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1.
Viruses ; 13(2)2021 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668405

RESUMEN

Porcine deltacoronavirus (PDCoV) is an emerging infectious disease of swine with zoonotic potential. Phylogenetic analysis suggests that PDCoV originated recently from a host-switching event between birds and mammals. Little is known about how PDCoV interacts with its differing hosts. Human-derived cell lines are susceptible to PDCoV infection. Herein, we compare the gene expression profiles of an established host swine cells to potential emerging host human cells after infection with PDCoV. Cell lines derived from intestinal lineages were used to reproduce the primary sites of viral infection in the host. Porcine intestinal epithelial cells (IPEC-J2) and human intestinal epithelial cells (HIEC) were infected with PDCoV. RNA-sequencing was performed on total RNA extracted from infected cells. Human cells exhibited a more pronounced response to PDCoV infection in comparison to porcine cells with more differentially expressed genes (DEGs) in human, 7486, in comparison to pig cells, 1134. On the transcriptional level, the adoptive host human cells exhibited more DEGs in response to PDCoV infection in comparison to the primary pig host cells, where different types of cytokines can control PDCoV replication and virus production. Key immune-associated DEGs and signaling pathways are shared between human and pig cells during PDCoV infection. These included genes related to the NF-kappa-B transcription factor family, the interferon (IFN) family, the protein-kinase family, and signaling pathways such as the apoptosis signaling pathway, JAK-STAT signaling pathway, inflammation/cytokine-cytokine receptor signaling pathway. MAP4K4 was unique in up-regulated DEGs in humans in the apoptosis signaling pathway. While similarities exist between human and pig cells in many pathways, our research suggests that the adaptation of PDCoV to the porcine host required the ability to down-regulate many response pathways including the interferon pathway. Our findings provide an important foundation that contributes to an understanding of the mechanisms of PDCoV infection across different hosts. To our knowledge, this is the first report of transcriptome analysis of human cells infected by PDCoV.


Asunto(s)
Infecciones por Coronavirus/metabolismo , Células Epiteliales/virología , Enfermedades de los Porcinos/metabolismo , Transcriptoma , Animales , Línea Celular , Citocinas/metabolismo , Regulación de la Expresión Génica , Humanos , Interferones/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Porcinos
2.
Infect Dis Poverty ; 10(1): 28, 2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33726861

RESUMEN

BACKGROUND: Coronaviruses (CoVs) are distributed worldwide and have various susceptible hosts; CoVs infecting humans are called human coronaviruses (HCoVs). Although HCoV-specific drugs are still lacking, many potent targets for drug discovery are being explored, and many vigorously designed clinical trials are being carried out in an orderly manner. The aim of this review was to gain a comprehensive understanding of the current status of drug development against HCoVs, particularly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MAIN TEXT: A scoping review was conducted by electronically searching research studies, reviews, and clinical trials in PubMed and the CNKI. Studies on HCoVs and therapeutic drug discovery published between January 2000 and October 2020 and in English or Chinese were included, and the information was summarized. Of the 3248 studies identified, 159 publication were finally included. Advances in drug development against HCoV, especially SARS-CoV-2, are summarized under three categories: antiviral drugs aimed at inhibiting the HCoV proliferation process, drugs acting on the host's immune system, and drugs derived from plants with potent activity. Furthermore, clinical trials of drugs targeting SARS-CoV-2 are summarized. CONCLUSIONS: During the spread of COVID-19 outbreak, great efforts have been made in therapeutic drug discovery against the virus, although the pharmacological effects and adverse reactions of some drugs under study are still unclear. However, well-designed high-quality studies are needed to further study the effectiveness and safety of these potential drugs so as to provide valid recommendations for better control of the COVID-19 pandemic.


Asunto(s)
Antivirales/farmacología , Infecciones por Coronavirus/virología , Coronavirus/efectos de los fármacos , Coronavirus/fisiología , Descubrimiento de Drogas , Antivirales/uso terapéutico , Biomarcadores , /metabolismo , Coronavirus/clasificación , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/metabolismo , Desarrollo de Medicamentos , Descubrimiento de Drogas/métodos , Regulación Viral de la Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Medicina Tradicional , Terapia Molecular Dirigida , Replicación Viral/efectos de los fármacos
3.
Sci Rep ; 11(1): 4108, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602998

RESUMEN

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.


