RESUMEN
SARS-CoV-2 promotes an imbalanced host response that underlies the development and severity of COVID-19. Infections with viruses are known to modulate transposable elements (TEs), which can exert downstream effects by modulating host gene expression, innate immune sensing, or activities encoded by their protein products. We investigated the impact of SARS-CoV-2 infection on TE expression using RNA-Seq data from cell lines and from primary patient samples. Using a bioinformatics tool, Telescope, we showed that SARS-CoV-2 infection led to upregulation or downregulation of TE transcripts, a subset of which differed from cells infected with SARS, Middle East respiratory syndrome coronavirus (MERS-CoV or MERS), influenza A virus (IAV), respiratory syncytial virus (RSV), and human parainfluenza virus type 3 (HPIV3). Differential expression of key retroelements specifically identified distinct virus families, such as Coronaviridae, with unique retroelement expression subdividing viral species. Analysis of ChIP-Seq data showed that TEs differentially expressed in SARS-CoV-2 infection were enriched for binding sites for transcription factors involved in immune responses and for pioneer transcription factors. In samples from patients with COVID-19, there was significant TE overexpression in bronchoalveolar lavage fluid and downregulation in PBMCs. Thus, although the host gene transcriptome is altered by infection with SARS-CoV-2, the retrotranscriptome may contain the most distinctive features of the cellular response to SARS-CoV-2 infection.
Asunto(s)
COVID-19/genética , Retrovirus Endógenos/genética , Elementos de Nucleótido Esparcido Largo/genética , Células A549 , Línea Celular , Secuenciación de Inmunoprecipitación de Cromatina , Biología Computacional , Infecciones por Coronavirus/genética , Elementos Transponibles de ADN/genética , Regulación hacia Abajo , Interacciones Microbiota-Huesped/genética , Humanos , Técnicas In Vitro , Virus de la Influenza A , Gripe Humana/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio , Virus de la Parainfluenza 3 Humana , RNA-Seq , Infecciones por Virus Sincitial Respiratorio/genética , Virus Sincitiales Respiratorios , Infecciones por Respirovirus/genética , Retroelementos/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/genética , Transcriptoma , Regulación hacia ArribaRESUMEN
SARS-CoV and SARS-CoV-2 encode spike proteins that bind human ACE2 on the cell surface to enter target cells during infection. A small fraction of humans encode variants of ACE2, thus altering the biochemical properties at the protein interaction interface. These and other ACE2 coding mutants can reveal how the spike proteins of each virus may differentially engage the ACE2 protein surface during infection. We created an engineered HEK 293T cell line for facile stable transgenic modification, and expressed the major human ACE2 allele or 28 of its missense mutants, 24 of which are possible through single nucleotide changes from the human reference sequence. Infection with SARS-CoV or SARS-CoV-2 spike pseudotyped lentiviruses revealed that high ACE2 cell-surface expression could mask the effects of impaired binding during infection. Drastically reducing ACE2 cell surface expression revealed a range of infection efficiencies across the panel of mutants. Our infection results revealed a non-linear relationship between soluble SARS-CoV-2 RBD binding to ACE2 and pseudovirus infection, supporting a major role for binding avidity during entry. While ACE2 mutants D355N, R357A, and R357T abrogated entry by both SARS-CoV and SARS-CoV-2 spike proteins, the Y41A mutant inhibited SARS-CoV entry much more than SARS-CoV-2, suggesting differential utilization of the ACE2 side-chains within the largely overlapping interaction surfaces utilized by the two CoV spike proteins. These effects correlated well with cytopathic effects observed during SARS-CoV-2 replication in ACE2-mutant cells. The panel of ACE2 mutants also revealed altered ACE2 surface dependencies by the N501Y spike variant, including a near-complete utilization of the K353D ACE2 variant, despite decreased infection mediated by the parental SARS-CoV-2 spike. Our results clarify the relationship between ACE2 abundance, binding, and infection, for various SARS-like coronavirus spike proteins and their mutants, and inform our understanding for how changes to ACE2 sequence may correspond with different susceptibilities to infection.
