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1.
mBio ; 12(2)2021 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-33727353

RESUMEN

The angiotensin-converting enzyme 2 (ACE2) receptor is a major severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host range determinant, and understanding SARS-CoV-2-ACE2 interactions will provide important insights into COVID-19 pathogenesis and animal model development. SARS-CoV-2 cannot infect mice due to incompatibility between its receptor binding domain and the murine ACE2 receptor. Through molecular modeling and empirical in vitro validation, we identified 5 key amino acid differences between murine and human ACE2 that mediate SARS-CoV-2 infection, generating a chimeric humanized murine ACE2. Additionally, we examined the ability of the humanized murine ACE2 receptor to permit infection by an additional preemergent group 2B coronavirus, WIV-1, providing evidence for the potential pan-virus capabilities of this chimeric receptor. Finally, we predicted the ability of these determinants to inform host range identification of preemergent coronaviruses by evaluating hot spot contacts between SARS-CoV-2 and additional potential host receptors. Our results identify residue determinants that mediate coronavirus receptor usage and host range for application in SARS-CoV-2 and emerging coronavirus animal model development.IMPORTANCE SARS-CoV-2 (the causative agent of COVID-19) is a major public health threat and one of two related coronaviruses that have caused epidemics in modern history. A method of screening potential infectible hosts for preemergent and future emergent coronaviruses would aid in mounting rapid response and intervention strategies during future emergence events. Here, we evaluated determinants of SARS-CoV-2 receptor interactions, identifying key changes that enable or prevent infection. The analysis detailed in this study will aid in the development of model systems to screen emergent coronaviruses as well as treatments to counteract infections.


Asunto(s)
/química , Betacoronavirus/fisiología , Replicación Viral , Secuencia de Aminoácidos , Animales , Betacoronavirus/metabolismo , Sitios de Unión , Línea Celular , Infecciones por Coronavirus/virología , Especificidad del Huésped , Humanos , Ratones , Modelos Moleculares , Mutación , Unión Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , /fisiología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo
2.
PLoS Biol ; 19(3): e3001128, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33750978

RESUMEN

The scientific community is focused on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease 2019 (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data, we compare within-host viral dynamics of SARS-CoV-2 with analogous dynamics of MERS-CoV and SARS-CoV. Our quantitative analyses using a mathematical model revealed that the within-host reproduction number at symptom onset of SARS-CoV-2 was statistically significantly larger than that of MERS-CoV and similar to that of SARS-CoV. In addition, the time from symptom onset to the viral load peak for SARS-CoV-2 infection was shorter than those of MERS-CoV and SARS-CoV. These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2-3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARS-CoV-2 and may be useful for development of antiviral therapies.


Asunto(s)
Betacoronavirus/fisiología , /virología , Antivirales/farmacología , Antivirales/uso terapéutico , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Humanos , Estudios Longitudinales , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Modelos Biológicos , Virus del SRAS/fisiología , Carga Viral/efectos de los fármacos
3.
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
4.
Cells ; 10(2)2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540583

RESUMEN

Many viruses disrupt host gene expression by degrading host mRNAs and/or manipulating translation activities to create a cellular environment favorable for viral replication. Often, virus-induced suppression of host gene expression, including those involved in antiviral responses, contributes to viral pathogenicity. Accordingly, clarifying the mechanisms of virus-induced disruption of host gene expression is important for understanding virus-host cell interactions and virus pathogenesis. Three highly pathogenic human coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2, have emerged in the past two decades. All of them encode nonstructural protein 1 (nsp1) in their genomes. Nsp1 of SARS-CoV and MERS-CoV exhibit common biological functions for inducing endonucleolytic cleavage of host mRNAs and inhibition of host translation, while viral mRNAs evade the nsp1-induced mRNA cleavage. SARS-CoV nsp1 is a major pathogenic determinant for this virus, supporting the notion that a viral protein that suppresses host gene expression can be a virulence factor, and further suggesting the possibility that SARS-CoV-2 nsp1, which has high amino acid identity with SARS-CoV nsp1, may serve as a major virulence factor. This review summarizes the gene expression suppression functions of nsp1 of CoVs, with a primary focus on SARS-CoV nsp1 and MERS-CoV nsp1.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/virología , Proteínas no Estructurales Virales/fisiología , Animales , Betacoronavirus/patogenicidad , Betacoronavirus/fisiología , Regulación de la Expresión Génica , Interacciones Microbiota-Huesped , Humanos , Ratones , ARN Mensajero/genética , Replicación Viral
5.
Viruses ; 13(2)2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33546185

RESUMEN

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG's antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.