Asunto(s)
Betacoronavirus/genética , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Codón/genética , Uso de Codones , Biología Computacional/métodos , Coronavirus/genética , Infecciones por Coronavirus/metabolismo , Genes Virales , Genoma Viral , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Filogenia , Virus del SRAS/genética , /genética
4.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-33525632

RESUMEN

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel epidemic strain of Betacoronavirus that is responsible for the current viral pandemic, coronavirus disease 2019 (COVID-19), a global health crisis. Other epidemic Betacoronaviruses include the 2003 SARS-CoV-1 and the 2009 Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the genomes of which, particularly that of SARS-CoV-1, are similar to that of the 2019 SARS-CoV-2. In this extensive review, we document the most recent information on Coronavirus proteins, with emphasis on the membrane proteins in the Coronaviridae family. We include information on their structures, functions, and participation in pathogenesis. While the shared proteins among the different coronaviruses may vary in structure and function, they all seem to be multifunctional, a common theme interconnecting these viruses. Many transmembrane proteins encoded within the SARS-CoV-2 genome play important roles in the infection cycle while others have functions yet to be understood. We compare the various structural and nonstructural proteins within the Coronaviridae family to elucidate potential overlaps and parallels in function, focusing primarily on the transmembrane proteins and their influences on host membrane arrangements, secretory pathways, cellular growth inhibition, cell death and immune responses during the viral replication cycle. We also offer bioinformatic analyses of potential viroporin activities of the membrane proteins and their sequence similarities to the Envelope (E) protein. In the last major part of the review, we discuss complement, stimulation of inflammation, and immune evasion/suppression that leads to CoV-derived severe disease and mortality. The overall pathogenesis and disease progression of CoVs is put into perspective by indicating several stages in the resulting infection process in which both host and antiviral therapies could be targeted to block the viral cycle. Lastly, we discuss the development of adaptive immunity against various structural proteins, indicating specific vulnerable regions in the proteins. We discuss current CoV vaccine development approaches with purified proteins, attenuated viruses and DNA vaccines.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/metabolismo , Proteínas de la Matriz Viral/metabolismo , Animales , Betacoronavirus/genética , Betacoronavirus/inmunología , /metabolismo , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Genoma Viral , Interacciones Huésped-Patógeno , Humanos , Evasión Inmune , Mapas de Interacción de Proteínas , /inmunología , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/inmunología , Internalización del Virus , Replicación Viral
5.
PLoS One ; 16(2): e0246901, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33596252

RESUMEN

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.


Asunto(s)
Betacoronavirus/metabolismo , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/virología , Imitación Molecular/fisiología , Dominios y Motivos de Interacción de Proteínas/inmunología , Betacoronavirus/genética , /virología , Infecciones por Coronavirus/genética , Bases de Datos Genéticas , Interacciones Huésped-Patógeno , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Dominios Proteicos , Dominios y Motivos de Interacción de Proteínas/genética , Proteoma , Virus del SRAS/genética , Virus del SRAS/metabolismo , /metabolismo , Proteínas Virales/metabolismo
6.
BMC Biol ; 19(1): 12, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33482803

RESUMEN

BACKGROUND: Pandemics, even more than other medical problems, require swift integration of knowledge. When caused by a new virus, understanding the underlying biology may help finding solutions. In a setting where there are a large number of loosely related projects and initiatives, we need common ground, also known as a "commons." Wikidata, a public knowledge graph aligned with Wikipedia, is such a commons and uses unique identifiers to link knowledge in other knowledge bases. However, Wikidata may not always have the right schema for the urgent questions. In this paper, we address this problem by showing how a data schema required for the integration can be modeled with entity schemas represented by Shape Expressions. RESULTS: As a telling example, we describe the process of aligning resources on the genomes and proteomes of the SARS-CoV-2 virus and related viruses as well as how Shape Expressions can be defined for Wikidata to model the knowledge, helping others studying the SARS-CoV-2 pandemic. How this model can be used to make data between various resources interoperable is demonstrated by integrating data from NCBI (National Center for Biotechnology Information) Taxonomy, NCBI Genes, UniProt, and WikiPathways. Based on that model, a set of automated applications or bots were written for regular updates of these sources in Wikidata and added to a platform for automatically running these updates. CONCLUSIONS: Although this workflow is developed and applied in the context of the COVID-19 pandemic, to demonstrate its broader applicability it was also applied to other human coronaviruses (MERS, SARS, human coronavirus NL63, human coronavirus 229E, human coronavirus HKU1, human coronavirus OC4).