Asunto(s)
Enzima Convertidora de Angiotensina 2/genética , COVID-19/etiología , SARS-CoV-2/fisiología , Síndrome Respiratorio Agudo Grave/etiología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , Glicoproteína de la Espiga del Coronavirus/fisiología , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/genética , COVID-19/virología , Células HEK293 , Humanos , Mutación Missense , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/virologíaRESUMEN
COVID 19 disease has become a global catastrophe over the past year that has claimed the lives of over two million people around the world. Despite the introduction of vaccines against the disease, there is still a long way to completely eradicate it. There are concerns about the complications following infection with SARS-CoV-2. This research aimed to evaluate the possible correlation between infection with SARS-CoV viruses and cancer in an in-silico study model. To do this, the relevent dataset was selected from GEO database. Identification of differentially expressed genes among defined groups including SARS-CoV, SARS-dORF6, SARS-BatSRBD, and H1N1 were screened where the |Log FC| ≥ 1and p < 0.05 were considered statistically significant. Later, the pathway enrichment analysis and gene ontology (GO) were used by Enrichr and Shiny GO databases. Evaluation with STRING online was applied to predict the functional interactions of proteins, followed by Cytoscape analysis to identify the master genes. Finally, analysis with GEPIA2 server was carried out to reveal the possible correlation between candidate genes and cancer development. The results showed that the main molecular function of up- and down-regulated genes was "double-stranded RNA binding" and actin-binding, respectively. STRING and Cytoscape analysis presented four genes, PTEN, CREB1, CASP3, and SMAD3 as the key genes involved in cancer development. According to TCGA database results, these four genes were up-regulated notably in pancreatic adenocarcinoma. Our findings suggest that pancreatic adenocarcinoma is the most probably malignancy happening after infection with SARS-CoV family.
Asunto(s)
Adenocarcinoma/etiología , COVID-19/complicaciones , Carcinogénesis/genética , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/complicaciones , Neoplasias Pancreáticas/etiología , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/complicaciones , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , COVID-19/genética , COVID-19/metabolismo , COVID-19/virología , Caspasa 3/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Regulación de la Expresión Génica , Ontología de Genes , Humanos , Gripe Humana/genética , Gripe Humana/metabolismo , Gripe Humana/virología , Fosfohidrolasa PTEN/genética , Mapas de Interacción de Proteínas , Riesgo , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/virología , Transducción de Señal/genética , Proteína smad3/genética , Regulación hacia Arriba/genéticaAsunto(s)
COVID-19 , Síndrome Respiratorio Agudo Grave , Humanos , ARN Viral/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/diagnóstico , Síndrome Respiratorio Agudo Grave/epidemiología , Síndrome Respiratorio Agudo Grave/genética , Manejo de EspecímenesRESUMEN
Worse outcomes occur in aged compared with young populations after infections with respiratory viruses, including pathogenic coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), and are associated with a suboptimal lung milieu ("inflammaging"). We previously showed that a single inducible phospholipase, PLA2G2D, is associated with a proresolving/antiinflammatory response in the lungs, and increases with age. Survival was increased in naive Pla2g2d-/- mice infected with SARS-CoV resulting from augmented respiratory dendritic cell (rDC) activation and enhanced priming of virus-specific T cells. Here, in contrast, we show that intranasal immunization provided no additional protection in middle-aged Pla2g2d-/- mice infected with any of the 3 pathogenic human coronaviruses because virtually no virus-specific antibodies or follicular helper CD4+ T (Tfh) cells were produced. Using MERS-CoV-infected mice, we found that these effects did not result from T or B cell intrinsic factors. Rather, they resulted from enhanced, and ultimately, pathogenic rDC activation, as manifested most prominently by enhanced IL-1ß expression. Wild-type rDC transfer to Pla2g2d-/- mice in conjunction with partial IL-1ß blockade reversed this defect and resulted in increased virus-specific antibody and Tfh responses. Together, these results indicate that PLA2G2D has an unexpected role in the lungs, serving as an important modulator of rDC activation, with protective and pathogenic effects in respiratory coronavirus infections and immunization, respectively.
