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1.
Cells ; 10(6)2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200572

RESUMO

The implications of the microbiome on Coronavirus disease 2019 (COVID-19) prognosis has not been thoroughly studied. In this study we aimed to characterize the lung and blood microbiome and their implication on COVID-19 prognosis through analysis of peripheral blood mononuclear cell (PBMC) samples, lung biopsy samples, and bronchoalveolar lavage fluid (BALF) samples. In all three tissue types, we found panels of microbes differentially abundant between COVID-19 and normal samples correlated to immune dysregulation and upregulation of inflammatory pathways, including key cytokine pathways such as interleukin (IL)-2, 3, 5-10 and 23 signaling pathways and downregulation of anti-inflammatory pathways including IL-4 signaling. In the PBMC samples, six microbes were correlated with worse COVID-19 severity, and one microbe was correlated with improved COVID-19 severity. Collectively, our findings contribute to the understanding of the human microbiome and suggest interplay between our identified microbes and key inflammatory pathways which may be leveraged in the development of immune therapies for treating COVID-19 patients.


Assuntos
COVID-19/diagnóstico , Leucócitos Mononucleares/microbiologia , Pulmão/microbiologia , Microbiota/fisiologia , Líquido da Lavagem Broncoalveolar/microbiologia , Líquido da Lavagem Broncoalveolar/virologia , COVID-19/imunologia , COVID-19/microbiologia , COVID-19/virologia , Estudos de Casos e Controles , Humanos , Leucócitos Mononucleares/virologia , Biópsia Líquida , Pulmão/patologia , Pulmão/virologia , Microbiota/genética , Microbiota/imunologia , Prognóstico , RNA Bacteriano/análise , RNA Fúngico/análise , RNA-Seq , SARS-CoV-2/fisiologia
2.
Cells ; 10(6)2021 06 10.
Artigo em Inglês | MEDLINE | ID: covidwho-1264420

RESUMO

The implications of the microbiome on Coronavirus disease 2019 (COVID-19) prognosis has not been thoroughly studied. In this study we aimed to characterize the lung and blood microbiome and their implication on COVID-19 prognosis through analysis of peripheral blood mononuclear cell (PBMC) samples, lung biopsy samples, and bronchoalveolar lavage fluid (BALF) samples. In all three tissue types, we found panels of microbes differentially abundant between COVID-19 and normal samples correlated to immune dysregulation and upregulation of inflammatory pathways, including key cytokine pathways such as interleukin (IL)-2, 3, 5-10 and 23 signaling pathways and downregulation of anti-inflammatory pathways including IL-4 signaling. In the PBMC samples, six microbes were correlated with worse COVID-19 severity, and one microbe was correlated with improved COVID-19 severity. Collectively, our findings contribute to the understanding of the human microbiome and suggest interplay between our identified microbes and key inflammatory pathways which may be leveraged in the development of immune therapies for treating COVID-19 patients.


Assuntos
COVID-19/diagnóstico , Leucócitos Mononucleares/microbiologia , Pulmão/microbiologia , Microbiota/fisiologia , Líquido da Lavagem Broncoalveolar/microbiologia , Líquido da Lavagem Broncoalveolar/virologia , COVID-19/imunologia , COVID-19/microbiologia , COVID-19/virologia , Estudos de Casos e Controles , Humanos , Leucócitos Mononucleares/virologia , Biópsia Líquida , Pulmão/patologia , Pulmão/virologia , Microbiota/genética , Microbiota/imunologia , Prognóstico , RNA Bacteriano/análise , RNA Fúngico/análise , RNA-Seq , SARS-CoV-2/fisiologia
3.
Nat Commun ; 12(1): 4068, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210968

RESUMO

SARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide-a well-tolerated drug widely used in advanced prostate cancer-reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.