Asunto(s)
Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Coronavirus Humano OC43/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Tapsigargina/farmacología , Animales , Antivirales/uso terapéutico , Betacoronavirus/fisiología , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Coronavirus Humano OC43/fisiología , Estrés del Retículo Endoplásmico , Humanos , Subtipo H1N1 del Virus de la Influenza A/fisiología , Ratones , Pruebas de Sensibilidad Microbiana , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/virología , Virus Sincitial Respiratorio Humano/fisiología , Ribavirina/farmacología , Tapsigargina/uso terapéutico , Replicación Viral/efectos de los fármacos
6.
Gene ; 766: 145145, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32941953

RESUMEN

COVID-19, a novel coronavirus-related illness, has spread worldwide. Patients with apparently mild/moderate symptoms can suddenly develop severe pneumonia. Therefore, almost all COVID-19 patients require hospitalization, which can reduce limited medical resources in addition to overwhelming medical facilities. To identify predictive markers for the development of severe pneumonia, a comprehensive analysis of serum chemokines and cytokines was conducted using serial serum samples from COVID-19 patients. The expression profiles were analyzed along the time axis. Serum samples of common diseases were enrolled from a BioBank to confirm the usefulness of predictive markers. Five factors, IFN-λ3, IL-6, IP-10, CXCL9, and CCL17, were identified as predicting the onset of severe/critical symptoms. The factors were classified into two categories. Category A included IFN-λ3, IL-6, IP-10, and CXCL9, and their values surged and decreased rapidly before the onset of severe pneumonia. Category B included CCL17, which provided complete separation between the mild/moderate and the severe/critical groups at an early phase of SARS-CoV-2 infection. The five markers provided a high predictive value (area under the receiver operating characteristic curve (AUROC): 0.9-1.0, p < 0.001). Low expression of CCL17 was specifically observed in pre-severe COVID-19 patients compared with other common diseases, and the predictive ability of CCL17 was confirmed in validation samples of COVID-19. The factors identified could be promising prognostic markers to distinguish between mild/moderate and severe/critical patients, enabling triage at an early phase of infection, thus avoiding overwhelming medical facilities.


Asunto(s)
Biomarcadores/sangre , Quimiocina CCL17/sangre , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/fisiopatología , Neumonía Viral/sangre , Neumonía Viral/fisiopatología , Betacoronavirus/fisiología , Citocinas/sangre , Hospitalización , Humanos , Pandemias , Índice de Severidad de la Enfermedad
7.
Ann Hum Biol ; 47(6): 506-513, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33228409