Asunto(s)
Anticuerpos Antivirales/inmunología , Formación de Anticuerpos , COVID-19/inmunología , Fosfolipasas A2 Grupo II/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , SARS-CoV-2/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , Animales , COVID-19/enzimología , COVID-19/genética , Chlorocebus aethiops , Fosfolipasas A2 Grupo II/deficiencia , Ratones , Ratones Noqueados , Síndrome Respiratorio Agudo Grave/enzimología , Síndrome Respiratorio Agudo Grave/genética , Células VeroRESUMEN
The kidney is one of the main targets attacked by viruses in patients with a coronavirus infection. Until now, SARS-CoV-2 has been identified as the seventh member of the coronavirus family capable of infecting humans. In the past two decades, humankind has experienced outbreaks triggered by two other extremely infective members of the coronavirus family; the MERS-CoV and the SARS-CoV. According to several investigations, SARS-CoV causes proteinuria and renal impairment or failure. The SARS-CoV was identified in the distal convoluted tubules of the kidney of infected patients. Also, renal dysfunction was observed in numerous cases of MERS-CoV infection. And recently, during the 2019-nCoV pandemic, it was found that the novel coronavirus not only induces acute respiratory distress syndrome (ARDS) but also can induce damages in various organs including the liver, heart, and kidney. The kidney tissue and its cells are targeted massively by the coronaviruses due to the abundant presence of ACE2 and Dpp4 receptors on kidney cells. These receptors are characterized as the main route of coronavirus entry to the victim cells. Renal failure due to massive viral invasion can lead to undesirable complications and enhanced mortality rate, thus more attention should be paid to the pathology of coronaviruses in the kidney. Here, we have provided the most recent knowledge on the coronaviruses (SARS, MERS, and COVID19) pathology and the mechanisms of their impact on the kidney tissue and functions.
Asunto(s)
COVID-19/mortalidad , Infecciones por Coronavirus/mortalidad , Coronavirus del Síndrome Respiratorio de Oriente Medio/patogenicidad , SARS-CoV-2/patogenicidad , Síndrome Respiratorio Agudo Grave/mortalidad , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/patogenicidad , Tropismo Viral/genética , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/genética , COVID-19/patología , COVID-19/virología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/metabolismo , Regulación de la Expresión Génica , Humanos , Riñón/metabolismo , Riñón/patología , Riñón/virología , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Unión Proteica , Receptores Virales/genética , Receptores Virales/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/patología , Síndrome Respiratorio Agudo Grave/virología , Índice de Severidad de la Enfermedad , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Análisis de SupervivenciaRESUMEN
The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.
Asunto(s)
COVID-19/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Predisposición Genética a la Enfermedad , Gripe Humana/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Antivirales/uso terapéutico , Variación Biológica Individual , COVID-19/genética , COVID-19/virología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/virología , Expresión Génica , Humanos , Inmunidad Innata , Factores Inmunológicos/uso terapéutico , Gripe Humana/tratamiento farmacológico , Gripe Humana/genética , Gripe Humana/virología , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/inmunología , Orthomyxoviridae/efectos de los fármacos , Orthomyxoviridae/inmunología , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/genética , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/efectos de los fármacos , Virus Sincitiales Respiratorios/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , SARS-CoV-2/clasificación , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/virología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Tratamiento Farmacológico de COVID-19RESUMEN
Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infects cells through interaction of its spike protein (SARS2-S) with angiotensin-converting enzyme 2 (ACE2) and activation by proteases, in particular transmembrane protease serine 2 (TMPRSS2). Viruses can also spread through fusion of infected with uninfected cells. We compared the requirements of ACE2 expression, proteolytic activation, and sensitivity to inhibitors for SARS2-S-mediated and SARS-CoV-S (SARS1-S)-mediated cell-cell fusion. SARS2-S-driven fusion was moderately increased by TMPRSS2 and strongly by ACE2, while SARS1-S-driven fusion was strongly increased by TMPRSS2 and less so by ACE2 expression. In contrast to that of SARS1-S, SARS2-S-mediated cell-cell fusion was efficiently activated by batimastat-sensitive metalloproteases. Mutation of the S1/S2 proteolytic cleavage site reduced effector cell-target cell fusion when ACE2 or TMPRSS2 was limiting and rendered SARS2-S-driven cell-cell fusion more dependent on TMPRSS2. When both ACE2 and TMPRSS2 were abundant, initial target cell-effector cell fusion was unaltered compared to that of wild-type (wt) SARS2-S, but syncytia remained smaller. Mutation of the S2 cleavage (S2') site specifically abrogated activation by TMPRSS2 for both cell-cell fusion and SARS2-S-driven pseudoparticle entry but still allowed for activation by metalloproteases for cell-cell fusion and by cathepsins for particle entry. Finally, we found that the TMPRSS2 inhibitor