Assuntos
Antagonistas de Androgênios/farmacologia , Benzamidas/farmacologia , COVID-19/tratamento farmacológico , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Serina Endopeptidases/metabolismo , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/síntese química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , COVID-19/virologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Pulmão/metabolismo , Pulmão/virologia , Masculino , Camundongos , SARS-CoV-2/efeitos dos fármacos , Serina Endopeptidases/genética
4.
Dis Model Mech ; 14(6)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34219165

RESUMO

The COVID-19 pandemic has emphasised the need to develop effective treatments to combat emerging viruses. Model systems that poorly represent a virus' cellular environment, however, may impede research and waste resources. Collaborations between cell biologists and virologists have led to the rapid development of representative organoid model systems to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We believe that lung organoids, in particular, have advanced our understanding of SARS-CoV-2 pathogenesis, and have laid a foundation to study future pandemic viruses and develop effective treatments.


Assuntos
COVID-19/virologia , Pulmão/virologia , Modelos Biológicos , Organoides/virologia , SARS-CoV-2 , Animais , COVID-19/epidemiologia , Humanos , Pandemias , Alvéolos Pulmonares/virologia , Projetos de Pesquisa/tendências , SARS-CoV-2/patogenicidade
5.
Viruses ; 13(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202029

RESUMO

The current COVID-19 pandemic has highlighted the urgent need to develop effective therapeutic strategies. We evaluated the in vitro antiviral effect against SARS-CoV-2 of a hepatitis B virus (HBV) hexamer peptide, Poly6, which is capable of eliciting an antiviral effect against human immunodeficiency virus -1 (HIV-1), as a novel HIV-1 integrase inhibitor, and a strong anticancer immune response in an IFN-I-dependent manner, as a novel potential adjuvant in anticancer immunotherapy. Here, we report that Poly6 exerts an anti-SARS-CoV-2 effect, with an estimated 50% inhibitory concentration of 2.617 µM, in the human bronchial epithelial cell line, Calu-3 but not in Vero-E6 cells, which are deficient in type 1 interferon (IFN-I) signaling. We proved via assays based on mRNA profiles, inhibitors, or blocking antibodies that Poly6 can exert an anti-SARS-CoV-2 effect in an IFN-I-dependent manner. We also found that Poly6 inhibits IL-6 production enhanced by SARS-CoV-2 in infected Calu-3 cells at both the transcription and the translation levels, mediated via IL-10 induction in an IFN-I-dependent manner. These results indicate the feasibility of Poly6 as an IFN-I-inducing COVID-19 drug with potent antiviral and anti-inflammatory activities.


Assuntos
Antivirais/farmacologia , Células Epiteliais/efeitos dos fármacos , Vírus da Hepatite B/química , Interferon Tipo I/imunologia , Peptídeos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Brônquios/citologia , Brônquios/virologia , Chlorocebus aethiops , Células Epiteliais/imunologia , Células Epiteliais/virologia , Vírus da Hepatite B/genética , Humanos , Pulmão/citologia , Pulmão/virologia , Peptídeos/imunologia , SARS-CoV-2/imunologia , Células Vero
6.
Sci Rep ; 11(1): 13854, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226597

RESUMO

To describe the long-term health outcomes of patients with COVID-19 and investigate the potential risk factors. Clinical data during hospitalization and at a mean (SD) day of 249 (15) days after discharge from 40 survivors with confirmed COVID-19 (including 25 severe cases) were collected and analyzed retrospectively. At follow-up, severe cases had higher incidences of persistent symptoms, DLCO impairment, and higher abnormal CT score as compared with mild cases. CT score at follow-up was positively correlated with age, LDH level, cumulative days of oxygen treatment, total dosage of glucocorticoids used, and CT peak score during hospitalization. DLCO% at follow-up was negatively correlated with cumulative days of oxygen treatment during hospitalization. DLCO/VA% at follow-up was positively correlated with BMI, and TNF-α level. Among the three groups categorized as survivors with normal DLCO, abnormal DLCO but normal DLCO/VA, and abnormal DLCO and DLCO/VA, survivors with abnormal DLCO and DLCO/VA had the lowest serum IL-2R, IL-8, and TNF-α level, while the survivors with abnormal DLCO but normal DLCO/VA had the highest levels of inflammatory cytokines during hospitalization. Altogether, COVID-19 had a greater long-term impact on the lung physiology of severe cases. The long-term radiological abnormality maybe relate to old age and the severity of COVID-19. Either absent or excess of inflammation during COVID-19 course would lead to the impairment of pulmonary diffusion function.


