Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 641
Filtrar
1.
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
2.
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
3.
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
4.
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
5.
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
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.
Emerg Microbes Infect ; 9(1): 2379-2380, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33059515

RESUMO

This commentary provides an overview and links to presentations of a recent virtual congress series organized by the International Society for Vaccines (ISV) focused on COVID-19 vaccines. The series provided the academic community and vaccine developers as well as the wider general public with balanced information of the global response and resources for COVID-19 vaccines under development featuring: 1) NGOs and the regulatory perspective, 2) the status of vaccine development efforts, and 3) panel discussions to present and discuss challenges. ISV is a non-profit scientific organization whose members work on all areas relevant to vaccines. ISV plans to host additional virtual symposia including regional meetings and incorporating other topics along with COVID-19 vaccines.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Desenvolvimento de Medicamentos/tendências , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
9.
Vaccine ; 38(48): 7612-7628, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33082015

RESUMO

SARS-CoV-2 causes a severe respiratory disease called COVID-19. Currently, global health is facing its devastating outbreak. However, there is no vaccine available against this virus up to now. In this study, a novel multi-epitope vaccine against SARS-CoV-2 was designed to provoke both innate and adaptive immune responses. The immunodominant regions of six non-structural proteins (nsp7, nsp8, nsp9, nsp10, nsp12 and nsp14) of SARS-CoV-2 were selected by multiple immunoinformatic tools to provoke T cell immune response. Also, immunodominant fragment of the functional region of SARS-CoV-2 spike (400-510 residues) protein was selected for inducing neutralizing antibodies production. The selected regions' sequences were connected to each other by furin-sensitive linker (RVRR). Moreover, the functional region of ß-defensin as a well-known agonist for the TLR-4/MD complex was added at the N-terminus of the vaccine using (EAAAK)3 linker. Also, a CD4 + T-helper epitope, PADRE, was used at the C-terminal of the vaccine by GPGPG and A(EAAAK)2A linkers to form the final vaccine construct. The physicochemical properties, allergenicity, antigenicity, functionality and population coverage of the final vaccine construct were analyzed. The final vaccine construct was an immunogenic, non-allergen and unfunctional protein which contained multiple CD8 + and CD4 + overlapping epitopes, IFN-γ inducing epitopes, linear and conformational B cell epitopes. It could form stable and significant interactions with TLR-4/MD according to molecular docking and dynamics simulations. Global population coverage of the vaccine for HLA-I and II were estimated 96.2% and 97.1%, respectively. At last, the final vaccine construct was reverse translated to design the DNA vaccine. Although the designed vaccine exhibited high efficacy in silico, further experimental validation is necessary.


Assuntos
Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Glicoproteína da Espícula de Coronavírus/imunologia , Proteínas não Estruturais Virais/imunologia , Vacinas Virais/biossíntese , Sequência de Aminoácidos , Betacoronavirus/patogenicidade , Biologia Computacional , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunogenicidade da Vacina , Simulação de Acoplamento Molecular , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Ligação Proteica , Estrutura Secundária de Proteína , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Vacinas Atenuadas , Vacinas de DNA , Vacinas de Subunidades , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Vacinas Virais/genética , Vacinas Virais/metabolismo
10.
Zool Res ; 41(6): 621-631, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33045777

RESUMO

Understanding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clarifying antiviral immunity in hosts are critical aspects for the development of vaccines and antivirals. Mice are frequently used to generate animal models of infectious diseases due to their convenience and ability to undergo genetic manipulation. However, normal adult mice are not susceptible to SARS-CoV-2. Here, we developed a viral receptor (human angiotensin-converting enzyme 2, hACE2) pulmonary transfection mouse model to establish SARS-CoV-2 infection rapidly in the mouse lung. Based on the model, the virus successfully infected the mouse lung 2 days after transfection. Viral RNA/protein, innate immune cell infiltration, inflammatory cytokine expression, and pathological changes in the infected lungs were observed after infection. Further studies indicated that neutrophils were the first and most abundant leukocytes to infiltrate the infected lungs after viral infection. In addition, using infected CXCL5-knockout mice, chemokine CXCL5 was responsible for neutrophil recruitment. CXCL5 knockout decreased lung inflammation without diminishing viral clearance, suggesting a potential target for controlling pneumonia.