Asunto(s)
/patología , Genómica/métodos , Bases del Conocimiento , Proteómica/métodos , /fisiología , /metabolismo , Coronavirus/genética , Coronavirus/fisiología , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Genoma Viral , Humanos , Internet , Pandemias , Proteínas Virales/genética , Proteínas Virales/metabolismo , Flujo de Trabajo
7.
Virology ; 556: 1-8, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33515858

RESUMEN

Porcine deltacoronavirus (PDCoV) is one of the emerged coronaviruses posing a significant threat to the swine industry. Previous work showed the presence of a viral accessory protein NS6 in PDCoV-infected cells. In this study, we detected the expression of the NS6 protein in small intestinal tissues of PDCoV-infected piglets. In addition, SDS-PAGE and Western blot analysis of sucrose gradient-purified virions showed the presence of a 13-kDa NS6 protein. Further evidences of the presence of NS6 in the PDCoV virions were obtained by immunogold staining of purified virions with anti-NS6 antiserum, and by immunoprecipitation of NS6 from purified virions. Finally, the anti-NS6 antibody was not able to neutralize PDCoV in cultured cells. These data establish for the first time that the accessory protein NS6 is expressed during infection in vivo and incorporated into PDCoV virions.


Asunto(s)
Infecciones por Coronavirus/veterinaria , Enfermedades de los Porcinos/virología , Proteínas no Estructurales Virales/metabolismo , Virión/metabolismo , Animales , Anticuerpos Antivirales/inmunología , Línea Celular , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/virología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virología , Ratones , Conejos , Porcinos , Enfermedades de los Porcinos/metabolismo , Proteínas no Estructurales Virales/inmunología
8.
Mol Biol Rep ; 48(2): 1763-1771, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33483864

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to the outbreak of coronavirus disease 2019 (COVID-19), a worldwide epidemic disease affecting increasing number of patients. Although the virus primarily targets respiratory system, cardiovascular involvement has been reported in accumulating studies. In this review, we first describe the cardiac disorders in human with various types of CoV infection, and in animals infected with coronavirus. Particularly, we will focus on the association of cardiovascular disorders upon SARS-CoV-2 infection, and prognostic cardiac biomarkers in COVID-19. Besides, we will discuss the possible mechanisms underlying cardiac injury resulted from SARS-CoV-2 infection including direct myocardial injury caused by viral infection, reduced level of ACE2, and inflammatory response during infection. Improved understandings of cardiac disorders associated with COVID-19 might predict clinical outcome and provide insights into more rational treatment responses in clinical practice.


Asunto(s)
/metabolismo , Biomarcadores/metabolismo , Enfermedades Cardiovasculares/metabolismo , /aislamiento & purificación , Animales , /virología , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/diagnóstico , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/virología , Interacciones Huésped-Patógeno , Humanos , Pronóstico , /fisiología
9.
BMC Bioinformatics ; 22(1): 18, 2021 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-33413085

RESUMEN

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)
/metabolismo , Infecciones por Coronavirus/metabolismo , Bases de Datos Genéticas , Bases de Datos de Proteínas , Síndrome Respiratorio Agudo Grave/metabolismo , Interfaz Usuario-Computador , /genética , /virología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Proteómica , Virus del SRAS/fisiología , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/patología , Síndrome Respiratorio Agudo Grave/virología
10.
Ann Med ; 53(1): 227-236, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-33345626