Assuntos
COVID-19/epidemiologia , Pulmão/virologia , Transtornos Respiratórios/virologia , SARS-CoV-2/patogenicidade , Sobreviventes , Adulto , Idoso , Seguimentos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transtornos Respiratórios/fisiopatologia , Fenômenos Fisiológicos Respiratórios , Estudos Retrospectivos , Sobreviventes/estatística & dados numéricos
7.
PLoS Pathog ; 17(7): e1009381, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34197564

RESUMO

Clearance of viral infections, such as SARS-CoV-2 and influenza A virus (IAV), must be fine-tuned to eliminate the pathogen without causing immunopathology. As such, an aggressive initial innate immune response favors the host in contrast to a detrimental prolonged inflammation. The complement pathway bridges innate and adaptive immune system and contributes to the response by directly clearing pathogens or infected cells, as well as recruiting proinflammatory immune cells and regulating inflammation. However, the impact of modulating complement activation in viral infections is still unclear. In this work, we targeted the complement decay-accelerating factor (DAF/CD55), a surface protein that protects cells from non-specific complement attack, and analyzed its role in IAV infections. We found that DAF modulates IAV infection in vivo, via an interplay with the antigenic viral proteins hemagglutinin (HA) and neuraminidase (NA), in a strain specific manner. Our results reveal that, contrary to what could be expected, DAF potentiates complement activation, increasing the recruitment of neutrophils, monocytes and T cells. We also show that viral NA acts on the heavily sialylated DAF and propose that the NA-dependent DAF removal of sialic acids exacerbates complement activation, leading to lung immunopathology. Remarkably, this mechanism has no impact on viral loads, but rather on the host resilience to infection, and may have direct implications in zoonotic influenza transmissions.


Assuntos
Antígenos CD55/fisiologia , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Pulmão/imunologia , Viremia/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Antígenos CD55/química , Antígenos CD55/deficiência , Quimiotaxia de Leucócito , Ativação do Complemento , Glicoproteínas de Hemaglutininação de Vírus da Influenza/fisiologia , Adaptação ao Hospedeiro , Especificidade de Hospedeiro , Interações Hospedeiro-Patógeno , Vírus da Influenza A Subtipo H1N1/enzimologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H1N1/fisiologia , Interferon gama/análise , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Ácido N-Acetilneuramínico , Neuraminidase/fisiologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Carga Viral , Proteínas Virais/fisiologia , Virulência , Replicação Viral , Perda de Peso
8.
PLoS One ; 16(7): e0252941, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34242213

RESUMO

Medical imaging as method to assess the longitudinal process of a SARS-CoV-2 infection in non-human primates is commonly used in research settings. Bronchoalveolar lavage (BAL) is regularly used to determine the local virus production and immune effects of SARS-CoV-2 in the lower respiratory tract. However, the potential interference of those two diagnostic modalities is unknown in non-human primates. The current study investigated the effect and duration of BAL on computed tomography (CT) in both healthy and experimentally SARS-CoV-2-infected female rhesus macaques (Macaca mulatta). In addition, the effect of subsequent BALs was reviewed. Thorax CTs and BALs were obtained from four healthy animals and 11 experimentally SARS-CoV-2-infected animals. From all animals, CTs were obtained just before BAL, and 24 hours post-BAL. Additionally, from the healthy animals, CTs immediately after, and four hours post-BAL were obtained. Thorax CTs were evaluated for alterations in lung density, measured in Hounsfield units, and a visual semi-quantitative scoring system. An increase in the lung density was observed on the immediately post-BAL CT but resolved within 24 hours in the healthy animals. In the infected animals, a significant difference in both the lung density and CT score was still found 24 hours after BAL. Furthermore, the differences between time points in CT score were increased for the second BAL. These results indicate that the effect of BAL on infected lungs is not resolved within the first 24 hours. Therefore, it is important to acknowledge the interference between BAL and CT in rhesus macaques.


