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1.
Washington; Organización Panamericana de la Salud; mar. 24, 2021. 9 p.
No convencional en Español | LILACS | ID: biblio-1151432

RESUMEN

A la fecha, 141 los países/territorios han detectado casos de infección por alguna de las tres variantes de preocupación (VOC) reconocidas actualmente por la Organización Mundial de la Salud (OMS). De ese total, 32 países/territorios corresponden a la Región de las Américas.


Asunto(s)
Neumonía Viral/genética , ADN Viral/genética , Infecciones por Coronavirus/genética , Pandemias/prevención & control , Monitoreo Epidemiológico , Betacoronavirus/inmunología , Mutación , Américas/epidemiología
2.
Washington; Organización Panamericana de la Salud; feb. 9, 2021. 3 p.
No convencional en Español | LILACS | ID: biblio-1151287

RESUMEN

La secuenciación genómica ha sido una herramienta esencial para generar datos virológicos, impulsar la respuesta del laboratorio y comprender mejor los patrones evolutivos y de dispersión del SARS-CoV-2. Además de la caracterización de los patrones de circulación global, la detección temprana de las variantes del SARS-CoV-2 dentro de cada país es fundamental para complementar la vigilancia epidemiológica y virológica.


Asunto(s)
Neumonía Viral/genética , Infecciones por Coronavirus/genética , Pandemias/prevención & control , Betacoronavirus/aislamiento & purificación , Manejo de Especímenes , Monitoreo Epidemiológico
3.
Nature ; 590(7847): 635-641, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33429418

RESUMEN

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia2. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.


Asunto(s)
/inmunología , Macrófagos Alveolares/inmunología , Neumonía Viral/inmunología , Neumonía Viral/virología , Linfocitos T/inmunología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Estudios de Cohortes , Humanos , Interferón gamma/inmunología , Interferones/inmunología , Interferones/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/virología , Neumonía Viral/genética , RNA-Seq , Transducción de Señal/inmunología , Análisis de la Célula Individual , Linfocitos T/metabolismo , Factores de Tiempo
4.
Am J Hum Genet ; 108(1): 194-201, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33357513

RESUMEN

Given the coronavirus disease 2019 (COVID-19) pandemic, investigations into host susceptibility to infectious diseases and downstream sequelae have never been more relevant. Pneumonia is a lung disease that can cause respiratory failure and hypoxia and is a common complication of infectious diseases, including COVID-19. Few genome-wide association studies (GWASs) of host susceptibility and severity of pneumonia have been conducted. We performed GWASs of pneumonia susceptibility and severity in the Vanderbilt University biobank (BioVU) with linked electronic health records (EHRs), including Illumina Expanded Multi-Ethnic Global Array (MEGAEX)-genotyped European ancestry (EA, n= 69,819) and African ancestry (AA, n = 15,603) individuals. Two regions of large effect were identified: the CFTR locus in EA (rs113827944; OR = 1.84, p value = 1.2 × 10-36) and HBB in AA (rs334 [p.Glu7Val]; OR = 1.63, p value = 3.5 × 10-13). Mutations in these genes cause cystic fibrosis (CF) and sickle cell disease (SCD), respectively. After removing individuals diagnosed with CF and SCD, we assessed heterozygosity effects at our lead variants. Further GWASs after removing individuals with CF uncovered an additional association in R3HCC1L (rs10786398; OR = 1.22, p value = 3.5 × 10-8), which was replicated in two independent datasets: UK Biobank (n = 459,741) and 7,985 non-overlapping BioVU subjects, who are genotyped on arrays other than MEGAEX. This variant was also validated in GWASs of COVID-19 hospitalization and lung function. Our results highlight the importance of the host genome in infectious disease susceptibility and severity and offer crucial insight into genetic effects that could potentially influence severity of COVID-19 sequelae.