RESUMEN

The models used to estimate disease transmission, susceptibility and severity determine what epidemiology can (and cannot tell) us about COVID-19. These include: 'model organisms' chosen for their phylogenetic/aetiological similarities; multivariable statistical models to estimate the strength/direction of (potentially causal) relationships between variables (through 'causal inference'), and the (past/future) value of unmeasured variables (through 'classification/prediction'); and a range of modelling techniques to predict beyond the available data (through 'extrapolation'), compare different hypothetical scenarios (through 'simulation'), and estimate key features of dynamic processes (through 'projection'). Each of these models: address different questions using different techniques; involve assumptions that require careful assessment; and are vulnerable to generic and specific biases that can undermine the validity and interpretation of their findings. It is therefore necessary that the models used: can actually address the questions posed; and have been competently applied. In this regard, it is important to stress that extrapolation, simulation and projection cannot offer accurate predictions of future events when the underlying mechanisms (and the contexts involved) are poorly understood and subject to change. Given the importance of understanding such mechanisms/contexts, and the limited opportunity for experimentation during outbreaks of novel diseases, the use of multivariable statistical models to estimate the strength/direction of potentially causal relationships between two variables (and the biases incurred through their misapplication/misinterpretation) warrant particular attention. Such models must be carefully designed to address: 'selection-collider bias', 'unadjusted confounding bias' and 'inferential mediator adjustment bias' - all of which can introduce effects capable of enhancing, masking or reversing the estimated (true) causal relationship between the two variables examined.1 Selection-collider bias occurs when these two variables independently cause a third (the 'collider'), and when this collider determines/reflects the basis for selection in the analysis. It is likely to affect all incompletely representative samples, although its effects will be most pronounced wherever selection is constrained (e.g. analyses focusing on infected/hospitalised individuals). Unadjusted confounding bias disrupts the estimated (true) causal relationship between two variables when: these share one (or more) common cause(s); and when the effects of these causes have not been adjusted for in the analyses (e.g. whenever confounders are unknown/unmeasured). Inferentially similar biases can occur when: one (or more) variable(s) (or 'mediators') fall on the causal path between the two variables examined (i.e. when such mediators are caused by one of the variables and are causes of the other); and when these mediators are adjusted for in the analysis. Such adjustment is commonplace when: mediators are mistaken for confounders; prediction models are mistakenly repurposed for causal inference; or mediator adjustment is used to estimate direct and indirect causal relationships (in a mistaken attempt at 'mediation analysis'). These three biases are central to ongoing and unresolved epistemological tensions within epidemiology. All have substantive implications for our understanding of COVID-19, and the future application of artificial intelligence to 'data-driven' modelling of similar phenomena. Nonetheless, competently applied and carefully interpreted, multivariable statistical models may yet provide sufficient insight into mechanisms and contexts to permit more accurate projections of future disease outbreaks.


Asunto(s)
Inteligencia Artificial , Betacoronavirus/fisiología , Infecciones por Coronavirus/epidemiología , Conocimiento , Modelos Estadísticos , Neumonía Viral/epidemiología , Simulación por Computador , Humanos , Pandemias
8.
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
9.
Pan Afr Med J ; 35(Suppl 2): 147, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33193962

RESUMEN

Coronavirus disease (COVID-19) caused by SARS-CoV-2-a new single-stranded RNA virus with respiratory system proclivity and epithelial cell- is a novel infectious disease that originated in Wuhan, China in December, 2019 and has spread to many countries with the total number of confirmed cases put at 20,259,579 cases as of 12th August, 2020. It is transmitted from human-to-human via droplets. When an infected person coughs or sneezes, these droplets find their way into the mouth or nostrils of another person that is within a close range. Alternatively it can be contracted by touching infected hard surfaces and using the same hands to touch the mouth, nose and eye(s). COVID-19 has been declared a global pandemic by the World Health Organization (WHO) on 11th March, 2020. There is currently no therapeutic substance accepted as a panacea for the prophylaxis of this infectious disease. As a result of this back drop, many nations have instituted fourteen (14) days quarantine for suspected cases, social distancing and border closure in an attempt to curb the spread of COVID-19. There has been several conspirary theories that emanated since the disease was declared a pandemic. This paper provides useful information to serve as reference to those who seek proper understanding of COVID-19 and its deleterious effects in the body, by distiguishing between the factsand the conspiracy theoriesof coronavirus disease.


Asunto(s)
Actitud Frente a la Salud , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/epidemiología , Deluciones , Pandemias , Neumonía Viral/epidemiología , Aerosoles , Microbiología del Aire , Betacoronavirus/fisiología , Bioterrorismo , Control de Enfermedades Transmisibles/organización & administración , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/transmisión , Decepción , Fómites , Genocidio , Agencias Gubernamentales , Personal de Salud , Humanos , Pandemias/prevención & control , Neumonía Viral/prevención & control , Neumonía Viral/terapia , Neumonía Viral/transmisión , Política , Cuarentena , Investigadores , Medios de Comunicación Sociales
10.
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
11.
Nat Commun ; 11(1): 5854, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33203890