Assuntos
COVID-19/diagnóstico por imagem , Pulmão/diagnóstico por imagem , SARS-CoV-2 , Tomografia Computadorizada por Raios X , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Pulmão/virologia , Macaca mulatta , Tórax/diagnóstico por imagem , Tórax/virologia
9.
J Infect Dev Ctries ; 15(6): 766-772, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34242184

RESUMO

INTRODUCTION: COVID-19 is the infection caused by the new coronavirus. Specific treatment for COVID-19 has not been established, yet. It is important to determine the disease severity of the patients at the first admission. Therefore, the exploration of biomarkers is deemed necessary. We aimed to assess the diagnostic and early prognostic value of CRP and LDH levels in possible COVID-19 patients presenting with a severe clinical picture. METHODOLOGY: We evaluated the correlations of relevant routine laboratory test results with disease severity in COVID-19 patients admitted to our infectious diseases clinic. Patients were divided into severe and non-severe disease groups based on clinical findings, oxygen saturation levels in the arterial blood, biochemical test results, and radiological findings. Differences in the findings between the two disease severity groups were examined to determine potential biomarkers. RESULTS: Median age and the CRP and LDH levels in the severe disease group were statistically significantly higher compared to the nonsevere group (p < 0.0001). No other parameters statistically significant differences have been observed between the two groups (P > 0.05). CONCLUSIONS: CRP and LDH levels were positively correlated with lung lesions in early-stage COVID-19, potentially reflecting disease severity. Because LDH and CRP levels can potentially reflect the pulmonary function, they can be potential predictors of COVID-19- related respiratory failure. For avoiding poor prognosis; LDH and CRP should be considered as potential predictors for identifying the need for thoracic CT scans, close monitoring of pulmonary function, and aggressive supportive therapy early in the course of COVID-19.


Assuntos
Proteína C-Reativa/análise , COVID-19/sangue , COVID-19/diagnóstico , L-Lactato Desidrogenase/sangue , Índice de Gravidade de Doença , Adulto , Biomarcadores/sangue , COVID-19/classificação , Feminino , Hospitalização , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Turquia
10.
Biomed Res Int ; 2021: 8160860, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34159203

RESUMO

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-19 (COVID-19), which is characterized by clinical manifestations such as pneumonia, lymphopenia, severe acute respiratory distress, and cytokine storm. S glycoprotein of SARS-CoV-2 binds to angiotensin-converting enzyme II (ACE-II) to enter into the lungs through membrane proteases consequently inflicting the extensive viral load through rapid replication mechanisms. Despite several research efforts, challenges in COVID-19 management still persist at various levels that include (a) availability of a low cost and rapid self-screening test, (b) lack of an effective vaccine which works against multiple variants of SARS-CoV-2, and (c) lack of a potent drug that can reduce the complications of COVID-19. The development of vaccines against SARS-CoV-2 is a complicated process due to the emergence of mutant variants with greater virulence and their ability to invoke intricate lung pathophysiology. Moreover, the lack of a thorough understanding about the virus transmission mechanisms and complete pathogenesis of SARS-CoV-2 is making it hard for medical scientists to develop a better strategy to prevent the spread of the virus and design a clinically viable vaccine to protect individuals from being infected. A recent report has tested the hypothesis of T cell immunity and found effective when compared to the antibody response in agammaglobulinemic patients. Understanding SARS-CoV-2-induced changes such as "Th-2 immunopathological variations, mononuclear cell & eosinophil infiltration of the lung and antibody-dependent enhancement (ADE)" in COVID-19 patients provides key insights to develop potential therapeutic interventions for immediate clinical management. Therefore, in this review, we have described the details of rapid detection methods of SARS-CoV-2 using molecular and serological tests and addressed different therapeutic modalities used for the treatment of COVID-19 patients. In addition, the current challenges against the development of vaccines for SARS-CoV-2 are also briefly described in this article.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Desenvolvimento de Medicamentos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Preparações Farmacêuticas/administração & dosagem , Carga Viral
11.
Sci Adv ; 7(25)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34134991

RESUMO

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R-like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2- and SARS-CoV-induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2-inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.