Assuntos
Betacoronavirus/imunologia , Quimiocina CXCL5/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata/imunologia , Neutrófilos/imunologia , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Animais , Betacoronavirus/genética , Betacoronavirus/fisiologia , Linhagem Celular , Quimiocina CXCL5/genética , Quimiocina CXCL5/metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neutrófilos/metabolismo , Neutrófilos/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/virologia
11.
Hum Genomics ; 14(1): 36, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33036646

RESUMO

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.


Assuntos
Algoritmos , Betacoronavirus/isolamento & purificação , Aberrações Cromossômicas , Cromossomos Humanos/genética , Infecções por Coronavirus/diagnóstico , Aprendizado de Máquina , Pneumonia Viral/diagnóstico , Índice de Gravidade de Doença , Betacoronavirus/genética , Estudos de Casos e Controles , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Conjuntos de Dados como Assunto , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/virologia , Fatores de Risco
13.
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
14.
Viruses ; 12(10)2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33092124

RESUMO

RNA interference (RNAi) represents a novel approach for alternative antiviral therapy. However, issues related to RNA delivery and stability have presented serious obstacles for obtaining good therapeutic efficacy. Viral vectors are capable of efficient delivery of RNAi as short interfering RNA (siRNA), short hairpin RNA (shRNA) and micro-RNA (miRNA). Efficacy in gene silencing for therapeutic applications against viral diseases has been demonstrated in various animal models. Rotavirus (RV) miR-7 can inhibit rotavirus replication by targeting the RV nonstructural protein 5. Viral gene silencing by targeting the RNAi pathway showed efficient suppression of hepatitis B virus replication by adeno-associated virus (AAV)-based delivery of RNAi hepatitis B virus (HBV) cassettes. Hepatitis C virus replication has been targeted by short hairpin RNA molecules expressed from lentivirus vectors. Potentially, RNAi-based approaches could be suitable for antiviral drugs against COVID-19.


Assuntos
Infecções por Coronavirus/terapia , Vetores Genéticos/administração & dosagem , Pneumonia Viral/terapia , Interferência de RNA , Terapêutica com RNAi/métodos , Animais , Antivirais/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Vetores Genéticos/genética , Humanos , MicroRNAs/genética , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/virologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética
17.
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
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
20.
Front Immunol ; 11: 574593, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072117

RESUMO

Familial Mediterranean Fever (FMF) and COVID-19 show a remarkable overlap of clinical symptoms and similar laboratory findings. Both are characterized by fever, abdominal/chest pain, elevation of C-reactive protein, and leukocytosis. In addition, colchicine and IL-1 inhibitors treatments that are effective in controlling inflammation in FMF patients have recently been proposed for off-label use in COVID-19 patients. Thus, FMF may resemble a milder recapitulation of the cytokine storm that is a hallmark of COVID-19 patients progressing to severe disease. We analyzed the sequence of the MEFV-encoded Pyrin protein - whose mutations cause FMF- in mammals, bats and pangolin. Intriguingly, although Pyrin is extremely conserved in species that are considered either a reservoir or intermediate hosts for SARS-CoV-2, some of the most common FMF-causing variants in humans are present as wildtype residues in these species. We propose that in humans, Pyrin may have evolved to fight highly pathogenic infections.


Assuntos
Betacoronavirus , Colchicina/uso terapêutico , Infecções por Coronavirus , Febre Familiar do Mediterrâneo , Mutação , Pandemias , Pneumonia Viral , Pirina , Animais , Betacoronavirus/genética , Betacoronavirus/imunologia , Proteína C-Reativa/genética , Proteína C-Reativa/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/imunologia , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pirina/genética , Pirina/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA