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1.
J Biosci ; 462021.
Artigo em Inglês | MEDLINE | ID: mdl-33709963

RESUMO

SARS-CoV-2 is a member of the Coronavirus family which recently originated from the Wuhan province of China and spread very rapidly through the world infecting more than 4 million people. In the past, other Coronaviruses have also been found to cause human infection, but not as widespread as COVID-19. Since Coronavirus sequences constantly change due to mutation and recombination, it is important to understand the pattern of changes and likely path the virus can take in the future. In this study, we have used the Shewhart control chart to identify and analyze hypervariable (hotspots) and hypovariable (coldspots) regions of the virus. Our analysis shows that SARS-CoV-2 has changed in a few regions of the genome. Analysis of SARS-CoV-1 and MERS sequences suggests that over time, mutations start accumulating in different regions and most likely SARS-CoV-2 may also follow a similar path. The results suggest a possible emergence of modified viruses over some time.


Assuntos
Variação Genética , Genoma Viral , /genética , China , Genômica/métodos , Genômica/estatística & dados numéricos , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Polimorfismo de Nucleotídeo Único , Vírus da SARS/genética , Proteínas Virais/genética
3.
Artif Cells Nanomed Biotechnol ; 49(1): 204-218, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33645342

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a zoo tonic, highly pathogenic virus. The new type of coronavirus with contagious nature spread from Wuhan (China) to the whole world in a very short time and caused the new coronavirus disease (COVID-19). COVID-19 has turned into a global public health crisis due to spreading by close person-to-person contact with high transmission capacity. Thus, research about the treatment of the damages caused by the virus or prevention from infection increases everyday. Besides, there is still no approved and definitive, standardized treatment for COVID-19. However, this disaster experienced by human beings has made us realize the significance of having a system ready for use to prevent humanity from viral attacks without wasting time. As is known, nanocarriers can be targeted to the desired cells in vitro and in vivo. The nano-carrier system targeting a specific protein, containing the enzyme inhibiting the action of the virus can be developed. The system can be used by simple modifications when we encounter another virus epidemic in the future. In this review, we present a potential treatment method consisting of a nanoparticle-ribozyme conjugate, targeting ACE-2 receptors by reviewing the virus-associated ribozymes, their structures, types and working mechanisms.


Assuntos
/tratamento farmacológico , Nanopartículas/administração & dosagem , RNA Catalítico/uso terapêutico , RNA Viral/antagonistas & inibidores , /efeitos dos fármacos , /antagonistas & inibidores , Ensaios Clínicos como Assunto , Portadores de Fármacos , Composição de Medicamentos , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Modelos Moleculares , Conformação de Ácido Nucleico , Interferência de RNA , RNA Catalítico/administração & dosagem , RNA Catalítico/química , RNA Catalítico/classificação , RNA não Traduzido/classificação , RNA não Traduzido/genética , RNA não Traduzido/uso terapêutico , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/genética , /fisiologia , Glicoproteína da Espícula de Coronavírus/fisiologia , Replicação Viral/efeitos dos fármacos
4.
Adv Exp Med Biol ; 1321: 81-96, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33656715

RESUMO

The new coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), turned into a pandemic affecting more than 200 countries. Due to the high rate of transmission and mortality, finding specific and effective treatment options for this infection is currently of urgent importance. Emerging technologies have created a promising platform for developing novel treatment options for various viral diseases such as the SARS-CoV-2 virus. Here, we have described potential novel therapeutic options based on the structure and pathophysiological mechanism of the SARS-CoV-2 virus, as well as the results of previous studies on similar viruses such as SARS and MERS. Many of these approaches can be used for controlling viral infection by reducing the viral damage or by increasing the potency of the host response. Owing to their high sensitivity, specificity, and reproducibility, siRNAs, aptamers, nanobodies, neutralizing antibodies, and different types of peptides can be used for interference with viral replication or for blocking internalization. Receptor agonists and interferon-inducing agents are also potential options to balance and enhance the innate immune response against SARS-CoV-2. Solid evidence on the efficacy and safety of such novel technologies is yet to be established although many well-designed clinical trials are underway to address these issues.