RESUMEN

SARS-CoV-2 infection is characterized by peak viral load in the upper airway prior to or at the time of symptom onset, an unusual feature that has enabled widespread transmission of the virus and precipitated a global pandemic. How SARS-CoV-2 is able to achieve high titer in the absence of symptoms remains unclear. Here, we examine the upper airway host transcriptional response in patients with COVID-19 (n = 93), other viral (n = 41) or non-viral (n = 100) acute respiratory illnesses (ARIs). Compared with other viral ARIs, COVID-19 is characterized by a pronounced interferon response but attenuated activation of other innate immune pathways, including toll-like receptor, interleukin and chemokine signaling. The IL-1 and NLRP3 inflammasome pathways are markedly less responsive to SARS-CoV-2, commensurate with a signature of diminished neutrophil and macrophage recruitment. This pattern resembles previously described distinctions between symptomatic and asymptomatic viral infections and may partly explain the propensity for pre-symptomatic transmission in COVID-19. We further use machine learning to build 27-, 10- and 3-gene classifiers that differentiate COVID-19 from other ARIs with AUROCs of 0.981, 0.954 and 0.885, respectively. Classifier performance is stable across a wide range of viral load, suggesting utility in mitigating false positive or false negative results of direct SARS-CoV-2 tests.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Inmunidad Innata/genética , Neumonía Viral/inmunología , Neumonía Viral/virología , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Diagnóstico Diferencial , Expresión Génica , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata/inmunología , Nasofaringe/inmunología , Nasofaringe/virología , Pandemias , Neumonía Viral/diagnóstico , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/virología , Sensibilidad y Especificidad , Carga Viral
12.
Elife ; 92020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-33164751

RESUMEN

Pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus 19 disease (COVID-19) which presents a large spectrum of manifestations with fatal outcomes in vulnerable people over 70-years-old and with hypertension, diabetes, obesity, cardiovascular disease, COPD, and smoking status. Knowledge of the entry receptor is key to understand SARS-CoV-2 tropism, transmission and pathogenesis. Early evidence pointed to angiotensin-converting enzyme 2 (ACE2) as SARS-CoV-2 entry receptor. Here, we provide a critical summary of the current knowledge highlighting the limitations and remaining gaps that need to be addressed to fully characterize ACE2 function in SARS-CoV-2 infection and associated pathogenesis. We also discuss ACE2 expression and potential role in the context of comorbidities associated with poor COVID-19 outcomes. Finally, we discuss the potential co-receptors/attachment factors such as neuropilins, heparan sulfate and sialic acids and the putative alternative receptors, such as CD147 and GRP78.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/virología , Peptidil-Dipeptidasa A/fisiología , Neumonía Viral/virología , Acoplamiento Viral , Basigina/fisiología , Comorbilidad , Infecciones por Coronavirus/epidemiología , Regulación Enzimológica de la Expresión Génica , Heparitina Sulfato/fisiología , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Neuropilina-1/fisiología , Oligopéptidos/fisiología , Especificidad de Órganos , Pandemias , Neumonía Viral/epidemiología , Unión Proteica , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores Virales , Sistema Renina-Angiotensina/fisiología , Sistema Respiratorio/enzimología , Ácidos Siálicos/fisiología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/fisiología , Internalización del Virus
13.
PLoS Negl Trop Dis ; 14(11): e0008831, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33166294