Asunto(s)
/complicaciones , Interacciones Huésped-Patógeno/genética , Neumonía Viral/complicaciones , Neumonía Viral/genética , Bronquitis/genética , /fisiopatología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Bases de Datos Genéticas , Registros Electrónicos de Salud , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Hemoglobinas/genética , Humanos , Pacientes Internos , Desequilibrio de Ligamiento , Masculino , Pacientes Ambulatorios , Neumonía Viral/patología , Neumonía Viral/fisiopatología , Polimorfismo de Nucleótido Simple/genética , Análisis de Componente Principal , Enfermedad Pulmonar Obstructiva Crónica/genética , Reproducibilidad de los Resultados , Reino Unido
5.
PLoS One ; 15(11): e0241264, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33201886

RESUMEN

BACKGROUND: Coronavirus disease 2019 (Covid-19) has rapidly infected millions of people worldwide. Recent studies suggest that racial minorities and patients with comorbidities are at higher risk of Covid-19. In this study, we analyzed the effects of clinical, regional, and genetic factors on Covid-19 positive status. METHODS: The UK Biobank is a longitudinal cohort study that recruited participants from 2006 to 2010 from throughout the United Kingdom. Covid-19 test results were provided to UK Biobank starting on March 16, 2020. The main outcome measure in this study was Covid-19 positive status, determined by the presence of any positive test for a single individual. Clinical risk factors were derived from UK Biobank at baseline, and regional risk factors were imputed using census features local to each participant's home zone. We used robust adjusted Poisson regression with clustering by testing laboratory to estimate relative risk. Blood types were derived using genetic variants rs8176719 and rs8176746, and genomewide tests of association were conducted using logistic-Firth hybrid regression. RESULTS: This prospective cohort study included 397,064 UK Biobank participants, of whom 968 tested positive for Covid-19. The unadjusted relative risk of Covid-19 for Black participants was 3.66 (95% CI 2.83-4.74), compared to White participants. Adjusting for Townsend deprivation index alone reduced the relative risk to 2.44 (95% CI 1.86-3.20). Comorbidities that significantly increased Covid-19 risk included chronic obstructive pulmonary disease (adjusted relative risk [ARR] 1.64, 95% CI 1.18-2.27), ischemic heart disease (ARR 1.48, 95% CI 1.16-1.89), and depression (ARR 1.32, 95% CI 1.03-1.70). There was some evidence that angiotensin converting enzyme inhibitors (ARR 1.48, 95% CI 1.13-1.93) were associated with increased risk of Covid-19. Each standard deviation increase in the number of total individuals living in a participant's locality was associated with increased risk of Covid-19 (ARR 1.14, 95% CI 1.08-1.20). Analyses of genetically inferred blood types confirmed that participants with type A blood had increased odds of Covid-19 compared to participants with type O blood (odds ratio [OR] 1.16, 95% CI 1.01-1.33). A meta-analysis of genomewide association studies across ancestry groups did not reveal any significant loci. Study limitations include confounding by indication, bias due to limited information on early Covid-19 test results, and inability to accurately gauge disease severity. CONCLUSIONS: When assessing the association of Black race with Covid-19, adjusting for deprivation reduced the relative risk of Covid-19 by 33%. In the context of sociological research, these findings suggest that discrimination in the labor market may play a role in the high relative risk of Covid-19 for Black individuals. In this study, we also confirmed the association of blood type A with Covid-19, among other clinical and regional factors.


Asunto(s)
Sistema del Grupo Sanguíneo ABO , Grupo de Ascendencia Continental Africana , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/genética , Neumonía Viral/epidemiología , Neumonía Viral/genética , Adulto , Anciano , Betacoronavirus , Bancos de Muestras Biológicas , Comorbilidad , Infecciones por Coronavirus/sangre , Depresión/epidemiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/epidemiología , Pandemias , Neumonía Viral/sangre , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Factores de Riesgo , Reino Unido/epidemiología
6.
Br J Community Nurs ; 25(11): 562-566, 2020 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-33161739

RESUMEN

In December 2019, a new species of coronavirus (SARS-CoV-2) was identified in a number of patients presenting with pneumonias of unknown aetiology in WuHan Province, China. Early epidemiological indications were of a zoonotic origin: many of the initial patients confirmed contact with a local wet market and the genomic sequencing showed similar characteristics with coronaviruses known to be carried by bats. The theory of subsequent human to human transmission became evident once global epidemiological reporting of COVID infection was established. Confirmation of the origins of infections caused by SARS-CoV-2 was enabled by the early sharing of the initial genomic sequence by China in January 2020 and since developed collaboratively on a globally accessible database, supported by the World Health Organization (https://tinyurl.com/rj32fp3).