Assuntos
Infecções por Coronavirus , Coronavírus da Síndrome Respiratória do Oriente Médio , Infecções por Coronavirus/tratamento farmacológico , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Pandemias , Reprodutibilidade dos Testes
5.
PLoS Negl Trop Dis ; 15(3): e0009227, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33647020

RESUMO

Since its first emergence in 2012, cases of infection with Middle East respiratory syndrome coronavirus (MERS-CoV) have continued to occur. At the end of January 2020, 2519 laboratory confirmed cases with a case-fatality rate of 34.3% have been reported. Approximately 84% of human cases have been reported in the tropical region of Saudi Arabia. The emergence of MERS-CoV has highlighted need for a rapid and accurate assay to triage patients with a suspected infection in a timely manner because of the lack of an approved vaccine or an effective treatment for MERS-CoV to prevent and control potential outbreaks. In this study, we present two rapid and visual nucleic acid assays that target the MERS-CoV UpE and N genes as a panel that combines reverse transcription recombinase polymerase amplification with a closed vertical flow visualization strip (RT-RPA-VF). This test panel was designed to improve the diagnostic accuracy through dual-target screening after referencing laboratory testing guidance for MERS-CoV. The limit of detection was 1.2×101 copies/µl viral RNA for the UpE assay and 1.2 copies/µl viral RNA for the N assay, with almost consistent with the sensitivity of the RT-qPCR assays. The two assays exhibited no cross-reactivity with multiple CoVs, including the bat severe acute respiratory syndrome related coronavirus (SARSr-CoV), the bat coronavirus HKU4, and the human coronaviruses 229E, OC43, HKU1 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Furthermore, the panel does not require sophisticated equipment and provides rapid detection within 30 min. This panel displays good sensitivity and specificity and may be useful to rapidly detect MERS-CoV early during an outbreak and for disease surveillance.


Assuntos
Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Técnicas de Diagnóstico Molecular/métodos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Humanos , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Transcrição Reversa , Arábia Saudita/epidemiologia , Sensibilidade e Especificidade , Proteínas não Estruturais Virais/genética
6.
PLoS One ; 16(2): e0246901, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33596252

RESUMO

The MERS-CoV, SARS-CoV, and SARS-CoV-2 are highly pathogenic viruses that can cause severe pneumonic diseases in humans. Unfortunately, there is a non-available effective treatment to combat these viruses. Domain-motif interactions (DMIs) are an essential means by which viruses mimic and hijack the biological processes of host cells. To disentangle how viruses achieve this process can help to develop new rational therapies. Data mining was performed to obtain DMIs stored as regular expressions (regexp) in 3DID and ELM databases. The mined regexp information was mapped on the coronaviruses' proteomes. Most motifs on viral protein that could interact with human proteins are shared across the coronavirus species, indicating that molecular mimicry is a common strategy for coronavirus infection. Enrichment ontology analysis for protein domains showed a shared biological process and molecular function terms related to carbon source utilization and potassium channel regulation. Some of the mapped motifs were nested on B, and T cell epitopes, suggesting that it could be as an alternative way for reverse vaccinology. The information obtained in this study could be used for further theoretic and experimental explorations on coronavirus infection mechanism and development of medicines for treatment.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Mimetismo Molecular/fisiologia , Domínios e Motivos de Interação entre Proteínas/imunologia , Betacoronavirus/genética , /virologia , Infecções por Coronavirus/genética , Bases de Dados Genéticas , Interações Hospedeiro-Patógeno , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Domínios Proteicos , Domínios e Motivos de Interação entre Proteínas/genética , Proteoma , Vírus da SARS/genética , Vírus da SARS/metabolismo , /metabolismo , Proteínas Virais/metabolismo
7.
Sci Rep ; 11(1): 4108, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602998

RESUMO

In December 2019, rising pneumonia cases caused by a novel ß-coronavirus (SARS-CoV-2) occurred in Wuhan, China, which has rapidly spread worldwide, causing thousands of deaths. The WHO declared the SARS-CoV-2 outbreak as a public health emergency of international concern, since then several scientists are dedicated to its study. It has been observed that many human viruses have codon usage biases that match highly expressed proteins in the tissues they infect and depend on the host cell machinery for the replication and co-evolution. In this work, we analysed 91 molecular features and codon usage patterns for 339 viral genes and 463 human genes that consisted of 677,873 codon positions. Hereby, we selected the highly expressed genes from human lung tissue to perform computational studies that permit to compare their molecular features with those of SARS, SARS-CoV-2 and MERS genes. The integrated analysis of all the features revealed that certain viral genes and overexpressed human genes have similar codon usage patterns. The main pattern was the A/T bias that together with other features could propitiate the viral infection, enhanced by a host dependant specialization of the translation machinery of only some of the overexpressed genes. The envelope protein E, the membrane glycoprotein M and ORF7 could be further benefited. This could be the key for a facilitated translation and viral replication conducting to different comorbidities depending on the genetic variability of population due to the host translation machinery. This is the first codon usage approach that reveals which human genes could be potentially deregulated due to the codon usage similarities between the host and the viral genes when the virus is already inside the human cells of the lung tissues. Our work leaded to the identification of additional highly expressed human genes which are not the usual suspects but might play a role in the viral infection and settle the basis for further research in the field of human genetics associated with new viral infections. To identify the genes that could be deregulated under a viral infection is important to predict the collateral effects and determine which individuals would be more susceptible based on their genetic features and comorbidities associated.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Códon/genética , Uso do Códon , Biologia Computacional/métodos , Coronavirus/genética , Infecções por Coronavirus/metabolismo , Genes Virais , Genoma Viral , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Filogenia , Vírus da SARS/genética , /genética
8.
Emerg Microbes Infect ; 10(1): 196-205, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33399028

RESUMO

ABSTRACT Following outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2002 and 2012, respectively, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third highly pathogenic emerging human coronavirus (hCoV). SARS-CoV-2 is currently causing the global coronavirus disease 2019 (COVID-19) pandemic. CoV infections in target cells may stimulate the formation of numerous double-membrane autophagosomes and induce autophagy. Several studies provided evidence that hCoV infections are closely related to various cellular aspects associated with autophagy. Autophagy may even promote hCoV infection and replication. However, so far it is unclear how hCoV infections induce autophagy and whether the autophagic machinery is necessary for viral propagation. Here, we summarize the most recent advances concerning the mutual interplay between the autophagic machinery and the three emerging hCoVs, SARS-CoV, MERS-CoV, and SARS-CoV-2 and the model system mouse hepatitis virus. We also discuss the applicability of approved and well-tolerated drugs targeting autophagy as a potential treatment against COVID-19.


Assuntos
Autofagossomos/virologia , Autofagia , /patogenicidade , Animais , Ensaios Clínicos como Assunto , Genoma Viral , Humanos , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Vírus da Hepatite Murina/patogenicidade , Vírus da SARS/genética , Vírus da SARS/patogenicidade , Internalização do Vírus/efeitos dos fármacos
9.
J Infect Public Health ; 14(2): 238-243, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33493920

RESUMO

BACKGROUND: The MERS-CoV was identified for the first time from Jeddah, Saudi Arabia in 2012 from a hospitalized patient. This virus has now been spread to 27 countries with a total of 858 deaths and 2494 confirmed cases and has become a serious concern for the human population. Camels are well known for the transmission of the virus to the human population. METHODS: In this report, we have discussed the designing, prediction, and evaluation of potential siRNAs against the orf1ab gene of MERS-CoV. The online software was used to predict and design the siRNAs and finally, total twenty-one siRNA were filtered out from four hundred and sixty-two sIRNAs as per their scoring and specificity criteria. We have used only ten siRNAs to evaluate their cytotoxicity and efficacy by reverse transfection approach in HEK-293-T cell lines. RESULTS: Based on the results and data generated; no cytotoxicity was observed for any siRNAs at various concentrations in HEK-293-T cells. The ct value of real-time PCR showed the inhibition of viral replication in siRNA-1, 2, 4, 6, and 9. The data generated provided the preliminary information and encouraged us to evaluate the remaining siRNAs separately as well as in combination to analyses the replication of MERS-CoV inhibition in other cell lines. CONCLUSION: Based on the results obtained; it is concluded that the prediction of siRNAs using online software resulted in the filtration of potential siRNAs with high accuracy and strength. This technology can be used to design and develop antiviral therapy not only for MERS-CoV but also against other viruses.


Assuntos
Genes Virais , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , RNA Interferente Pequeno/genética , Animais , Camelus , Infecções por Coronavirus , Células HEK293 , Humanos , Software
10.
Infect Genet Evol ; 88: 104708, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33421654

RESUMO

The pandemic due to novel coronavirus, SARS-CoV-2 is a serious global concern now. More than thousand new COVID-19 infections are getting reported daily for this virus across the globe. Thus, the medical research communities are trying to find the remedy to restrict the spreading of this virus, while the vaccine development work is still under research in parallel. In such critical situation, not only the medical research community, but also the scientists in different fields like microbiology, pharmacy, bioinformatics and data science are also sharing effort to accelerate the process of vaccine development, virus prediction, forecasting the transmissible probability and reproduction cases of virus for social awareness. With the similar context, in this article, we have studied sequence variability of the virus primarily focusing on three aspects: (a) sequence variability among SARS-CoV-1, MERS-CoV and SARS-CoV-2 in human host, which are in the same coronavirus family, (b) sequence variability of SARS-CoV-2 in human host for 54 different countries and (c) sequence variability between coronavirus family and country specific SARS-CoV-2 sequences in human host. For this purpose, as a case study, we have performed topological analysis of 2391 global genomic sequences of SARS-CoV-2 in association with SARS-CoV-1 and MERS-CoV using an integrated semi-alignment based computational technique. The results of the semi-alignment based technique are experimentally and statistically found similar to alignment based technique and computationally faster. Moreover, the outcome of this analysis can help to identify the nations with homogeneous SARS-CoV-2 sequences, so that same vaccine can be applied to their heterogeneous human population.


Assuntos
/epidemiologia , Infecções por Coronavirus/epidemiologia , Variação Genética , Genoma Viral , Pandemias , Síndrome Respiratória Aguda Grave/epidemiologia , África/epidemiologia , América/epidemiologia , Ásia/epidemiologia , Austrália/epidemiologia , Sequência de Bases , /virologia , Biologia Computacional/métodos , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Europa (Continente)/epidemiologia , Interações Hospedeiro-Patógeno/genética , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Vírus da SARS/genética , Vírus da SARS/patogenicidade , Alinhamento de Sequência , Síndrome Respiratória Aguda Grave/transmissão , Síndrome Respiratória Aguda Grave/virologia
11.
BMC Infect Dis ; 21(1): 84, 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33468070

RESUMO

BACKGROUND: Diabetes is a risk factor for infection with coronaviruses. This study describes the demographic, clinical data, and outcomes of critically ill patients with diabetes and Middle East Respiratory Syndrome (MERS). METHODS: This retrospective cohort study was conducted at 14 hospitals in Saudi Arabia (September 2012-January 2018). We compared the demographic characteristics, underlying medical conditions, presenting symptoms and signs, management and clinical course, and outcomes of critically ill patients with MERS who had diabetes compared to those with no diabetes. Multivariable logistic regression analysis was performed to determine if diabetes was an independent predictor of 90-day mortality. RESULTS: Of the 350 critically ill patients with MERS, 171 (48.9%) had diabetes. Patients with diabetes were more likely to be older, and have comorbid conditions, compared to patients with no diabetes. They were more likely to present with respiratory failure requiring intubation, vasopressors, and corticosteroids. The median time to clearance of MERS-CoV RNA was similar (23 days (Q1, Q3: 17, 36) in patients with diabetes and 21.0 days (Q1, Q3: 10, 33) in patients with no diabetes). Mortality at 90 days was higher in patients with diabetes (78.9% versus 54.7%, p < 0.0001). Multivariable regression analysis showed that diabetes was an independent risk factor for 90-day mortality (odds ratio, 2.09; 95% confidence interval, 1.18-3.72). CONCLUSIONS: Half of the critically ill patients with MERS have diabetes; which is associated with more severe disease. Diabetes is an independent predictor of mortality among critically patients with MERS.