RESUMEN

The coronavirus disease-2019 (COVID-19), an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2), has hit the world very hard by affecting millions of people across countries hence posing a major health threat on a global scale. This novel virus is thought to enter and cause infection in its host through the attachment of its structural protein known as the S-glycoprotein to angiotensin-converting enzyme 2 (ACE2). Given the rapid spread of COVID-19 with its consequences globally, it is mandatory that health caregivers and researchers across all disciplines abreast themselves with the potential effects that this novel virus may have on their fields and the medical society at large. During the infection, the cardiovascular system is affected by unknown pathomechanistic processes, hence accounting for an increased prevalence of cardiovascular diseases (CVDs) among COVID-19 patients. As cardiovascular researchers, we are more concerned about the cardiovascular aspect of SARS-CoV-2/COVID-19. Hence, this concise review addresses these aspects where CVD as a risk factor of COVID-19, the prevalence of CVDs in COVID-19, and the potential cardiovascular disorders which may evolve owing to COVID-19 are discussed. A better understanding of these issues will be pivotal to improve cardiovascular health during this SARS-CoV-2/COVID-19 pandemic and beyond.


Asunto(s)
/metabolismo , Infecciones por Coronavirus/metabolismo , Endotelio Vascular/metabolismo , /metabolismo , /fisiopatología , Infecciones por Coronavirus/fisiopatología , Humanos , Sistema Renina-Angiotensina
11.
Microb Pathog ; 150: 104719, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33373693

RESUMEN

The recent outbreak of Covid-19 is posing a severe threat to public health globally. Coronaviruses (CoVs) are the largest known group of positive-sense RNA viruses surviving on an extensive number of natural hosts. CoVs are enveloped and non-segmented viruses with a size between 80 and 120 nm. CoV attachment to the surface receptor and its subsequent entrance into cells is mediated by Spike glycoprotein (S). For enhanced CoV entry and successful pathogenesis of CoV, proteolytic processing and receptor-binding act synergistically for induction of large-scale S conformational changes. The shape, size and orientation of receptor-binding domains in viral attachment proteins are well conserved among viruses of different classes that utilize the same receptor. Therefore, investigations unraveling the distribution of cellular receptors with respect to CoV entry, structural aspects of glycoproteins and related conformational changes are highly significant for understanding virus invasion and infection spread. We present the characteristic features of CoV S-Proteins, their significance for CoVs and related receptor binding activities for pathogenesis and viral survival. We are analyzing the novel role of S-protein of CoVs along with their interactive receptors for improving host immunity and decreasing infection spread. This is hoped that presented information will open new ways in tackling coronavirus, especially for the ongoing epidemic.


Asunto(s)
Infecciones por Coronavirus/virología , Coronavirus/fisiología , Glicoproteína de la Espiga del Coronavirus/metabolismo , /metabolismo , Animales , Sitios de Unión , /metabolismo , Coronavirus/genética , Coronavirus/inmunología , Infecciones por Coronavirus/metabolismo , Humanos , Unión Proteica , Conformación Proteica , /fisiología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Internalización del Virus , Replicación Viral
12.
Pharmacol Res Perspect ; 9(1): e00691, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33378565

RESUMEN

Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA-approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in-depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state-of-the-art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA-approved and preclinical drugs targeting viral conserved elements.


Asunto(s)
/metabolismo , Infecciones por Coronavirus/metabolismo , Coronavirus/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , /antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/metabolismo , Antivirales/administración & dosificación , Antivirales/metabolismo , Azoles/administración & dosificación , Azoles/metabolismo , Coronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/metabolismo , Humanos , Naftoquinonas/administración & dosificación , Naftoquinonas/metabolismo , Compuestos de Organoselenio/administración & dosificación , Compuestos de Organoselenio/metabolismo , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico
13.
Viruses ; 13(1)2020 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-33375371