Asunto(s)
Betacoronavirus/genética , Evolución Biológica , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/transmisión , Genómica , Neumonía Viral/genética , Neumonía Viral/transmisión , Zoonosis/genética , Zoonosis/transmisión , Animales , China/epidemiología , Infecciones por Coronavirus/epidemiología , Transmisión de Enfermedad Infecciosa , Humanos , Pandemias , Neumonía Viral/epidemiología
7.
J Genet ; 992020.
Artículo en Inglés | MEDLINE | ID: mdl-33168795

RESUMEN

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide and with notable heterogeneity in its clinical presentation. Probability of contracting this highly contagious infection is similar across age groups but disease severity and fatality among aged patients with or without comorbidities are reportedly higher. Previous studies suggest that age associated transcriptional changes in lung and immune system results in a proinflammatory state and increased susceptibility to infectious lung diseases. Similarly, SARS-CoV-2 infection could augment ageing-related gene expression alterations resulting in severe outcomes in elderly patients. To identify genes that can potentially increase covid-19 disease severity in ageing people, we compared age associated gene expression changes with disease-associated expression changes in lung/BALF and whole blood obtained from publicly available data. We observed (i) a significant overlap of gene expression profiles of patients' BALF and blood with lung and blood of the healthy group, respectively; (ii) a more pronounced overlap in blood compared to lung; and (iii) a similar overlap between host genes interacting with SARS-CoV-2 and ageing blood transcriptome. Pathway enrichment analysis of overlapping gene sets suggest that infection alters expression of genes already dysregulated in the elderly, which together may lead to poor prognosis. eQTLs in these genes may also confer poor outcome in young patients worsening with age and comorbidities. Further, the pronounced overlap observed in blood may explain clinical symptoms including blood clots, strokes, heart attack, multi-organ failure etc. in severe cases. This model based on a limited patient dataset seems robust and holds promise for testing larger tissue specific datasets from patients with varied severity and across populations.


Asunto(s)
Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/genética , Regulación de la Expresión Génica , Neumonía Viral/diagnóstico , Neumonía Viral/genética , Transcriptoma , Anciano , Betacoronavirus , Broncoconstricción , Estudios de Casos y Controles , Humanos , Pandemias , Pronóstico , Sitios de Carácter Cuantitativo
8.
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
9.
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
11.
Signal Transduct Target Ther ; 5(1): 256, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33139693

RESUMEN

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is spreading globally and poses a huge threat to human health. Besides common respiratory symptoms, some patients with COVID-19 experience gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and loss of appetite. SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2 (ACE2) and there is increasing evidence of a possible fecal-oral transmission route. In addition, there exist multiple abnormalities in liver enzymes. COVID-19-related liver injury may be due to drug-induced liver injury, systemic inflammatory reaction, and hypoxia-ischemia reperfusion injury. The direct toxic attack of SARS-CoV-2 on the liver is still questionable. This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Infecciones por Coronavirus/epidemiología , Enfermedades Gastrointestinales/epidemiología , Hepatopatías/epidemiología , Neumonía Viral/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/virología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Heces/virología , Enfermedades Gastrointestinales/complicaciones , Enfermedades Gastrointestinales/genética , Enfermedades Gastrointestinales/virología , Tracto Gastrointestinal/lesiones , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/virología , Humanos , Hígado/fisiopatología , Hígado/virología , Hepatopatías/genética , Hepatopatías/patología , Hepatopatías/virología , Pandemias , Peptidil-Dipeptidasa A/genética , Neumonía Viral/genética , Neumonía Viral/patología , Neumonía Viral/virología
12.
ACS Chem Neurosci ; 11(22): 3701-3703, 2020 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-33140636

RESUMEN

Cell entry, the fundamental step in cross-species transmission of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is initiated by the recognition of the host cell angiotensin-converting enzyme-2 (ACE2) receptor by the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. To date, several peptides have been proposed against SARS-CoV-2 both as inhibitor agents or as detection tools that can also be attached to the surfaces of nanoparticle carriers. But owing to their natural amino acid sequences, such peptides cannot be considered as efficient therapeutic candidates from a biostability point of view. This discussion demonstrates the design strategy of synthetic nonprotein amino acid substituted peptides with enhanced biostability and binding affinity, the implication of which can make those peptides potential therapeutic agents for inhibition and simple detection tools.