Assuntos
Infecções por Coronavirus/complicações , Complicações do Diabetes/epidemiologia , Diabetes Mellitus/epidemiologia , Corticosteroides , Adulto , Fatores Etários , Idoso , Líquido da Lavagem Broncoalveolar/virologia , Estudos de Coortes , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Nasofaringe/virologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Estudos Retrospectivos , Fatores de Risco , Arábia Saudita/epidemiologia , Escarro/virologia , Traqueia/virologia
12.
Ann Clin Microbiol Antimicrob ; 20(1): 8, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33461573

RESUMO

The Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has gained research attention worldwide, given the current pandemic. Nevertheless, a previous zoonotic and highly pathogenic coronavirus, the Middle East Respiratory Syndrome coronavirus (MERS-CoV), is still causing concern, especially in Saudi Arabia and neighbour countries. The MERS-CoV has been reported from respiratory samples in more than 27 countries, and around 2500 cases have been reported with an approximate fatality rate of 35%. After its emergence in 2012 intermittent, sporadic cases, nosocomial infections and many community clusters of MERS continued to occur in many countries. Human-to-human transmission resulted in the large outbreaks in Saudi Arabia. The inherent genetic variability among various clads of the MERS-CoV might have probably paved the events of cross-species transmission along with changes in the inter-species and intra-species tropism. The current review is drafted using an extensive review of literature on various databases, selecting of publications irrespective of favouring or opposing, assessing the merit of study, the abstraction of data and analysing data. The genome of MERS-CoV contains around thirty thousand nucleotides having seven predicted open reading frames. Spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins are the four main structural proteins. The surface located spike protein (S) of betacoronaviruses has been established to be one of the significant factors in their zoonotic transmission through virus-receptor recognition mediation and subsequent initiation of viral infection. Three regions in Saudi Arabia (KSA), Eastern Province, Riyadh and Makkah were affected severely. The epidemic progression had been the highest in 2014 in Makkah and Riyadh and Eastern Province in 2013. With a lurking epidemic scare, there is a crucial need for effective therapeutic and immunological remedies constructed on sound molecular investigations.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , /genética , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Glicoproteína da Espícula de Coronavírus/genética , /genética , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/virologia , Surtos de Doenças , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Filogenia , RNA Viral/genética , Arábia Saudita/epidemiologia
13.
Nat Commun ; 12(1): 216, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431849

RESUMO

While a number of human coronaviruses are believed to be originated from ancestral viruses in bats, it remains unclear if bat coronaviruses are ready to cause direct bat-to-human transmission. Here, we report the isolation of a MERS-related coronavirus, Tylonycteris-bat-CoV-HKU4, from lesser bamboo bats. Tylonycteris-bat-CoV-HKU4 replicates efficiently in human colorectal adenocarcinoma and hepatocarcinoma cells with cytopathic effects, and can utilize human-dipeptidyl-peptidase-4 and dromedary camel-dipeptidyl-peptidase-4 as the receptors for cell entry. Flow cytometry, co-immunoprecipitation and surface plasmon resonance assays show that Tylonycteris-bat-CoV-HKU4-receptor-binding-domain can bind human-dipeptidyl-peptidase-4, dromedary camel-dipeptidyl-peptidase-4, and Tylonycteris pachypus-dipeptidyl-peptidase-4. Tylonycteris-bat-CoV-HKU4 can infect human-dipeptidyl-peptidase-4-transgenic mice by intranasal inoculation with self-limiting disease. Positive virus and inflammatory changes were detected in lungs and brains of infected mice, associated with suppression of antiviral cytokines and activation of proinflammatory cytokines and chemokines. The results suggest that MERS-related bat coronaviruses may overcome species barrier by utilizing dipeptidyl-peptidase-4 and potentially emerge in humans by direct bat-to-human transmission.