Assuntos
Antivirais/farmacologia , Apoptose/efeitos dos fármacos , COVID-19/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , eIF-2 Quinase/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Enzima de Conversão de Angiotensina 2/genética , Animais , Apoptose/fisiologia , COVID-19/etiologia , COVID-19/patologia , Linhagem Celular , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/patologia , Dipeptidil Peptidase 4/genética , Células Epiteliais/virologia , Feminino , Humanos , Indóis/farmacologia , Pulmão/virologia , Masculino , Camundongos Transgênicos , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética
12.
FASEB J ; 35(7): e21713, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34105201

RESUMO

Syrian golden hamsters (Mesocricetus auratus) infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) manifests lung pathology. In this study, efforts were made to check the infectivity of a local SARS-CoV-2 isolate in a self-limiting and non-lethal hamster model and evaluate the differential expression of lung proteins during acute infection and convalescence. The findings of this study confirm the infectivity of this isolate in vivo. Analysis of clinical parameters and tissue samples show the pathophysiological manifestation of SARS-CoV-2 infection similar to that reported earlier in COVID-19 patients and hamsters infected with other isolates. However, diffuse alveolar damage (DAD), a common histopathological feature of human COVID-19 was only occasionally noticed. The lung-associated pathological changes were very prominent on the 4th day post-infection (dpi), mostly resolved by 14 dpi. Here, we carried out the quantitative proteomic analysis of the lung tissues from SARS-CoV-2-infected hamsters on day 4 and day 14 post-infection. This resulted in the identification of 1585 proteins of which 68 proteins were significantly altered between both the infected groups. Pathway analysis revealed complement and coagulation cascade, platelet activation, ferroptosis, and focal adhesion as the top enriched pathways. In addition, we also identified altered expression of two pulmonary surfactant-associated proteins (Sftpd and Sftpb), known for their protective role in lung function. Together, these findings will aid in understanding the mechanism(s) involved in SARS-CoV-2 pathogenesis and progression of the disease.


Assuntos
COVID-19/metabolismo , COVID-19/patologia , Interações Hospedeiro-Patógeno , Pulmão/metabolismo , Pulmão/virologia , Proteômica , SARS-CoV-2/patogenicidade , Animais , COVID-19/virologia , Cricetinae , Modelos Animais de Doenças , Feminino , Pulmão/patologia , Masculino , Proteoma/análise , Proteoma/biossíntese , Reprodutibilidade dos Testes , Carga Viral
13.
Viruses ; 13(5)2021 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063247

RESUMO

In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emerged to severely impact the global population, creating an unprecedented need for effective treatments. This study aims to investigate the potential of Scutellaria barbata D. Don (SB) as a treatment for SARS-CoV-2 infection through the inhibition of the proteases playing important functions in the infection by SARS-CoV-2. FRET assay was applied to investigate the inhibitory effects of SB on the two proteases involved in SARS-CoV-2 infection, Mpro and TMPRSS2. Additionally, to measure the potential effectiveness of SB treatment on infection inhibition, cellular models based on the Calu3 and VeroE6 cells and their TMPRSS2- expressing derivatives were assessed by viral pseudoparticles (Vpp) infection assays. The experimental approaches were conjugated with LC/MS analyses of the aqueous extracts of SB to identify the major constituent compounds, followed by a literature review to determine the potential active components of the inhibitory effects on protease activities. Our results showed that SB extracts inhibited the enzyme activities of Mpro and TMPRSS2. Furthermore, SB extracts effectively inhibited SARS-CoV-2 Vpp infection through a TMPRSS2-dependent mechanism. The aqueous extract analysis identified six major constituent compounds present in SB. Some of them have been known associated with inhibitory activities of TMPRSS2 or Mpro. Thus, SB may effectively prevent SARS-CoV-2 infection and replication through inhibiting Mpro and TMPRSS2 protease activities.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/metabolismo , Extratos Vegetais/farmacologia , Serina Endopeptidases/metabolismo , Animais , COVID-19/metabolismo , Linhagem Celular , Chlorocebus aethiops , Proteases 3C de Coronavírus/efeitos dos fármacos , Humanos , Pulmão/virologia , Pandemias , Peptídeo Hidrolases , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/metabolismo , Proteólise , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Serina Endopeptidases/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos
14.
Viruses ; 13(6)2021 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071034