RESUMEN

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) poses a persistent threat to global public health. Although primarily a respiratory illness, extrapulmonary manifestations of COVID-19 include gastrointestinal, cardiovascular, renal and neurological diseases. Recent studies suggest that dysfunction of the endothelium during COVID-19 may exacerbate these deleterious events by inciting inflammatory and microvascular thrombotic processes. Although controversial, there is evidence that SARS-CoV-2 may infect endothelial cells by binding to the angiotensin-converting enzyme 2 (ACE2) cellular receptor using the viral Spike protein. In this review, we explore current insights into the relationship between SARS-CoV-2 infection, endothelial dysfunction due to ACE2 downregulation, and deleterious pulmonary and extra-pulmonary immunothrombotic complications in severe COVID-19. We also discuss preclinical and clinical development of therapeutic agents targeting SARS-CoV-2-mediated endothelial dysfunction. Finally, we present evidence of SARS-CoV-2 replication in primary human lung and cardiac microvascular endothelial cells. Accordingly, in striving to understand the parameters that lead to severe disease in COVID-19 patients, it is important to consider how direct infection of endothelial cells by SARS-CoV-2 may contribute to this process.


Asunto(s)
/metabolismo , Células Endoteliales/metabolismo , Endotelio/metabolismo , /inmunología , Proteína ADAM17/metabolismo , Antivirales/uso terapéutico , Coronavirus , Infecciones por Coronavirus/metabolismo , Células Endoteliales/inmunología , Endotelio/inmunología , Endotelio/virología , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Humanos , Pulmón/metabolismo , Trombosis , Replicación Viral
14.
Database (Oxford) ; 20202020 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-33216893

RESUMEN

DPL (http://www.peptide-ligand.cn/) is a comprehensive database of peptide ligand (DPL). DPL1.0 holds 1044 peptide ligand entries and provides references for the study of the polypeptide platform. The data were collected from PubMed-NCBI, PDB, APD3, CAMPR3, etc. The lengths of the base sequences are varied from 3 to78. DPL database has 923 linear peptides and 88 cyclic peptides. The functions of peptides collected by DPL are very wide. It includes 540 entries of antiviral peptides (including SARS-CoV-2), 55 entries of signal peptides, 48 entries of protease inhibitors, 45 entries of anti-hypertension, 37 entries of anticancer peptides, etc. There are 270 different kinds of peptide targets. All peptides in DPL have clear binding targets. Most of the peptides and receptors have 3D structures experimentally verified or predicted by CYCLOPS, I-TASSER and SWISS-MODEL. With the rapid development of the COVID-2019 epidemic, this database also collects the research progress of peptides against coronavirus. In conclusion, DPL is a unique resource, which allows users easily to explore the targets, different structures as well as properties of peptides.


Asunto(s)
Antivirales/química , Betacoronavirus/química , Bases de Datos Farmacéuticas , Bases de Datos de Proteínas , Modelos Moleculares , Péptidos/química , Secuencia de Aminoácidos , Betacoronavirus/genética , Betacoronavirus/metabolismo , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/metabolismo , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/metabolismo , Dominios Proteicos
15.
J Transl Med ; 18(1): 441, 2020 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-33218357

RESUMEN

The novel coronavirus disease (COVID-19) is posing a serious challenge to the health-care systems worldwide, with an enormous impact on health conditions and loss of lives. Notably, obesity and its related comorbidities are strictly related with worse clinical outcomes of COVID-19 disease. Recently, there is a growing interest in the clinical use of ketogenic diets (KDs), particularly in the context of severe obesity with related metabolic complications. KDs have been proven effective for a rapid reduction of fat mass, preserving lean mass and providing an adequate nutritional status. In particular, the physiological increase in plasma levels of ketone bodies exerts important anti-inflammatory and immunomodulating effects, which may reveal as precious tools to prevent infection and potential adverse outcomes of COVID-19 disease. We discuss here the importance of KDs for a rapid reduction of several critical risk factors for COVID-19, such as obesity, type 2 diabetes and hypertension, based on the known effects of ketone bodies on inflammation, immunity, metabolic profile and cardiovascular function. We do believe that a rapid reduction of all modifiable risk factors, especially obesity with its metabolic complications, should be a pillar of public health policies and interventions, in view of future waves of SARS-CoV-2 infection.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/metabolismo , Dieta Cetogénica , Glucosa/metabolismo , Cetonas/metabolismo , Neumonía Viral/metabolismo , Infecciones por Coronavirus/inmunología , Humanos , Inflamación/patología , Pandemias , Neumonía Viral/inmunología
16.
Int J Mol Sci ; 21(22)2020 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-33203141