RESUMEN

A new coronavirus (SARS-CoV-2) emerged in the winter of 2019 in Wuhan, China, and rapidly spread around the world. The extent and efficiency of SARS-CoV-2 pandemic is far greater than previous coronaviruses that emerged in the 21st Century. Here, we modeled stability of SARS-CoV-2 on skin, paper currency, and clothing to determine if these surfaces may factor in the fomite transmission dynamics of SARS-CoV-2. Skin, currency, and clothing samples were exposed to SARS-CoV-2 under laboratory conditions and incubated at three different temperatures (4°C± 2°C, 22°C± 2°C, and 37°C ± 2°C). We evaluated stability at 0 hours (h), 4 h, 8 h, 24 h, 72 h, 96 h, 7 days, and 14 days post-exposure. SARS-CoV-2 was stable on skin through the duration of the experiment at 4°C (14 days). Virus remained stable on skin for at least 96 h at 22°C and for at least 8h at 37°C. There were minimal differences between the tested currency samples. The virus remained stable on the $1 U.S.A. Bank Note for at least 96 h at 4°C while we did not detect viable virus on the $20 U.S.A. Bank Note samples beyond 72 h. The virus remained stable on both Bank Notes for at least 8 h at 22°C and 4 h at 37°C. Clothing samples were similar in stability to the currency. Viable virus remained for at least 96 h at 4°C and at least 4 h at 22°C. We did not detect viable virus on clothing samples at 37°C after initial exposure. This study confirms the inverse relationship between virus stability and temperature. Furthermore, virus stability on skin demonstrates the need for continued hand hygiene practices to minimize fomite transmission both in the general population as well as in workplaces where close contact is common.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/virología , Neumonía Viral/virología , Piel/virología , Vestuario , Infecciones por Coronavirus/transmisión , Microbiología Ambiental , Humanos , Pandemias , Neumonía Viral/transmisión , Propiedades de Superficie , Temperatura
14.
Antimicrob Resist Infect Control ; 9(1): 185, 2020 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-33168097

RESUMEN

BACKGROUND: Prehospital professionals such as emergency physicians or paramedics must be able to choose and adequately don and doff personal protective equipment (PPE) in order to avoid COVID-19 infection. Our aim was to evaluate the impact of a gamified e-learning module on adequacy of PPE in student paramedics. METHODS: This was a web-based, randomized 1:1, parallel-group, triple-blind controlled trial. Student paramedics from three Swiss schools were invited to participate. They were informed they would be presented with both an e-learning module and an abridged version of the current regional prehospital COVID-19 guidelines, albeit not in which order. After a set of 22 questions designed to assess baseline knowledge, the control group was shown the guidelines before answering a set of 14 post-intervention questions. The e-learning group was shown the gamified e-learning module right after the guidelines, and before answering post-intervention questions. The primary outcome was the difference in the percentage of adequate choices of PPE before and after the intervention. RESULTS: The participation rate was of 71% (98/138). A total of 90 answer sets was analyzed. Adequate choice of PPE increased significantly both in the control (50% [33;83] vs 25% [25;50], P = .013) and in the e-learning group (67% [50;83] vs 25% [25;50], P = .001) following the intervention. Though the median of the difference was higher in the e-learning group, there was no statistically significant superiority over the control (33% [0;58] vs 17% [- 17;42], P = .087). The e-learning module was of greatest benefit in the subgroup of student paramedics who were actively working in an ambulance company (42% [8;58] vs 25% [- 17;42], P = 0.021). There was no significant effect in student paramedics who were not actively working in an ambulance service (0% [- 25;33] vs 17% [- 8;50], P = .584). CONCLUSIONS: The use of a gamified e-learning module increases the rate of adequate choice of PPE only among student paramedics actively working in an ambulance service. In this subgroup, combining this teaching modality with other interventions might help spare PPE and efficiently protect against COVID-19 infection.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/prevención & control , Personal de Salud/educación , Pandemias/prevención & control , Equipo de Protección Personal , Neumonía Viral/prevención & control , Adulto , Técnicos Medios en Salud/educación , Técnicos Medios en Salud/normas , Betacoronavirus/genética , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/virología , Educación a Distancia/estadística & datos numéricos , Europa (Continente) , Femenino , Personal de Salud/normas , Humanos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional , Internet , Conocimiento , Aprendizaje , Masculino , Equipo de Protección Personal/normas , Neumonía Viral/epidemiología , Neumonía Viral/transmisión , Neumonía Viral/virología , Estudiantes/psicología , Adulto Joven
15.
Cells ; 9(11)2020 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-33171736

RESUMEN

Viruses exhibit an elegant simplicity, as they are so basic, but so frightening. Although only a few are life threatening, they have substantial implications for human health and the economy, as exemplified by the ongoing coronavirus pandemic. Viruses are rather small infectious agents found in all types of life forms, from animals and plants to prokaryotes and archaebacteria. They are obligate intracellular parasites, and as such, subvert many molecular and cellular processes of the host cell to ensure their own replication, amplification, and subsequent spread. This special issue addresses the cell biology of viral infections based on a collection of original research articles, communications, opinions, and reviews on various aspects of virus-host cell interactions. Together, these articles not only provide a glance into the latest research on the cell biology of viral infections, but also include novel technological developments.


