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1.
Am J Hum Genet ; 108(1): 194-201, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33357513

RESUMO

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.


Assuntos
/complicações , Interações Hospedeiro-Patógeno/genética , Pneumonia Viral/complicações , Pneumonia Viral/genética , Bronquite/genética , /fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Bases de Dados Genéticas , Registros Eletrônicos de Saúde , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hemoglobinas/genética , Humanos , Pacientes Internados , Desequilíbrio de Ligação , Masculino , Pacientes Ambulatoriais , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal , Doença Pulmonar Obstrutiva Crônica/genética , Reprodutibilidade dos Testes , Reino Unido
2.
Sci Rep ; 10(1): 19395, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173052

RESUMO

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.


Assuntos
Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Perfilação da Expressão Gênica , Pulmão/metabolismo , Terapia de Alvo Molecular , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Surfactantes Pulmonares/metabolismo , Biologia de Sistemas , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Epigênese Genética , Humanos , Pulmão/efeitos dos fármacos , Especificidade de Órgãos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Proteínas Virais/metabolismo
3.
ACS Chem Neurosci ; 11(22): 3701-3703, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33140636

RESUMO

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.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Desenho de Fármacos , Fragmentos de Peptídeos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Sequência de Aminoácidos , Antivirais/metabolismo , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Ligação Proteica/fisiologia , Análise de Sequência de Proteína/métodos
4.
PLoS One ; 15(11): e0241264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33201886

RESUMO

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.


Assuntos
Sistema ABO de Grupos Sanguíneos , Grupo com Ancestrais do Continente Africano , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Adulto , Idoso , Betacoronavirus , Bancos de Espécimes Biológicos , Comorbidade , Infecções por Coronavirus/sangue , Depressão/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/epidemiologia , Pandemias , Pneumonia Viral/sangue , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fatores de Risco , Reino Unido/epidemiologia
5.
J Genet ; 992020.
Artigo em Inglês | MEDLINE | ID: mdl-33168795

RESUMO

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.


Assuntos
Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/genética , Regulação da Expressão Gênica , Pneumonia Viral/diagnóstico , Pneumonia Viral/genética , Transcriptoma , Idoso , Betacoronavirus , Broncoconstrição , Estudos de Casos e Controles , Humanos , Pandemias , Prognóstico , Locos de Características Quantitativas
6.
Br J Community Nurs ; 25(11): 562-566, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33161739

RESUMO

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).


Assuntos
Betacoronavirus/genética , Evolução Biológica , Infecções por Coronavirus/genética , Infecções por Coronavirus/transmissão , Genômica , Pneumonia Viral/genética , Pneumonia Viral/transmissão , Zoonoses/genética , Zoonoses/transmissão , Animais , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Transmissão de Doença Infecciosa , Humanos , Pandemias , Pneumonia Viral/epidemiologia
8.
Comput Biol Med ; 126: 104051, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33131530

RESUMO

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.


Assuntos
Antivirais , Betacoronavirus , Infecções por Coronavirus , Bases de Dados Genéticas , Descoberta de Drogas , Modelos Biológicos , Pandemias , Pneumonia Viral , Antivirais/química , Antivirais/farmacocinética , Antivirais/uso terapêutico , Betacoronavirus/genética , Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Proteômica
9.
BMC Med ; 18(1): 346, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33143712

RESUMO

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.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normas , Betacoronavirus/genética , Técnicas de Laboratório Clínico , Infecções por Coronavirus/genética , Humanos , Estudos Longitudinais , Pandemias , Pneumonia Viral/genética
10.
Biomed Pharmacother ; 131: 110738, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33152914

RESUMO

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.


Assuntos
Betacoronavirus/genética , Sistemas CRISPR-Cas , Infecções por Coronavirus/terapia , Edição de Genes , Terapia Genética/métodos , Pneumonia Viral/terapia , RNA Viral/genética , Betacoronavirus/efeitos dos fármacos , Proteínas Associadas a CRISPR/farmacologia , Sequência Conservada , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Genoma Viral , Humanos , Pandemias , Pneumonia Viral/genética , RNA Guia/genética , RNA Viral/antagonistas & inibidores
11.
Int J Med Sci ; 17(18): 3125-3145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173434

RESUMO

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.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa/métodos , Fitoterapia/métodos , Pneumonia Viral/tratamento farmacológico , Algoritmos , Antivirais/isolamento & purificação , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Desenvolvimento de Medicamentos , Medicamentos de Ervas Chinesas/classificação , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Pandemias , Fitoterapia/classificação , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
12.
Signal Transduct Target Ther ; 5(1): 256, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139693

RESUMO

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.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Infecções por Coronavirus/epidemiologia , Gastroenteropatias/epidemiologia , Hepatopatias/epidemiologia , Pneumonia Viral/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Fezes/virologia , Gastroenteropatias/complicações , Gastroenteropatias/genética , Gastroenteropatias/virologia , Trato Gastrointestinal/lesões , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Humanos , Fígado/fisiopatologia , Fígado/virologia , Hepatopatias/genética , Hepatopatias/patologia , Hepatopatias/virologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia
13.
Invest Ophthalmol Vis Sci ; 61(12): 13, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33049061