Assuntos
Quirópteros/virologia , Infecções por Coronavirus/virologia , Dipeptidil Peptidase 4/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Animais , Encéfalo/patologia , Células CACO-2 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/transmissão , Citocinas/metabolismo , Dipeptidil Peptidase 4/genética , Células HEK293 , Especificidade de Hospedeiro , Humanos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética
14.
J Med Virol ; 93(4): 1843-1846, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33314219

RESUMO

In this commentary, we shed light on the role of the mammalian target of rapamycin (mTOR) pathway in viral infections. The mTOR pathway has been demonstrated to be modulated in numerous RNA viruses. Frequently, inhibiting mTOR results in suppression of virus growth and replication. Recent evidence points towards modulation of mTOR in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We discuss the current literature on mTOR in SARS-CoV-2 and highlight evidence in support of a role for mTOR inhibitors in the treatment of coronavirus disease 2019.


Assuntos
/tratamento farmacológico , Vírus de RNA/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , 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 , Vírus de RNA/genética , Vírus de RNA/patogenicidade , /patogenicidade , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Replicação Viral
15.
Sci Rep ; 10(1): 22366, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33353955

RESUMO

Corona Virus Disease 2019 (COVID-19) caused by the emerged coronavirus SARS-CoV-2 is spreading globally. The origin of SARS-Cov-2 and its evolutionary relationship is still ambiguous. Several reports attempted to figure out this critical issue by genome-based phylogenetic analysis, yet limited progress was obtained, principally owing to the disability of these methods to reasonably integrate phylogenetic information from all genes of SARS-CoV-2. Supertree method based on multiple trees can produce the overall reasonable phylogenetic tree. However, the supertree method has been barely used for phylogenetic analysis of viruses. Here we applied the matrix representation with parsimony (MRP) pseudo-sequence supertree analysis to study the origin and evolution of SARS-CoV-2. Compared with other phylogenetic analysis methods, the supertree method showed more resolution power for phylogenetic analysis of coronaviruses. In particular, the MRP pseudo-sequence supertree analysis firmly disputes bat coronavirus RaTG13 be the last common ancestor of SARS-CoV-2, which was implied by other phylogenetic tree analysis based on viral genome sequences. Furthermore, the discovery of evolution and mutation in SARS-CoV-2 was achieved by MRP pseudo-sequence supertree analysis. Taken together, the MRP pseudo-sequence supertree provided more information on the SARS-CoV-2 evolution inference relative to the normal phylogenetic tree based on full-length genomic sequences.


Assuntos
/virologia , Quirópteros/virologia , Taxa de Mutação , Filogenia , /genética , Sequência de Aminoácidos , Animais , Genoma Viral , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Vírus da SARS/genética , Síndrome Respiratória Aguda Grave/virologia
16.
PLoS One ; 15(12): e0244025, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33351847