bromhexine, unlike the inhibitor camostat, was unable to reduce TMPRSS2-activated cell-cell fusion by SARS1-S and SARS2-S. Paradoxically, bromhexine enhanced cell-cell fusion in the presence of TMPRSS2, while its metabolite ambroxol exhibited inhibitory activity under some conditions. On Calu-3 lung cells, ambroxol weakly inhibited SARS2-S-driven lentiviral pseudoparticle entry, and both substances exhibited a dose-dependent trend toward weak inhibition of authentic SARS-CoV-2.IMPORTANCE Cell-cell fusion allows viruses to infect neighboring cells without the need to produce free virus and contributes to tissue damage by creating virus-infected syncytia. Our results demonstrate that the S2' cleavage site is essential for activation by TMPRSS2 and unravel important differences between SARS-CoV and SARS-CoV-2, among those, greater dependence of SARS-CoV-2 on ACE2 expression and activation by metalloproteases for cell-cell fusion. Bromhexine, reportedly an inhibitor of TMPRSS2, is currently being tested in clinical trials against coronavirus disease 2019. Our results indicate that bromhexine enhances fusion under some conditions. We therefore caution against the use of bromhexine in high dosages until its effects on SARS-CoV-2 spike activation are better understood. The related compound ambroxol, which similarly to bromhexine is clinically used as an expectorant, did not exhibit activating effects on cell-cell fusion. Both compounds exhibited weak inhibitory activity against SARS-CoV-2 infection at high concentrations, which might be clinically attainable for ambroxol.
Asunto(s)
COVID-19/metabolismo , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus , Ambroxol/farmacología , Sustitución de Aminoácidos , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Bromhexina/farmacología , COVID-19/genética , Línea Celular , Humanos , Mutación Missense , Proteolisis/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , SARS-CoV-2/genética , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Síndrome Respiratorio Agudo Grave/genética , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
BACKGROUND: The ongoing global COVID-19 pandemic is caused by SARS-CoV-2, a novel coronavirus first discovered at the end of 2019. It has led to more than 50 million confirmed cases and more than 1 million deaths across 219 countries as of 11 November 2020, according to WHO statistics. SARS-CoV-2, SARS-CoV, and MERS-CoV are similar. They are highly pathogenic and threaten public health, impair the economy, and inflict long-term impacts on society. No drug or vaccine has been approved as a treatment for these viruses. Efforts to develop antiviral measures have been hampered by the insufficient understanding of how the human body responds to viral infections at the cellular and molecular levels. RESULTS: In this study, journal articles and transcriptomic and proteomic data surveying coronavirus infections were collected. Response genes and proteins were then identified by differential analyses comparing gene/protein levels between infected and control samples. Finally, the H2V database was created to contain the human genes and proteins that respond to SARS-CoV-2, SARS-CoV, and MERS-CoV infection. CONCLUSIONS: H2V provides molecular information about the human response to infection. It can be a powerful tool to discover cellular pathways and processes relevant for viral pathogenesis to identify potential drug targets. It is expected to accelerate the process of antiviral agent development and to inform preparations for potential future coronavirus-related emergencies. The database is available at: http://www.zhounan.org/h2v .
Asunto(s)
COVID-19/metabolismo , Infecciones por Coronavirus/metabolismo , Bases de Datos Genéticas , Bases de Datos de Proteínas , Síndrome Respiratorio Agudo Grave/metabolismo , Interfaz Usuario-Computador , COVID-19/genética , COVID-19/patología , COVID-19/virología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Proteómica , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , SARS-CoV-2/fisiología , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/patología , Síndrome Respiratorio Agudo Grave/virologíaRESUMEN
The ongoing COVID-19 pandemic caused by the coronavirus, SARS-CoV-2, has already caused in excess of 1.25 million deaths worldwide, and the number is increasing. Knowledge of the host transcriptional response against this virus and how the pathways are activated or suppressed compared to other human coronaviruses (SARS-CoV, MERS-CoV) that caused outbreaks previously can help in the identification of potential drugs for the treatment of COVID-19. Hence, we used time point meta-analysis to investigate available SARS-CoV and MERS-CoV in-vitro transcriptome datasets in order to identify the significant genes and pathways that are dysregulated at each time point. The subsequent over-representation analysis (ORA) revealed that several pathways are significantly dysregulated at each time point after both SARS-CoV and MERS-CoV infection. We also performed gene set enrichment analyses of SARS-CoV and MERS-CoV with that of SARS-CoV-2 at the same time point and cell line, the results of which revealed that common pathways are activated and suppressed in all three coronaviruses. Furthermore, an analysis of an in-vivo transcriptomic dataset of COVID-19 patients showed that similar pathways are enriched to those identified in the earlier analyses. Based on these findings, a drug repurposing analysis was performed to identify potential drug candidates for combating COVID-19.