RESUMO

There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Agonistas de Receptores de GABA-A/uso terapêutico , Vírus da Hepatite Murina/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Animais , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Camundongos , Vírus da Hepatite Murina/patogenicidade , Pneumonia/mortalidade , Pneumonia/virologia , Índice de Gravidade de Doença , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos , Ácido gama-Aminobutírico/uso terapêutico
15.
Front Immunol ; 12: 683902, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1282386

RESUMO

Respiratory syncytial virus (RSV) is a public health concern that causes acute lower respiratory tract infection. So far, no vaccine candidate under development has reached the market and the only licensed product to prevent RSV infection in at-risk infants and young children is a monoclonal antibody (Synagis®). Polyclonal human anti-RSV hyper-immune immunoglobulins (Igs) have also been used but were superseded by Synagis® owing to their low titer and large infused volume. Here we report a new drug class of immunoglobulins, derived from human non hyper-immune plasma that was generated by an innovative bioprocess, called Ig cracking, combining expertises in plasma-derived products and affinity chromatography. By using the RSV fusion protein (F protein) as ligand, the Ig cracking process provided a purified and concentrated product, designated hyper-enriched anti-RSV IgG, composed of at least 15-20% target-specific-antibodies from normal plasma. These anti-RSV Ig displayed a strong in vitro neutralization effect on RSV replication. Moreover, we described a novel prophylactic strategy based on local nasal administration of this unique hyper-enriched anti-RSV IgG solution using a mouse model of infection with bioluminescent RSV. Our results demonstrated that very low doses of hyper-enriched anti-RSV IgG can be administered locally to ensure rapid and efficient inhibition of virus infection. Thus, the general hyper-enriched Ig concept appeared a promising approach and might provide solutions to prevent and treat other infectious diseases. Importance: Respiratory Syncytial Virus (RSV) is the major cause of acute lower respiratory infections in children, and is also recognized as a cause of morbidity in the elderly. There are still no vaccines and no efficient antiviral therapy against this virus. Here, we described an approach of passive immunization with a new class of hyper-enriched anti-RSV immunoglobulins (Ig) manufactured from human normal plasma. This new class of immunoglobulin plasma derived product is generated by an innovative bioprocess, called Ig cracking, which requires a combination of expertise in both plasma derived products and affinity chromatography. The strong efficacy in a small volume of these hyper-enriched anti-RSV IgG to inhibit the viral infection was demonstrated using a mouse model. This new class of immunoglobulin plasma-derived products could be applied to other pathogens to address specific therapeutic needs in the field of infectious diseases or even pandemics, such as COVID-19.


Assuntos
Anticorpos Antivirais/administração & dosagem , Imunização Passiva , Imunoglobulina G/administração & dosagem , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sincicial Respiratório Humano/imunologia , Administração Intranasal , Animais , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/isolamento & purificação , Modelos Animais de Doenças , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/isolamento & purificação , Pulmão/efeitos dos fármacos , Pulmão/virologia , Testes de Neutralização , Infecções por Vírus Respiratório Sincicial/virologia , Conchas Nasais/efeitos dos fármacos , Conchas Nasais/virologia , Proteínas Virais de Fusão/imunologia , Replicação Viral/efeitos dos fármacos
17.
Viruses ; 13(5)2021 05 02.
Artigo em Inglês | MEDLINE | ID: covidwho-1224250

RESUMO

In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emerged to severely impact the global population, creating an unprecedented need for effective treatments. This study aims to investigate the potential of Scutellaria barbata D. Don (SB) as a treatment for SARS-CoV-2 infection through the inhibition of the proteases playing important functions in the infection by SARS-CoV-2. FRET assay was applied to investigate the inhibitory effects of SB on the two proteases involved in SARS-CoV-2 infection, Mpro and TMPRSS2. Additionally, to measure the potential effectiveness of SB treatment on infection inhibition, cellular models based on the Calu3 and VeroE6 cells and their TMPRSS2- expressing derivatives were assessed by viral pseudoparticles (Vpp) infection assays. The experimental approaches were conjugated with LC/MS analyses of the aqueous extracts of SB to identify the major constituent compounds, followed by a literature review to determine the potential active components of the inhibitory effects on protease activities. Our results showed that SB extracts inhibited the enzyme activities of Mpro and TMPRSS2. Furthermore, SB extracts effectively inhibited SARS-CoV-2 Vpp infection through a TMPRSS2-dependent mechanism. The aqueous extract analysis identified six major constituent compounds present in SB. Some of them have been known associated with inhibitory activities of TMPRSS2 or Mpro. Thus, SB may effectively prevent SARS-CoV-2 infection and replication through inhibiting Mpro and TMPRSS2 protease activities.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/metabolismo , Extratos Vegetais/farmacologia , Serina Endopeptidases/metabolismo , Animais , COVID-19/metabolismo , Linhagem Celular , Chlorocebus aethiops , Proteases 3C de Coronavírus/efeitos dos fármacos , Humanos , Pulmão/virologia , Pandemias , Peptídeo Hidrolases , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/metabolismo , Proteólise , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Serina Endopeptidases/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos
18.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: covidwho-1244036

RESUMO

Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10-5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5.


Assuntos
COVID-19/genética , COVID-19/metabolismo , Predisposição Genética para Doença , Receptores CCR5/genética , Receptores CCR5/metabolismo , Alelos , Brônquios/metabolismo , Brônquios/patologia , Brônquios/virologia , COVID-19/fisiopatologia , Cromossomos Humanos/genética , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
19.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: covidwho-1244035

RESUMO

Previous studies have shown that COVID-19 leads to thrombotic complications, which have been associated with high morbidity and mortality rates. Neutrophils are the largest population of white blood cells and play a pivotal role in innate immunity. During an infection, neutrophils migrate from circulation to the infection site, contributing to killing pathogens. This mechanism is regulated by chemokines such as IL-8. Moreover, it was shown that neutrophils play an important role in thromboinflammation. Through a diverse repertoire of mechanisms, neutrophils, apart from directly killing pathogens, are able to activate the formation of thrombi. In COVID-19 patients, neutrophil activation promotes neutrophil extracellular trap (NET) formation, platelet aggregation, and cell damage. Furthermore, neutrophils participate in the pathogenesis of endothelitis. Overall, this review summarizes recent progress in research on the pathogenesis of COVID-19, highlighting the role of the prothrombotic action of neutrophils in NET formation.


Assuntos
COVID-19/imunologia , Armadilhas Extracelulares/imunologia , Imunidade Inata , Pulmão/imunologia , Neutrófilos/imunologia , Trombose/imunologia , COVID-19/complicações , COVID-19/patologia , COVID-19/terapia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/virologia , Armadilhas Extracelulares/virologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Rim/citologia , Rim/imunologia , Rim/patologia , Rim/virologia , Pulmão/citologia , Pulmão/patologia , Pulmão/virologia , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/virologia , SARS-CoV-2 , Trombose/complicações , Trombose/patologia , Trombose/virologia
20.
Viruses ; 13(6)2021 05 23.
Artigo em Inglês | MEDLINE | ID: covidwho-1242675

RESUMO

There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Agonistas de Receptores de GABA-A/uso terapêutico , Vírus da Hepatite Murina/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Animais , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Camundongos , Vírus da Hepatite Murina/patogenicidade , Pneumonia/mortalidade , Pneumonia/virologia , Índice de Gravidade de Doença , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos , Ácido gama-Aminobutírico/uso terapêutico
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