fisiologia , Transcriptoma/efeitos dos fármacos
12.
J Virol ; 94(23)2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-32938761

RESUMO

SARS-CoV-2, a novel coronavirus (CoV) that causes COVID-19, has recently emerged causing an ongoing outbreak of viral pneumonia around the world. While distinct from SARS-CoV, both group 2B CoVs share similar genome organization, origins to bat CoVs, and an arsenal of immune antagonists. In this report, we evaluate type I interferon (IFN-I) sensitivity of SARS-CoV-2 relative to the original SARS-CoV. Our results indicate that while SARS-CoV-2 maintains similar viral replication to SARS-CoV, the novel CoV is much more sensitive to IFN-I. In Vero E6 and in Calu3 cells, SARS-CoV-2 is substantially attenuated in the context of IFN-I pretreatment, whereas SARS-CoV is not. In line with these findings, SARS-CoV-2 fails to counteract phosphorylation of STAT1 and expression of ISG proteins, while SARS-CoV is able to suppress both. Comparing SARS-CoV-2 and influenza A virus in human airway epithelial cultures, we observe the absence of IFN-I stimulation by SARS-CoV-2 alone but detect the failure to counteract STAT1 phosphorylation upon IFN-I pretreatment, resulting in near ablation of SARS-CoV-2 infection. Next, we evaluated IFN-I treatment postinfection and found that SARS-CoV-2 was sensitive even after establishing infection. Finally, we examined homology between SARS-CoV and SARS-CoV-2 in viral proteins shown to be interferon antagonists. The absence of an equivalent open reading frame 3b (ORF3b) and genetic differences versus ORF6 suggest that the two key IFN-I antagonists may not maintain equivalent function in SARS-CoV-2. Together, the results identify key differences in susceptibility to IFN-I responses between SARS-CoV and SARS-CoV-2 that may help inform disease progression, treatment options, and animal model development.IMPORTANCE With the ongoing outbreak of COVID-19, differences between SARS-CoV-2 and the original SARS-CoV could be leveraged to inform disease progression and eventual treatment options. In addition, these findings could have key implications for animal model development as well as further research into how SARS-CoV-2 modulates the type I IFN response early during infection.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Interferon Tipo I/farmacologia , Interferon-alfa/farmacologia , Vírus da SARS/efeitos dos fármacos , Animais , Antivirais/antagonistas & inibidores , Antivirais/metabolismo , Betacoronavirus/imunologia , Betacoronavirus/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Interferon Tipo I/antagonistas & inibidores , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Interferon-alfa/antagonistas & inibidores , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , Fosforilação , Proteínas Recombinantes/farmacologia , Vírus da SARS/imunologia , Vírus da SARS/fisiologia , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Células Vero , Proteínas Virais/química , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos
13.
Bioessays ; 42(11): e2000078, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32893352

RESUMO

Intermediate filaments (IFs) formed by vimentin are less understood than their cytoskeletal partners, microtubules and F-actin, but the unique physical properties of IFs, especially their resistance to large deformations, initially suggest a mechanical function. Indeed, vimentin IFs help regulate cell mechanics and contractility, and in crowded 3D environments they protect the nucleus during cell migration. Recently, a multitude of studies, often using genetic or proteomic screenings show that vimentin has many non-mechanical functions within and outside of cells. These include signaling roles in wound healing, lipogenesis, sterol processing, and various functions related to extracellular and cell surface vimentin. Extracellular vimentin is implicated in marking circulating tumor cells, promoting neural repair, and mediating the invasion of host cells by viruses, including SARS-CoV, or bacteria such as Listeria and Streptococcus. These findings underscore the fundamental role of vimentin in not only cell mechanics but also a range of physiological functions. Also see the video abstract here https://youtu.be/YPfoddqvz-g.