Asunto(s)
Antivirales , COVID-19/metabolismo , Bases de Datos de Ácidos Nucleicos , Reposicionamiento de Medicamentos , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Transcriptoma , COVID-19/genética , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , SARS-CoV-2/genética , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/genética , Tratamiento Farmacológico de COVID-19RESUMEN
The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) emergence in 2003 introduced the first serious human coronavirus pathogen to an unprepared world. To control emerging viruses, existing successful anti(retro)viral therapies can inspire antiviral strategies, as conserved viral enzymes (eg., viral proteases and RNA-dependent RNA polymerases) represent targets of choice. Since 2003, much effort has been expended in the characterization of the SARS-CoV replication/transcription machinery. Until recently, a pure and highly active preparation of SARS-CoV recombinant RNA synthesis machinery was not available, impeding target-based high throughput screening of drug candidates against this viral family. The current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic revealed a new pathogen whose RNA synthesis machinery is highly (>96 % aa identity) homologous to SARS-CoV. This phylogenetic relatedness highlights the potential use of conserved replication enzymes to discover inhibitors against this significant pathogen, which in turn, contributes to scientific preparedness against emerging viruses. Here, we report the use of a purified and highly active SARS-CoV replication/transcription complex (RTC) to set-up a high-throughput screening of Coronavirus RNA synthesis inhibitors. The screening of a small (1520 compounds) chemical library of FDA-approved drugs demonstrates the robustness of our assay and will allow to speed-up drug discovery against the SARS-CoV-2.
Asunto(s)
Colorantes Fluorescentes , Ensayos Analíticos de Alto Rendimiento , ARN Viral , ARN Polimerasa Dependiente del ARN/metabolismo , Síndrome Respiratorio Agudo Grave/diagnóstico , Síndrome Respiratorio Agudo Grave/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Antivirales/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Activación Enzimática , Ensayos Analíticos de Alto Rendimiento/métodos , Ensayos Analíticos de Alto Rendimiento/normas , Humanos , Concentración 50 Inhibidora , ARN Mensajero/genética , Moldes GenéticosRESUMEN
The COVID-19 pandemic has emerged as a global health emergency due to its association with severe pneumonia and relative high mortality. However, the molecular characteristics and pathological features underlying COVID-19 pneumonia remain largely unknown. To characterize molecular mechanisms underlying COVID-19 pathogenesis in the lung tissue using a proteomic approach, fresh lung tissues were obtained from newly deceased patients with COVID-19 pneumonia. After virus inactivation, a quantitative proteomic approach combined with bioinformatics analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. We identified significant differentially expressed proteins involved in a variety of fundamental biological processes including cellular metabolism, blood coagulation, immune response, angiogenesis, and cell microenvironment regulation. Several inflammatory factors were upregulated, which was possibly caused by the activation of NF-κB signaling. Extensive dysregulation of the lung proteome in response to SARS-CoV-2 infection was discovered. Our results systematically outlined the molecular pathological features in terms of the lung response to SARS-CoV-2 infection, and provided the scientific basis for the therapeutic target that is urgently needed to control the COVID-19 pandemic.
Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/genética , Lesión Pulmonar/genética , Neumonía Viral/genética , Proteoma/genética , Proteómica/métodos , Síndrome Respiratorio Agudo Grave/genética , Anciano , Autopsia , COVID-19 , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Citocinas/genética , Citocinas/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ontología de Genes , Humanos , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Lesión Pulmonar/virología , Masculino , Redes y Vías Metabólicas , Anotación de Secuencia Molecular , FN-kappa B/genética , FN-kappa B/metabolismo , Pandemias , Neumonía Viral/metabolismo , Neumonía Viral/patología , Neumonía Viral/virología , Proteoma/metabolismo , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/patología , Síndrome Respiratorio Agudo Grave/virología , Índice de Severidad de la Enfermedad , Transducción de SeñalRESUMEN
A recent genetic association study1 identified a gene cluster on chromosome 3 as a risk locus for respiratory failure after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A separate study (COVID-19 Host Genetics Initiative)2 comprising 3,199 hospitalized patients with coronavirus disease 2019 (COVID-19) and control individuals showed that this cluster is the major genetic risk factor for severe symptoms after SARS-CoV-2 infection and hospitalization. Here we show that the risk is conferred by a genomic segment of around 50 kilobases in size that is inherited from Neanderthals and is carried by around 50% of people in south Asia and around 16% of people in Europe.
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COVID-19/genética , COVID-19/fisiopatología , Predisposición Genética a la Enfermedad , Hombre de Neandertal/genética , Animales , Asia/etnología , COVID-19/complicaciones , Estudios de Casos y Controles , Cromosomas Humanos Par 3/genética , Europa (Continente)/etnología , Variación Genética/genética , Estudio de Asociación del Genoma Completo , Haplotipos/genética , Hospitalización , Humanos , Desequilibrio de Ligamiento/genética , Familia de Multigenes/genética , Filogenia , Síndrome Respiratorio Agudo Grave/complicaciones , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/fisiopatologíaAsunto(s)
Enfermedades Cardiovasculares/genética , Infecciones por Coronavirus/epidemiología , Insuficiencia de la Válvula Mitral/epidemiología , Peptidil-Dipeptidasa A/genética , Neumonía Viral/epidemiología , Síndrome Respiratorio Agudo Grave/genética , Activación Transcripcional/genética , Enzima Convertidora de Angiotensina 2 , Área Bajo la Curva , COVID-19 , Enfermedades Cardiovasculares/epidemiología , Estudios de Casos y Controles , Comorbilidad , Infecciones por Coronavirus/diagnóstico , Femenino , Alemania , Humanos , Incidencia , Modelos Logísticos , Masculino , Insuficiencia de la Válvula Mitral/genética , Pandemias , Neumonía Viral/diagnóstico , Proteómica/métodos , ARN Mensajero/análisis , Medición de Riesgo , Síndrome Respiratorio Agudo Grave/diagnóstico , Síndrome Respiratorio Agudo Grave/epidemiología , Análisis de Supervivencia , Regulación hacia Arriba/genéticaRESUMEN
The COVID-19 pandemic has strengthened the interest in the biological mechanisms underlying the complex interplay between infectious agents and the human host. The spectrum of phenotypes associated with the SARS-CoV-2 infection, ranging from the absence of symptoms to severe systemic complications, raised the question as to what extent the variable response to coronaviruses (CoVs) is influenced by the variability of the hosts' genetic background.To explore the current knowledge about this question, we designed a systematic review encompassing the scientific literature published from Jan. 2003 to June 2020, to include studies on the contemporary outbreaks caused by SARS-CoV-1, MERS-CoV and SARS-CoV-2 (namely SARS, MERS and COVID-19 diseases). Studies were eligible if human genetic variants were tested as predictors of clinical phenotypes.An ad hoc protocol for the rapid review process was designed according to the PRISMA paradigm and registered at the PROSPERO database (ID: CRD42020180860). The systematic workflow provided 32 articles eligible for data abstraction (28 on SARS, 1 on MERS, 3 on COVID-19) reporting data on 26 discovery cohorts. Most studies considered the definite clinical diagnosis as the primary outcome, variably coupled with other outcomes (severity was the most frequently analysed). Ten studies analysed HLA haplotypes (1 in patients with COVID-19) and did not provide consistent signals of association with disease-associated phenotypes. Out of 22 eligible articles that investigated candidate genes (2 as associated with COVID-19), the top-ranked genes in the number of studies were ACE2, CLEC4M (L-SIGN), MBL, MxA (n = 3), ACE, CD209, FCER2, OAS-1, TLR4, TNF-α (n = 2). Only variants in MBL and MxA were found as possibly implicated in CoV-associated phenotypes in at least two studies. The number of studies for each predictor was insufficient to conduct meta-analyses.Studies collecting large cohorts from different ancestries are needed to further elucidate the role of host genetic variants in determining the response to CoVs infection. Rigorous design and robust statistical methods are warranted.