RESUMO

Purpose: The coronavirus disease 2019 (COVID-19) pandemic severely challenges public health and necessitates the need for increasing our understanding of COVID-19 pathogenesis, especially host factors facilitating virus infection and propagation. The aim of this study was to investigate key factors for cellular susceptibility to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection in the ocular surface cells. Methods: We combined co-expression and SARS-CoV-2 interactome network to predict key genes at COVID-19 in ocular infection based on the premise that genes underlying a disease are often functionally related and functionally related genes are often co-expressed. Results: The co-expression network was constructed by mapping the well-known angiotensin converting enzyme (ACE2), TMPRSS2, and host susceptibility genes implicated in COVID-19 genomewide association study (GWAS) onto a cornea, retinal pigment epithelium, and lung. We found a significant co-expression module of these genes in the cornea, revealing that cornea is potential extra-respiratory entry portal of SARS-CoV-2. Strikingly, both co-expression and interaction networks show a significant enrichment in mitochondrial function, which are the hub of cellular oxidative homeostasis, inflammation, and innate immune response. We identified a corneal mitochondrial susceptibility module (CMSM) of 14 mitochondrial genes by integrating ACE2 co-expression cluster and SARS-CoV-2 interactome. The gene ECSIT, as a cytosolic adaptor protein involved in inflammatory responses, exhibits the strongest correlation with ACE2 in CMSM, which has shown to be an important risk factor for SARS-CoV-2 infection and prognosis. Conclusions: Our co-expression and protein interaction network analysis uncover that the mitochondrial function related genes in cornea contribute to the dissection of COVID-19 susceptibility and potential therapeutic interventions.


Assuntos
Betacoronavirus , Córnea/metabolismo , Infecções por Coronavirus/genética , Regulação da Expressão Gênica , Genes Mitocondriais/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , RNA/genética , Linhagem Celular , Córnea/patologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Peptidil Dipeptidase A/biossíntese , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo
14.
Mol Med ; 26(1): 95, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054759

RESUMO

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.


Assuntos
Infecções por Coronavirus/imunologia , Epigênese Genética/imunologia , Fibrose Pulmonar Idiopática/imunologia , Mecanotransdução Celular/imunologia , Pneumonia Viral/imunologia , Embolia Pulmonar/imunologia , Insuficiência Respiratória/imunologia , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Fenômenos Biomecânicos , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/virologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/patologia , Mecanotransdução Celular/genética , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Embolia Pulmonar/genética , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Insuficiência Respiratória/virologia , Estresse Mecânico
15.
ACS Chem Neurosci ; 11(22): 3697-3700, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33119251

RESUMO

Of the single-celled eukaryotic microbes, Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp. are known to cause fatal encephalitis in humans. Being eukaryotes, these cells have been used as a model for studying and understanding complex cellular processes in humans like cell motility, phagocytosis, and metabolism. The ongoing pandemic caused by SARS-CoV-2 that infects multiple organs has emerged as a challenge to unravel its mode of infection and the pathogenicity resulting in eukaryotic cell death. Working with these single-celled eukaryotic microbes provided us the opportunity to plan bioinformatic approaches to look into the likelihood of studying the known and alternative mode of infection of the SARS-CoV-2 in eukaryotic cells. Genome databases of N. fowleri, B. mandrillaris, and Acanthamoeba spp. were used to explore the expression of angiotensin-converting enzyme 2 (ACE2), androgen-regulated serine protease precursor (TMPRSS2), CD4, CD147, and furin that are known to be cardinal for SARS-CoV-2 in recognition and binding to human cells. It was hypothesized that if a receptor-dependent or phagocytosis-assisted SARS-CoV-2 uptake does occur in free-living amoebae (FLA), this model can provide an alternative to human cells to study cellular recognition and binding of SARS-CoV-2 that can help design drugs and treatment modalities in COVID-19. We show that, of the FLA, ACE2 and TMPRSS2 are not expressed in Acanthamoeba spp. and B. mandrillaris, but primitive forms of these cell recognition proteins were seen to be encoded in N. fowleri. Acanthamoeba spp. and N. fowleri encode for human-like furin which is a known SARS-CoV-2 spike protein involved in host cell recognition and binding.


Assuntos
Amoeba/virologia , Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Modelos Animais de Doenças , Pneumonia Viral/fisiopatologia , Sequência de Aminoácidos , Amoeba/genética , Animais , Betacoronavirus/genética , Infecções por Coronavirus/genética , Humanos , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Estrutura Secundária de Proteína , Tropismo Viral/fisiologia
16.
Int J Biol Sci ; 16(15): 3028-3036, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061814

RESUMO

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, with acute respiratory failure as the most significant symptom, has led to a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is considered as the most important receptor of SARS-CoV-2 and wildly expressed in human tissues. Whereas, the extremely low expression of ACE2 in lung could hardly interpret the severe symptom of pneumonia in COVID-19 patients. Here we profiled two SARS-CoV-2 infection related genes, the transmembrane serine protease 2 (TMPRSS2) and the interferon-inducible transmembrane protein 3 (IFITM3), in human tissues and organs. Consistent with the expression and distribution of ACE2, TMPRSS2 was also highly expressed in digestive, urinary and reproductive systems, but low expressed in lung. Notably, the anti-virus protein IFITM3 also expressed much lower in lung than other tissues, which might be related to the severe lung symptoms of COVID-19. In addition, the low expression of IFITM3 in immune cells suggested that SARS-CoV-2 might attack lymphocytes and induce the cytokine release syndrome (CRS). Furthermore, cancer patients were considered as more susceptible to SARS-CoV-2 infection. Our data supposed that fourteen types of tumors might have different susceptibility to the virus according to ACE2, TMPRSS2 and IFITM3 expression patterns. Interestingly the prognosis of six types of cancers including breast carcinoma (BRCA), lung adenocarcinoma (LUAD), uterine corpus endometrial carcinoma (UCEC), renal clear cell carcinoma (KIRC), prostate adenocarcinoma (PRAD), and hepatocellular carcinoma (LIHC) were closely related to these gene expressions. Our study explored the expression and distribution profiles of two potential novel molecules that might participate in SARS-CoV-2 infection and involved in immunity, which may provide a functional basis for preventing infection of SARS-CoV-2.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/fisiologia , Neoplasias/metabolismo , Proteínas de Ligação a RNA/fisiologia , Receptores Virais/fisiologia , Serina Endopeptidases/fisiologia , Betacoronavirus , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Análise Mutacional de DNA , Regulação da Expressão Gênica , Voluntários Saudáveis , Humanos , Proteínas de Membrana/genética , Neoplasias/diagnóstico , Neoplasias/genética , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Prognóstico , Proteínas de Ligação a RNA/genética , Receptores Virais/genética , Serina Endopeptidases/genética , Distribuição Tecidual
17.
Lancet Neurol ; 19(11): 919-929, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33031735

RESUMO

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).


Assuntos
Betacoronavirus/isolamento & purificação , Encéfalo/patologia , Encéfalo/virologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia/métodos , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neuropatologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Transcriptoma/genética
18.
Sci Rep ; 10(1): 17628, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077837

RESUMO

Genes are organized in functional modules (or pathways), thus their action and their dysregulation in diseases may be better understood by the identification of the modules most affected by the disease (aka disease modules, or active subnetworks). We describe how an algorithm based on the Core&Peel method is used to detect disease modules in co-expression networks of genes. We first validate Core&Peel for the general task of functional module detection by comparison with 42 methods participating in the Disease Module Identification DREAM challenge. Next, we use four specific disease test cases (colorectal cancer, prostate cancer, asthma, and rheumatoid arthritis), four state-of-the-art algorithms (ModuleDiscoverer, Degas, KeyPathwayMiner, and ClustEx), and several pathway databases to validate the proposed algorithm. Core&Peel is the only method able to find significant associations of the predicted disease module with known validated relevant pathways for all four diseases. Moreover, for the two cancer datasets, Core&Peel detects further eight relevant pathways not discovered by the other methods used in the comparative analysis. Finally, we apply Core&Peel and other methods to explore the transcriptional response of human cells to SARS-CoV-2 infection, finding supporting evidence for drug repositioning efforts at a pre-clinical level.


Assuntos
Algoritmos , Infecções por Coronavirus/patologia , Redes Reguladoras de Genes/genética , Neoplasias/patologia , Pneumonia Viral/patologia , Infecções por Coronavirus/genética , Bases de Dados Genéticas , Reposicionamento de Medicamentos , Perfilação da Expressão Gênica , Ontologia Genética , Estudo de Associação Genômica Ampla , Humanos , Neoplasias/genética , Pandemias , Pneumonia Viral/genética , Interface Usuário-Computador
19.
Clin Epigenetics ; 12(1): 156, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087172

RESUMO

Epigenetics is a relatively new field of science that studies the genetic and non-genetic aspects related to heritable phenotypic changes, frequently caused by environmental and metabolic factors. In the host, the epigenetic machinery can regulate gene expression through a series of reversible epigenetic modifications, such as histone methylation and acetylation, DNA/RNA methylation, chromatin remodeling, and non-coding RNAs. The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, and spread worldwide, causes it. COVID-19 severity and consequences largely depend on patient age and health status. In this review, we will summarize and comparatively analyze how viruses regulate the host epigenome. Mainly, we will be focusing on highly pathogenic respiratory RNA virus infections such as coronaviruses. In this context, epigenetic alterations might play an essential role in the onset of coronavirus disease complications. Although many therapeutic approaches are under study, more research is urgently needed to identify effective vaccine or safer chemotherapeutic drugs, including epigenetic drugs, to cope with this viral outbreak and to develop pre- and post-exposure prophylaxis against COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Epigênese Genética , Regulação Viral da Expressão Gênica , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/imunologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Inflamação/imunologia , Pandemias , Pneumonia Viral/imunologia , Processamento Pós-Transcricional do RNA
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