Asunto(s)
Antivirales/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Diseño de Fármacos , Fragmentos de Péptidos/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Secuencia de Aminoácidos , Antivirales/metabolismo , Betacoronavirus/efectos de los fármacos , Betacoronavirus/genética , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/metabolismo , Humanos , Pandemias , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Neumonía Viral/genética , Neumonía Viral/metabolismo , Unión Proteica/fisiología , Análisis de Secuencia de Proteína/métodos
13.
BMC Med ; 18(1): 346, 2020 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-33143712

RESUMEN

BACKGROUND: Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) are pivotal to detecting current coronavirus disease (COVID-19) and duration of detectable virus indicating potential for infectivity. METHODS: We conducted an individual participant data (IPD) systematic review of longitudinal studies of RT-PCR test results in symptomatic SARS-CoV-2. We searched PubMed, LitCOVID, medRxiv, and COVID-19 Living Evidence databases. We assessed risk of bias using a QUADAS-2 adaptation. Outcomes were the percentage of positive test results by time and the duration of detectable virus, by anatomical sampling sites. RESULTS: Of 5078 studies screened, we included 32 studies with 1023 SARS-CoV-2 infected participants and 1619 test results, from - 6 to 66 days post-symptom onset and hospitalisation. The highest percentage virus detection was from nasopharyngeal sampling between 0 and 4 days post-symptom onset at 89% (95% confidence interval (CI) 83 to 93) dropping to 54% (95% CI 47 to 61) after 10 to 14 days. On average, duration of detectable virus was longer with lower respiratory tract (LRT) sampling than upper respiratory tract (URT). Duration of faecal and respiratory tract virus detection varied greatly within individual participants. In some participants, virus was still detectable at 46 days post-symptom onset. CONCLUSIONS: RT-PCR misses detection of people with SARS-CoV-2 infection; early sampling minimises false negative diagnoses. Beyond 10 days post-symptom onset, lower RT or faecal testing may be preferred sampling sites. The included studies are open to substantial risk of bias, so the positivity rates are probably overestimated.


Asunto(s)
Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/diagnóstico , Neumonía Viral/diagnóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/normas , Betacoronavirus/genética , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/genética , Humanos , Estudios Longitudinales , Pandemias , Neumonía Viral/genética
14.
Comput Biol Med ; 126: 104051, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33131530

RESUMEN

SARS-CoV-2 has ushered a global pandemic with no effective drug being available at present. Although several FDA-approved drugs are currently under clinical trials for drug repositioning, there is an on-going global effort for new drug identification. In this paper, using multi-omics (interactome, proteome, transcriptome, and bibliome) data and subsequent integrated analysis, we present the biological events associated with SARS-CoV-2 infection and identify several candidate drugs against this viral disease. We found that: (i) Interactome-based infection pathways differ from the other three omics-based profiles. (ii) Viral process, mRNA splicing, cytokine and interferon signaling, and ubiquitin mediated proteolysis are important pathways in SARS-CoV-2 infection. (iii) SARS-CoV-2 infection also shares pathways with Influenza A, Epstein-Barr virus, HTLV-I, Measles, and Hepatitis virus. (iv) Further, bacterial, parasitic, and protozoan infection pathways such as Tuberculosis, Malaria, and Leishmaniasis are also shared by this virus. (v) A total of 50 candidate drugs, including the prophylaxis agents and pathway specific inhibitors are identified against COVID-19. (vi) Betamethasone, Estrogen, Simvastatin, Hydrocortisone, Tositumomab, Cyclosporin A etc. are among the important drugs. (vii) Ozone, Nitric oxide, plasma components, and photosensitizer drugs are also identified as possible therapeutic candidates. (viii) Curcumin, Retinoic acids, Vitamin D, Arsenic, Copper, and Zinc may be the candidate prophylaxis agents. Nearly 70% of our identified agents are previously suggested to have anti-COVID-19 effects or under clinical trials. Among our identified drugs, the ones that are not yet tested, need validation with caution while an appropriate drug combination from these candidate drugs along with a SARS-CoV-2 specific antiviral agent is needed for effective COVID-19 management.


Asunto(s)
Antivirales , Betacoronavirus , Infecciones por Coronavirus , Bases de Datos Genéticas , Descubrimiento de Drogas , Modelos Biológicos , Pandemias , Neumonía Viral , Antivirales/química , Antivirales/farmacocinética , Antivirales/uso terapéutico , Betacoronavirus/genética , Betacoronavirus/metabolismo , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/metabolismo , Humanos , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/genética , Neumonía Viral/metabolismo , Proteómica
15.
Biomed Pharmacother ; 131: 110738, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33152914

RESUMEN

The novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be considered as the most important current global issue, as it has caused the novel coronavirus disease (COVID-19) pandemic, which has resulted in high mortality and morbidity rates all around the world. Although scientists are trying to discover novel therapies and develop and evaluate various previous treatments, at the time of writing this paper, there was no definite therapy and vaccine for COVID-19. So, as COVID-19 has called ideas for treatment, controlling, and diagnosis, we discussed the application of Clustered Regularly Interspaced Short Palindromic Repeats/Cas13 (CRISPR/Cas13) as a treatment of COVID-19, which received less attention compared with other potential therapeutic options.