Assuntos
Filamentos Intermediários/fisiologia , Mecanotransdução Celular/fisiologia , Vimentina/fisiologia , Animais , Fenômenos Fisiológicos Bacterianos , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Filamentos Intermediários/química , Fenômenos Mecânicos , Vírus da SARS/fisiologia , Vimentina/química , Internalização do Vírus
14.
Sci Rep ; 10(1): 14214, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848162

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple 500 ns or 1 µs all-atom molecular dynamics simulations were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike (S) protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV-2 and SARS-CoV utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 S protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493 and Gln498 of SARS-CoV-2 and Asp38, Glu35 and Lys353 of ACE2 were observed, which were absent in the ACE2-SARS-CoV interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Molecular mechanics-generalized Born surface area based free energy of binding was observed to be higher for SARS-CoV-2 in all simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/virologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Sequência Conservada , Interações Hospedeiro-Patógeno , Humanos , Modelos Moleculares , Pandemias , Peptidil Dipeptidase A/química , Ligação Proteica , Conformação Proteica , Glicoproteína da Espícula de Coronavírus/química
15.
Viruses ; 12(8)2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32806708

RESUMO

The fatal acute respiratory coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since COVID-19 was declared a pandemic by the World Health Organization in March 2020, infection and mortality rates have been rising steadily worldwide. The lack of a vaccine, as well as preventive and therapeutic strategies, emphasize the need to develop new strategies to mitigate SARS-CoV-2 transmission and pathogenesis. Since mouse hepatitis virus (MHV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2 share a common genus, lessons learnt from MHV and SARS-CoV could offer mechanistic insights into SARS-CoV-2. This review provides a comprehensive review of MHV in mice and SARS-CoV-2 in humans, thereby highlighting further translational avenues in the development of innovative strategies in controlling the detrimental course of SARS-CoV-2. Specifically, we have focused on various aspects, including host species, organotropism, transmission, clinical disease, pathogenesis, control and therapy, MHV as a model for SARS-CoV and SARS-CoV-2 as well as mouse models for infection with SARS-CoV and SARS-CoV-2. While MHV in mice and SARS-CoV-2 in humans share various similarities, there are also differences that need to be addressed when studying murine models. Translational approaches, such as humanized mouse models are pivotal in studying the clinical course and pathology observed in COVID-19 patients. Lessons from prior murine studies on coronavirus, coupled with novel murine models could offer new promising avenues for treatment of COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Vírus da Hepatite Murina/fisiologia , Pneumonia Viral/virologia , Animais , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/transmissão , Modelos Animais de Doenças , Especificidade de Hospedeiro , Humanos , Camundongos , Vírus da Hepatite Murina/genética , Vírus da Hepatite Murina/patogenicidade , Pandemias , Vírus da SARS/genética , Vírus da SARS/patogenicidade , Vírus da SARS/fisiologia , Internalização do Vírus , Replicação Viral
16.
Eur Rev Med Pharmacol Sci ; 24(14): 7816-7825, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32744709

RESUMO

Currently, the outbreak and spread of coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), are increasing worldwide. Furthermore, it has been considered as a major challenge, which threatens human beings and affects all aspects of their life. Understanding the cellular and molecular pathophysiology of the disease is currently under the focus of investigations. Accordingly, this turns the human scientific community attention to find a solution for addressing the challenge. The development of vaccines and efficient therapeutic modality is critical. So, both primary and clinical scientists are not only trying to decipher the structure of SARS-CoV-2, but also attempting to understand the underlying molecular mechanisms that cause tissues and cell injuries. SARS-CoV and SARS-CoV2 are highly homologous and share a highly similar function and behavior patterns. Therefore, this might guide us toward decoding the molecular mechanisms that are behind the SARS-CoV2 pathologic effects. It is noteworthy to mention that, the undesired host immune reactions play important roles in the pathophysiology of the disease, and it also seems that, renin-angiotensin signaling (RAS) is a key contributor in this regard. In this review, we provided a vision, highlight as well as discussing on potential therapeutic targets that might be considered to address the COVID-19 challenge.