Asunto(s)
Betacoronavirus/genética , Infecciones por Coronavirus/genética , Interacciones Huésped-Patógeno/genética , Neumonía Viral/genética , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/epidemiología , Variación Genética/genética , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/patogenicidad , Pandemias , Fenotipo , Neumonía Viral/epidemiología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/patogenicidad , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/epidemiología , Síndrome Respiratorio Agudo Grave/genéticaRESUMEN
BACKGROUND: Susceptibility to severe viral infections was reported to be associated with genetic variants in immune response genes using case reports and GWAS studies. SARS-CoV-2 is an emergent viral disease that caused millions of COVID-19 cases all over the world. Around 15 % of cases are severe and some of them are accompanied by dysregulated immune system and cytokine storm. There is increasing evidence that severe manifestations of COVID-19 might be attributed to human genetic variants in genes related to immune deficiency and or inflammasome activation (cytokine storm). OBJECTIVE: Identify the candidate genes that are likely to aid in explaining severe COVID-19 and provide insights to understand the pathogenesis of severe COVID-19. METHODS: In this article, we systematically reviewed genes related to viral susceptibility that were reported in human genetic studies (Case-reports and GWAS) to understand the role of host viral interactions and to provide insights into the pathogenesis of severe COVID-19. RESULTS: We found 40 genes associated with viral susceptibility and 21 of them were associated with severe SARS-CoV disease and severe COVID-19. Some of those genes were implicated in TLR pathways, others in C-lectin pathways, and others were related to inflammasome activation (cytokine storm). CONCLUSION: This compilation represents a list of candidate genes that are likely to aid in explaining severe COVID-19 which are worthy of inclusion in gene panels and during meta-analysis of different variants in host genetics studies of COVID-19. In addition, we provide several hypotheses for severe COVID-19 and possible therapeutic targets.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/genética , Pandemias , Neumonía Viral/genética , Adolescente , Adulto , Factores de Edad , Alelos , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Interacciones Huésped-Patógeno/genética , Humanos , Inflamasomas/genética , Lectinas/genética , Persona de Mediana Edad , Modelos Genéticos , Terapia Molecular Dirigida , Mutación , Polimorfismo de Nucleótido Simple , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/genética , Transducción de Señal/genética , Receptor Toll-Like 3/genética , Receptores Toll-Like/genética , Virosis/genética , Adulto Joven , Tratamiento Farmacológico de COVID-19RESUMEN
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mainly affects the lungs. Sarcoidosis is an autoinflammatory disease characterized by the diffusion of granulomas in the lungs and other organs. Here, we discuss how the two diseases might involve some common mechanistic cellular pathways around the regulation of autophagy.
Asunto(s)
Autofagia/efectos de los fármacos , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Edema Pulmonar/tratamiento farmacológico , Sarcoidosis/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Autofagia/genética , Azitromicina/uso terapéutico , Betacoronavirus/crecimiento & desarrollo , COVID-19 , Cloroquina/uso terapéutico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Isoniazida/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/genética , Neumonía Viral/virología , Edema Pulmonar/epidemiología , Edema Pulmonar/genética , Edema Pulmonar/virología , Rifampin/uso terapéutico , SARS-CoV-2 , Sarcoidosis/epidemiología , Sarcoidosis/genética , Sarcoidosis/virología , Síndrome Respiratorio Agudo Grave/epidemiología , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/virología , Índice de Severidad de la EnfermedadRESUMEN
Coronaviruses are specific crown-shaped viruses that were first identified in the 1960s, and three typical examples of the most recent coronavirus disease outbreaks include severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. Particularly, COVID-19 is currently causing a worldwide pandemic, threatening the health of human beings globally. The identification of viral pathogenic mechanisms is important for further developing effective drugs and targeted clinical treatment methods. The delayed revelation of viral infectious mechanisms is currently one of the technical obstacles in the prevention and treatment of infectious diseases. In this study, we proposed a random walk model to identify the potential pathological mechanisms of COVID-19 on a virus-human protein interaction network, and we effectively identified a group of proteins that have already been determined to be potentially important for COVID-19 infection and for similar SARS infections, which help further developing drugs and targeted therapeutic methods against COVID-19. Moreover, we constructed a standard computational workflow for predicting the pathological biomarkers and related pharmacological targets of infectious diseases.