RESUMO

Coronaviruses such as SARS-CoV-2 regularly infect host tissues that express antiviral proteins (AVPs) in abundance. Understanding how they evolve to adapt or evade host immune responses is important in the effort to control the spread of infection. Two AVPs that may shape viral genomes are the zinc finger antiviral protein (ZAP) and the apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like 3 (APOBEC3). The former binds to CpG dinucleotides to facilitate the degradation of viral transcripts while the latter frequently deaminates C into U residues which could generate notable viral sequence variations. We tested the hypothesis that both APOBEC3 and ZAP impose selective pressures that shape the genome of an infecting coronavirus. Our investigation considered a comprehensive number of publicly available genomes for seven coronaviruses (SARS-CoV-2, SARS-CoV, and MERS infecting Homo sapiens, Bovine CoV infecting Bos taurus, MHV infecting Mus musculus, HEV infecting Sus scrofa, and CRCoV infecting Canis lupus familiaris). We show that coronaviruses that regularly infect tissues with abundant AVPs have CpG-deficient and U-rich genomes; whereas those that do not infect tissues with abundant AVPs do not share these sequence hallmarks. Among the coronaviruses surveyed herein, CpG is most deficient in SARS-CoV-2 and a temporal analysis showed a marked increase in C to U mutations over four months of SARS-CoV-2 genome evolution. Furthermore, the preferred motifs in which these C to U mutations occur are the same as those subjected to APOBEC3 editing in HIV-1. These results suggest that both ZAP and APOBEC3 shape the SARS-CoV-2 genome: ZAP imposes a strong CpG avoidance, and APOBEC3 constantly edits C to U. Evolutionary pressures exerted by host immune systems onto viral genomes may motivate novel strategies for SARS-CoV-2 vaccine development.


Assuntos
/genética , Coronavirus/genética , Citidina Desaminase/genética , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Animais , /virologia , Bovinos , Coronavirus/classificação , Coronavirus/patogenicidade , Cães , Evolução Molecular , Genoma Viral/genética , Humanos , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Vírus da SARS/genética , Vírus da SARS/patogenicidade , /patogenicidade , Suínos/virologia
17.
Sensors (Basel) ; 20(22)2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33218097

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic is considered a public health emergency of international concern. The 2019 novel coronavirus (2019-nCoV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused this pandemic has spread rapidly to over 200 countries, and has drastically affected public health and the economies of states at unprecedented levels. In this context, efforts around the world are focusing on solving this problem in several directions of research, by: (i) exploring the origin and evolution of the phylogeny of the SARS-CoV-2 viral genome; (ii) developing nanobiosensors that could be highly effective in detecting the new coronavirus; (iii) finding effective treatments for COVID-19; and (iv) working on vaccine development. In this paper, an overview of the progress made in the development of nanobiosensors for the detection of human coronaviruses (SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV) is presented, along with specific techniques for modifying the surface of nanobiosensors. The newest detection methods of the influenza virus responsible for acute respiratory syndrome were compared with conventional methods, highlighting the newest trends in diagnostics, applications, and challenges of SARS-CoV-2 (COVID-19 causative virus) nanobiosensors.


Assuntos
Betacoronavirus/isolamento & purificação , Técnicas Biossensoriais , Infecções por Coronavirus/diagnóstico , Nanotecnologia , Pneumonia Viral/diagnóstico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Pandemias , Pneumonia Viral/virologia
18.
Front Immunol ; 11: 552909, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013925

RESUMO

The 2019 novel coronavirus (SARS-CoV-2) pandemic has caused a global health emergency. The outbreak of this virus has raised a number of questions: What is SARS-CoV-2? How transmissible is SARS-CoV-2? How severely affected are patients infected with SARS-CoV-2? What are the risk factors for viral infection? What are the differences between this novel coronavirus and other coronaviruses? To answer these questions, we performed a comparative study of four pathogenic viruses that primarily attack the respiratory system and may cause death, namely, SARS-CoV-2, severe acute respiratory syndrome (SARS-CoV), Middle East respiratory syndrome (MERS-CoV), and influenza A viruses (H1N1 and H3N2 strains). This comparative study provides a critical evaluation of the origin, genomic features, transmission, and pathogenicity of these viruses. Because the coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 is ongoing, this evaluation may inform public health administrators and medical experts to aid in curbing the pandemic's progression.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/epidemiologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Pneumonia Viral/epidemiologia , Vírus da SARS/genética , Síndrome Respiratória Aguda Grave/epidemiologia , Animais , Betacoronavirus/patogenicidade , Aves/virologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Genoma Viral , Humanos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Aviária/epidemiologia , Influenza Aviária/transmissão , Influenza Aviária/virologia , Influenza Humana/transmissão , Influenza Humana/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Pandemias , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/transmissão , Síndrome Respiratória Aguda Grave/virologia , Virulência/imunologia
19.
Sci Rep ; 10(1): 16944, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037310