Asunto(s)
Virosis/patología , Animales , Betacoronavirus/fisiología , Interacciones Huésped-Patógeno , Humanos , Transducción de Señal , Virosis/metabolismo , Virosis/virología , Virus Zika/fisiología
16.
Int J Med Sci ; 17(18): 2974-2986, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33173418

RESUMEN

In the ongoing COVID-19 pandemic, all COVID-19 patients are naïve patients as it is the first-time humans have been exposed to the SARS-CoV-2 virus. As with exposure to many viruses, individuals with pre-existing, compromised immune systems may be at increased risk of developing severe symptoms and/or dying because of (SARS-CoV-2) infection. To learn more about such individuals, we conducted a search and review of published reports on the clinical characteristics and outcomes of COVID-19 patients with pre-existing, compromised immune systems. Here we present our review of patients who possess pre-existing primary antibody deficiency (PAD) and those who are organ transplant recipients on maintenance immunosuppressants. Our review indicates different clinical outcomes for the patients with pre-existing PAD, depending on the underlying causes. For organ transplant recipients, drug-induced immune suppression alone does not appear to enhance COVID-19 mortality risk - rather, advanced age, comorbidities, and the development of secondary complications appears required.


Asunto(s)
Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/diagnóstico , Enfermedades del Sistema Inmune/complicaciones , Enfermedades del Sistema Inmune/diagnóstico , Huésped Inmunocomprometido , Neumonía Viral/complicaciones , Neumonía Viral/diagnóstico , Betacoronavirus/inmunología , Betacoronavirus/fisiología , Comorbilidad , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Humanos , Huésped Inmunocomprometido/inmunología , Inmunosupresores/uso terapéutico , Mortalidad , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/inmunología , Enfermedades de Inmunodeficiencia Primaria/mortalidad , Pronóstico , Receptores de Trasplantes/estadística & datos numéricos
17.
Int J Med Sci ; 17(18): 3125-3145, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33173434

RESUMEN

The use of multipronged measures, including traditional Chinese medicine (TCM), has greatly increased in response to the COVID-19 pandemic, and we found the use of TCM and is positively correlated with the regional cure rate in China (R=0.77, P<10-5). We analyzed 185 commonly administered TCM recipes comprised of 210 herbs nationwide to reveal mechanistic insight. Eight out of the 10 most commonly used herbs showed anti-coronavirus potential by intersecting with COVID-19 targets. Intriguingly, 17 compounds from the 5 most commonly used herbs were revealed to have direct anti-SARS-CoV-2 potential by docking with the two core structures [CoV spike (S) glycoprotein (6SVB) and CoV 3CL hydrolase (6LU7)]. Seven reported COVID-19 drugs served as positive controls; among them, retionavir (-7.828 kcal/mol) and remdesivir (-8.738 kcal/mol) performed best with 6VSB and 6LU7, respectively. The top candidate was madreselvin B (6SVB: -8.588 kcal/mol and 6LU7: -9.017 kcal/mol), an appreciable component of Flos Lonicerae. Eighty-six compounds from 22 unlisted herbs were further identified among 2,042 natural compounds, completing our arsenal for TCM formulations. The mechanisms have been implicated as multifactorial, including activation of immunoregulation (Th2, PPAR and IL10), suppression of acute inflammatory responses (IL-6, IL-1α/ß, TNF, COX2/1, etc.), enhancement of antioxidative activity (CAT and SOD1), and modulation of apoptosis (inhibited CASP3). It is of interest to understand the biological mechanisms of TCM recipes. We then analyzed 18 representative remedies based on molecular targets associated with 14 medical conditions over the disease course, e.g., pyrexia, coughing, asthenia, lymphopenia, cytokine storm, etc. The significant level of coherence (SLC) revealed, in part, the potential uses and properties of corresponding TCMs. Thus, herbal plants coordinate to combat COVID-19 in multiple dimensions, casting a light of hope before effective vaccines are developed.