Asunto(s)
Betacoronavirus/genética , Sistemas CRISPR-Cas , Infecciones por Coronavirus/terapia , Edición Génica , Terapia Genética/métodos , Neumonía Viral/terapia , ARN Viral/genética , Betacoronavirus/efectos de los fármacos , Proteínas Asociadas a CRISPR/farmacología , Secuencia Conservada , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/genética , Genoma Viral , Humanos , Pandemias , Neumonía Viral/genética , ARN Guia/genética , ARN Viral/antagonistas & inhibidores
16.
Lancet Neurol ; 19(11): 919-929, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33031735

RESUMEN

BACKGROUND: Prominent clinical symptoms of COVID-19 include CNS manifestations. However, it is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, gains access to the CNS and whether it causes neuropathological changes. We investigated the brain tissue of patients who died from COVID-19 for glial responses, inflammatory changes, and the presence of SARS-CoV-2 in the CNS. METHODS: In this post-mortem case series, we investigated the neuropathological features in the brains of patients who died between March 13 and April 24, 2020, in Hamburg, Germany. Inclusion criteria comprised a positive test for SARS-CoV-2 by quantitative RT-PCR (qRT-PCR) and availability of adequate samples. We did a neuropathological workup including histological staining and immunohistochemical staining for activated astrocytes, activated microglia, and cytotoxic T lymphocytes in the olfactory bulb, basal ganglia, brainstem, and cerebellum. Additionally, we investigated the presence and localisation of SARS-CoV-2 by qRT-PCR and by immunohistochemistry in selected patients and brain regions. FINDINGS: 43 patients were included in our study. Patients died in hospitals, nursing homes, or at home, and were aged between 51 years and 94 years (median 76 years [IQR 70-86]). We detected fresh territorial ischaemic lesions in six (14%) patients. 37 (86%) patients had astrogliosis in all assessed regions. Activation of microglia and infiltration by cytotoxic T lymphocytes was most pronounced in the brainstem and cerebellum, and meningeal cytotoxic T lymphocyte infiltration was seen in 34 (79%) patients. SARS-CoV-2 could be detected in the brains of 21 (53%) of 40 examined patients, with SARS-CoV-2 viral proteins found in cranial nerves originating from the lower brainstem and in isolated cells of the brainstem. The presence of SARS-CoV-2 in the CNS was not associated with the severity of neuropathological changes. INTERPRETATION: In general, neuropathological changes in patients with COVID-19 seem to be mild, with pronounced neuroinflammatory changes in the brainstem being the most common finding. There was no evidence for CNS damage directly caused by SARS-CoV-2. The generalisability of these findings needs to be validated in future studies as the number of cases and availability of clinical data were low and no age-matched and sex-matched controls were included. FUNDING: German Research Foundation, Federal State of Hamburg, EU (eRARE), German Center for Infection Research (DZIF).


Asunto(s)
Betacoronavirus/aislamiento & purificación , Encéfalo/patología , Encéfalo/virología , Infecciones por Coronavirus/patología , Neumonía Viral/patología , Anciano , Anciano de 80 o más Años , Autopsia/métodos , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/genética , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Neuropatología , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/genética , Transcriptoma/genética
18.
Hum Genomics ; 14(1): 35, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33008459