RESUMO

The Spike protein of the novel coronavirus SARS-CoV2 contains an insertion 680SPRRAR↓SV687 forming a cleavage motif RxxR for furin-like enzymes at the boundary of S1/S2 subunits. Cleavage at S1/S2 is important for efficient viral entry into target cells. The insertion is absent in other CoV-s of the same clade, including SARS-CoV1 that caused the 2003 outbreak. However, an analogous cleavage motif was present at S1/S2 of the Spike protein of the more distant Middle East Respiratory Syndrome coronavirus MERS-CoV. We show that a crucial third arginine at the left middle position, comprising a motif RRxR is required for furin recognition in vitro, while the general motif RxxR in common with MERS-CoV is not sufficient for cleavage. Further, we describe a surprising finding that the two serines at the edges of the insert SPRRAR↓SV can be efficiently phosphorylated by proline-directed and basophilic protein kinases. Both phosphorylations switch off furin's ability to cleave the site. Although phospho-regulation of secreted proteins is still poorly understood, further studies, supported by a recent report of ten in vivo phosphorylated sites in the Spike protein of SARS-CoV2, could potentially uncover important novel regulatory mechanisms for SARS-CoV2.


Assuntos
Betacoronavirus/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Vírus da SARS/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Motivos de Aminoácidos/genética , Sequência de Aminoácidos , Furina/metabolismo , Fosforilação , Proteólise , Glicoproteína da Espícula de Coronavírus/genética , Internalização do Vírus
20.
Sci Rep ; 10(1): 16615, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024203

RESUMO

Middle East Respiratory Syndrome coronavirus (MERS-CoV) is a highly virulent pathogen that causes Middle East Respiratory Syndrome (MERS). Anti-MERS-CoV antibodies play an integral role in the prevention and treatment against MERS-CoV infections. Bioactivity is a key quality attribute of therapeutic antibodies, and high accuracy and precision are required. The major methods for evaluating the antiviral effect of antiviral antibodies include neutralization assays using live viruses or pseudoviruses are highly variable. Recent studies have demonstrated that the antibody-dependent cellular cytotoxicity (ADCC) activity of antiviral antibodies is more consistent with the virus clearance effect in vivo than neutralization activity. However, no reports evaluating the ADCC activity of anti-MERS antibodies have been published to date. Here, we describe the development of a robust and reliable cell-based reporter gene assay for the determination of ADCC activity of anti-MERS antibodies using 293T/MERS cells stably expressing the spike protein of MERS-CoV (MERS-S) as target cells and the engineered Jurkat/NFAT-luc/FcγRIIIa stably expressing FcγRIIIA and NFAT reporter gene as effector cells. According to the ICH-Q2 analytical method guidelines, we carefully optimized the experimental conditions and assessed the performance of our assay. In addition, we found that the ADCC activity of afucosylated anti-MERS antibodies is higher than their fucosylated counterparts. The establishment of this ADCC determination system provides a novel method for evaluating the bioactivity of anti-MERS antibodies and improving ADCC activity through modification of N-glycosylation of the Fc segment.


Assuntos
Anticorpos Antivirais/análise , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Infecções por Coronavirus/imunologia , Testes Imunológicos de Citotoxicidade/métodos , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Infecções por Coronavirus/virologia , Genes Reporter , Células HEK293 , Humanos , Células Jurkat , Luciferases/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Fatores de Transcrição NFATC/genética , Receptores de IgG/genética , Receptores de IgG/imunologia , Elementos de Resposta , Glicoproteína da Espícula de Coronavírus/metabolismo , Transfecção
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