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Medicina China Tradicional/métodos , Fitoterapia/métodos , Neumonía Viral/tratamiento farmacológico , Algoritmos , Antivirales/aislamiento & purificación , Antivirales/farmacología , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/fisiología , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/genética , Desarrollo de Medicamentos , Medicamentos Herbarios Chinos/clasificación , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Pandemias , Fitoterapia/clasificación , Neumonía Viral/epidemiología , Neumonía Viral/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
18.
J Mol Model ; 26(12): 338, 2020 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-33175236

RESUMEN

A novel coronavirus (SARS-CoV-2) identified in Wuhan state of China in 2019 is the causative agent of deadly disease COVID-19. It has spread across the globe (more than 210 countries) within a short period. Coronaviruses pose serious health threats to both humans and animals. A recent publication reported an experimental 3D complex structure of the S protein of SARS-CoV-2 showed that the ectodomain of the SARS-CoV-2 S protein binds to the peptidase domain (PD) of human ACE2 with a dissociation constant (Kd) of ~ 15 nM. In this study, we focused on inhibitors for ACE2: S protein complex using virtual screening and inhibition studies through molecular docking for over 200,000 natural compounds. Toxicity analysis was also performed for the best hits, and the final complex structures for four complexes were subjected to 400 ns molecular dynamics simulations for stability testing. We found two natural origin inhibitors for the S protein: human ACE2 complex (Andrographolide and Pterostilbene) which displayed better inhibition potential for ACE2 receptor and its binding with the S protein of SARS-CoV-2. Comparative studies were also performed to test and verify that these two drug candidates are also better than hydroxychloroquine which is known to inhibit this complex. However, we needed better potential drug candidates to overcome the side effects of hydroxychloroquine. Supplementary experimental studies need to be carried forward to corroborate the viability of these two new inhibitors for ACE2: S protein complex so as to curb down COVID-19.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/epidemiología , Péptido Hidrolasas/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/epidemiología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Betacoronavirus/genética , Infecciones por Coronavirus/virología , Reposicionamiento de Medicamentos , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Pandemias , Péptido Hidrolasas/genética , Peptidil-Dipeptidasa A/genética , Neumonía Viral/virología , Dominios Proteicos , Glicoproteína de la Espiga del Coronavirus/genética
20.
Nat Commun ; 11(1): 5874, 2020 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-33208736

RESUMEN

Non-structural proteins (nsp) constitute the SARS-CoV-2 replication and transcription complex (RTC) to play a pivotal role in the virus life cycle. Here we determine the atomic structure of a SARS-CoV-2 mini RTC, assembled by viral RNA-dependent RNA polymerase (RdRp, nsp12) with a template-primer RNA, nsp7 and nsp8, and two helicase molecules (nsp13-1 and nsp13-2), by cryo-electron microscopy. Two groups of mini RTCs with different conformations of nsp13-1 are identified. In both of them, nsp13-1 stabilizes overall architecture of the mini RTC by contacting with nsp13-2, which anchors the 5'-extension of RNA template, as well as interacting with nsp7-nsp8-nsp12-RNA. Orientation shifts of nsp13-1 results in its variable interactions with other components in two forms of mini RTC. The mutations on nsp13-1:nsp12 and nsp13-1:nsp13-2 interfaces prohibit the enhancement of helicase activity achieved by mini RTCs. These results provide an insight into how helicase couples with polymerase to facilitate its function in virus replication and transcription.


Asunto(s)
Betacoronavirus/química , Betacoronavirus/fisiología , Replicación Viral , Betacoronavirus/genética , Betacoronavirus/metabolismo , Sitios de Unión , Microscopía por Crioelectrón , Humanos , Metiltransferasas/química , Metiltransferasas/genética , Metiltransferasas/metabolismo , Modelos Moleculares , Mutación , Unión Proteica , Conformación Proteica , ARN Helicasas/química , ARN Helicasas/genética , ARN Helicasas/metabolismo , ARN Viral/metabolismo , Relación Estructura-Actividad , Transcripción Genética , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo
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