RESUMEN

Precision medicine aims to empower clinicians to predict the most appropriate course of action for patients with complex diseases like cancer, diabetes, cardiomyopathy, and COVID-19. With a progressive interpretation of the clinical, molecular, and genomic factors at play in diseases, more effective and personalized medical treatments are anticipated for many disorders. Understanding patient's metabolomics and genetic make-up in conjunction with clinical data will significantly lead to determining predisposition, diagnostic, prognostic, and predictive biomarkers and paths ultimately providing optimal and personalized care for diverse, and targeted chronic and acute diseases. In clinical settings, we need to timely model clinical and multi-omics data to find statistical patterns across millions of features to identify underlying biologic pathways, modifiable risk factors, and actionable information that support early detection and prevention of complex disorders, and development of new therapies for better patient care. It is important to calculate quantitative phenotype measurements, evaluate variants in unique genes and interpret using ACMG guidelines, find frequency of pathogenic and likely pathogenic variants without disease indicators, and observe autosomal recessive carriers with a phenotype manifestation in metabolome. Next, ensuring security to reconcile noise, we need to build and train machine-learning prognostic models to meaningfully process multisource heterogeneous data to identify high-risk rare variants and make medically relevant predictions. The goal, today, is to facilitate implementation of mainstream precision medicine to improve the traditional symptom-driven practice of medicine, and allow earlier interventions using predictive diagnostics and tailoring better-personalized treatments. We strongly recommend automated implementation of cutting-edge technologies, utilizing machine learning (ML) and artificial intelligence (AI) approaches for the multimodal data aggregation, multifactor examination, development of knowledgebase of clinical predictors for decision support, and best strategies for dealing with relevant ethical issues.


Asunto(s)
Infecciones por Coronavirus/genética , Diabetes Mellitus/genética , Neoplasias/genética , Neumonía Viral/genética , Medicina de Precisión/tendencias , Cardiomiopatías , Infecciones por Coronavirus/epidemiología , Análisis de Datos , Diabetes Mellitus/epidemiología , Genómica/tendencias , Humanos , Metabolómica/tendencias , Neoplasias/epidemiología , Pandemias , Neumonía Viral/epidemiología , Proteómica/tendencias
19.
Hum Genomics ; 14(1): 36, 2020 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-33036646

RESUMEN

INTRODUCTION: The course of COVID-19 varies from asymptomatic to severe in patients. The basis for this range in symptoms is unknown. One possibility is that genetic variation is partly responsible for the highly variable response. We evaluated how well a genetic risk score based on chromosomal-scale length variation and machine learning classification algorithms could predict severity of response to SARS-CoV-2 infection. METHODS: We compared 981 patients from the UK Biobank dataset who had a severe reaction to SARS-CoV-2 infection before 27 April 2020 to a similar number of age-matched patients drawn for the general UK Biobank population. For each patient, we built a profile of 88 numbers characterizing the chromosomal-scale length variability of their germ line DNA. Each number represented one quarter of the 22 autosomes. We used the machine learning algorithm XGBoost to build a classifier that could predict whether a person would have a severe reaction to COVID-19 based only on their 88-number classification. RESULTS: We found that the XGBoost classifier could differentiate between the two classes at a significant level (p = 2 · 10-11) as measured against a randomized control and (p = 3 · 10-14) as measured against the expected value of a random guessing algorithm (AUC = 0.5). However, we found that the AUC of the classifier was only 0.51, too low for a clinically useful test. CONCLUSION: Genetics play a role in the severity of COVID-19, but we cannot yet develop a useful genetic test to predict severity.


Asunto(s)
Algoritmos , Betacoronavirus/aislamiento & purificación , Aberraciones Cromosómicas , Cromosomas Humanos/genética , Infecciones por Coronavirus/diagnóstico , Aprendizaje Automático , Neumonía Viral/diagnóstico , Índice de Severidad de la Enfermedad , Betacoronavirus/genética , Estudios de Casos y Controles , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Conjuntos de Datos como Asunto , Humanos , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/genética , Neumonía Viral/virología , Factores de Riesgo
20.
Signal Transduct Target Ther ; 5(1): 235, 2020 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-33037188

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.


Asunto(s)
Apoptosis/inmunología , Betacoronavirus/patogenicidad , Caspasa 8/inmunología , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Necroptosis/inmunología , Neumonía Viral/inmunología , Fibrosis Pulmonar/inmunología , Animales , Caspasa 8/genética , Línea Celular Tumoral , Quimiocina CCL5/genética , Quimiocina CCL5/inmunología , Quimiocina CXCL10/genética , Quimiocina CXCL10/inmunología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/virología , Modelos Animales de Enfermedad , Células Epiteliales/inmunología , Células Epiteliales/patología , Células Epiteliales/virología , Regulación de la Expresión Génica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-7/genética , Interleucina-7/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Ratones , Ratones Transgénicos , Pandemias , Neumonía Viral/genética , Neumonía Viral/patología , Neumonía Viral/virología , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/virología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
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