RESUMEN

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger "cytokine storm" leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on "multi-targeted" therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Neprilisina/antagonistas & inhibidores , Neumonía Viral/tratamiento farmacológico , Aminobutiratos/administración & dosificación , Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/administración & dosificación , Animales , Infecciones por Coronavirus/metabolismo , Combinación de Medicamentos , Humanos , Neprilisina/metabolismo , Pandemias , Neumonía Viral/metabolismo , Tetrazoles/administración & dosificación , Tetrazoles/uso terapéutico , Valsartán/administración & dosificación , Valsartán/uso terapéutico
17.
Nat Commun ; 11(1): 5838, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33203860

RESUMEN

Emergence of SARS-CoV-2 causing COVID-19 has resulted in hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that Syrian hamsters, in contrast to mice, are highly permissive to SARS-CoV-2 and develop bronchopneumonia and strong inflammatory responses in the lungs with neutrophil infiltration and edema, further confirmed as consolidations visualized by micro-CT alike in clinical practice. Moreover, we identify an exuberant innate immune response as key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Modelos Animales de Enfermedad , Neumonía Viral/patología , Neumonía Viral/virología , Factor de Transcripción STAT2/metabolismo , Transducción de Señal , Animales , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/metabolismo , Cricetinae , Inmunidad Innata , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Pulmón/patología , Pulmón/virología , Ratones , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/metabolismo , Factor de Transcripción STAT2/genética , Replicación Viral
18.
Sci Rep ; 10(1): 19395, 2020 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-33173052

RESUMEN

An incomplete understanding of the molecular mechanisms behind impairment of lung pathobiology by COVID-19 complicates its clinical management. In this study, we analyzed the gene expression pattern of cells obtained from biopsies of COVID-19-affected patient and compared to the effects observed in typical SARS-CoV-2 and SARS-CoV-infected cell-lines. We then compared gene expression patterns of COVID-19-affected lung tissues and SARS-CoV-2-infected cell-lines and mapped those to known lung-related molecular networks, including hypoxia induced responses, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism; all of which are suspected to be downregulated following SARS-CoV-2 infection based on the observed symptomatic impairments. Network analyses suggest that SARS-CoV-2 infection might lead to acute lung injury in COVID-19 by affecting surfactant proteins and their regulators SPD, SPC, and TTF1 through NSP5 and NSP12; thrombosis regulators PLAT, and EGR1 by ORF8 and NSP12; and mitochondrial NDUFA10, NDUFAF5, and SAMM50 through NSP12. Furthermore, hypoxia response through HIF-1 signaling might also be targeted by SARS-CoV-2 proteins. Drug enrichment analysis of dysregulated genes has allowed us to propose novel therapies, including lung surfactants, respiratory stimulants, sargramostim, and oseltamivir. Our study presents a distinct mechanism of probable virus induced lung damage apart from cytokine storm.


Asunto(s)
Infecciones por Coronavirus/genética , Infecciones por Coronavirus/metabolismo , Perfilación de la Expresión Génica , Pulmón/metabolismo , Terapia Molecular Dirigida , Neumonía Viral/genética , Neumonía Viral/metabolismo , Surfactantes Pulmonares/metabolismo , Biología de Sistemas , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Epigénesis Genética , Humanos , Pulmón/efectos de los fármacos , Especificidad de Órganos , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/inmunología , Proteínas Virales/metabolismo
19.
Int J Mol Sci ; 21(22)2020 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-33207699

RESUMEN

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0_22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1_22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1_20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets.


Asunto(s)
Infecciones por Coronavirus/metabolismo , Metaboloma , Neumonía Viral/metabolismo , Anciano , Anciano de 80 o más Años , Aminoácidos/sangre , Ácido Araquidónico/sangre , Biomarcadores/sangre , Ciclo del Ácido Cítrico , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/patología , Femenino , Gluconeogénesis , Humanos , Masculino , Persona de Mediana Edad , Ácido Oléico/sangre , Pandemias , Fosfatidilcolinas/sangre , Fosfatidiletanolaminas/sangre , Fosfolipasas A2/sangre , Neumonía Viral/sangre , Neumonía Viral/patología , Triglicéridos/sangre
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