Assuntos
Betacoronavirus/fisiologia , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/patologia , Basigina/metabolismo , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Integrinas/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Vírus da SARS/isolamento & purificação , Síndrome Respiratória Aguda Grave/virologia , Troponina I/metabolismo
17.
Cells ; 9(9)2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32854433

RESUMO

Coronaviruses (CoVs) are a diverse family of the enveloped human and animal viruses reported as causative agents for respiratory and intestinal infections. The high pathogenic potential of human CoVs, including SARS-CoV, MERS-CoV and SARS-CoV-2, is closely related to the invasion mechanisms underlying the attachment and entry of viral particles to the host cells. There is increasing evidence that sialylated compounds of cellular glycocalyx can serve as an important factor in the mechanism of CoVs infection. Additionally, the sialic acid-mediated cross-reactivity with the host immune lectins is known to exert the immune response of different intensity in selected pathological stages. Here, we focus on the last findings in the field of glycobiology in the context of the role of sialic acid in tissue tropism, viral entry kinetics and immune regulation in the CoVs infections.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Citocinas/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Ácido N-Acetilneuramínico/metabolismo , Pneumonia Viral/imunologia , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/imunologia , Animais , Infecções por Coronavirus/virologia , Humanos , Camundongos , Pandemias , Pneumonia Viral/virologia , Receptores de Reconhecimento de Padrão/metabolismo , Síndrome Respiratória Aguda Grave/virologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Receptores Toll-Like/metabolismo , Internalização do Vírus
18.
Methods Mol Biol ; 2203: 1-29, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833200

RESUMO

Coronaviruses (CoVs), enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, an unusually large RNA genome, and a unique replication strategy. CoVs cause a variety of diseases in mammals and birds ranging from enteritis in cows and pigs, and upper respiratory tract and kidney disease in chickens to lethal human respiratory infections. Most recently, the novel coronavirus, SARS-CoV-2, which was first identified in Wuhan, China in December 2019, is the cause of a catastrophic pandemic, COVID-19, with more than 8 million infections diagnosed worldwide by mid-June 2020. Here we provide a brief introduction to CoVs discussing their replication, pathogenicity, and current prevention and treatment strategies. We will also discuss the outbreaks of the highly pathogenic Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV), which are relevant for understanding COVID-19.


Assuntos
Doenças dos Animais/virologia , Betacoronavirus/fisiologia , Galinhas/virologia , Infecções por Coronavirus/virologia , Coronavirus/fisiologia , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/virologia , Doenças dos Animais/diagnóstico , Doenças dos Animais/epidemiologia , Doenças dos Animais/prevenção & controle , Animais , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Bovinos , Coronavirus/genética , Coronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Vírus da SARS/genética , Vírus da SARS/patogenicidade , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/diagnóstico , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Glicoproteína da Espícula de Coronavírus/genética , Suínos , Vírion , Replicação Viral
19.
J Chem Inf Model ; 60(10): 5255-5264, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-32846088

RESUMO

The surface of proteins is vital in determining protein functions. Herein, a program, Protein Surface Printer (PSP), is built that performs multiple functions in quantifying protein surface domains. Two proteins, PETase and cytochrome P450, are used to validate that the program supports atomistic simulations with different combinations of programs and force fields. A case study is conducted on the structural analysis of the spike proteins of SARS-CoV-2 and SARS-CoV and the human cell receptor ACE2. Although the surface domains of both spike proteins are highly similar, their receptor-binding domains (RBDs) and the O-linked glycan domains are structurally different. The O-linked glycan domain of SARS-CoV-2 is highly positively charged, which may promote binding to negatively charged human cells.


Assuntos
Betacoronavirus/metabolismo , Peptidil Dipeptidase A/metabolismo , Vírus da SARS/metabolismo , Software , Glicoproteína da Espícula de Coronavírus/metabolismo , Betacoronavirus/química , Betacoronavirus/fisiologia , Sítios de Ligação , Infecções por Coronavirus/metabolismo , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Pandemias , Peptidil Dipeptidase A/química , Pneumonia Viral/metabolismo , Ligação Proteica , Domínios Proteicos , Vírus da SARS/química , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/metabolismo , Glicoproteína da Espícula de Coronavírus/química
20.
Emerg Infect Dis ; 26(12): 2961-2965, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32730733

RESUMO

Severe acute respiratory syndrome coronavirus 2 did not replicate efficiently in 13 bat cell lines, whereas severe acute respiratory syndrome coronavirus replicated efficiently in kidney cells of its ancestral host, the Rhinolophus sinicus bat, suggesting different evolutionary origins. Structural modeling showed that RBD/RsACE2 binding may contribute to the differential cellular tropism.


Assuntos
Vírus da SARS/fisiologia , Tropismo Viral/genética , Animais , Quirópteros/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Pandemias , Vírus da SARS/genética , Replicação Viral
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