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1.
Viruses ; 13(6)2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064104

RESUMO

Patients with coronavirus disease 2019 (COVID-19) predominantly have a respiratory tract infection with various symptoms and high mortality is associated with respiratory failure second to severe disease. The risk factors leading to severe disease remain unclear. Here, we reanalyzed a published single-cell RNA-Seq (scRNA-Seq) dataset and found that bronchoalveolar lavage fluid (BALF) of patients with severe disease compared to those with mild disease contained decreased TH17-type cells, decreased IFNA1-expressing cells with lower expression of toll-like receptor 7 (TLR7) and TLR8, increased IgA-expressing B cells, and increased hyperactive epithelial cells (and/or macrophages) expressing matrix metalloproteinases (MMPs), hyaluronan synthase 2 (HAS2), and plasminogen activator inhibitor-1 (PAI-1), which may together contribute to the pulmonary pathology in severe COVID-19. We propose IFN-I (and TLR7/TLR8) and PAI-1 as potential biomarkers to predict the susceptibility to severe COVID-19.


Assuntos
COVID-19/patologia , Pulmão/patologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/imunologia , COVID-19/metabolismo , Bases de Dados Genéticas , Humanos , Hialuronan Sintases/metabolismo , Imunoglobulina A/metabolismo , Interferon-alfa/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Metaloproteinases da Matriz/metabolismo , Mucina-1/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA-Seq , SARS-CoV-2 , Células Th17/metabolismo , Células Th17/patologia
2.
Appl Microbiol Biotechnol ; 105(10): 4005-4015, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33950278

RESUMO

The coronavirus disease (COVID-19) caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide. Given that this contagious viral outbreak is still unfolding, it is urgent to understand the pathogenesis of SARS-CoV-2 infection and explore effective treatments to protect patients from developing a severe illness related to COVID-19. Recently, IFN-α has been considered a potential therapeutic strategy to treat COVID-19 disease, mainly because the innate immune system rapidly produces IFN-α as the first line of defense to combat viral infections. However, IFN-α can also play a role in immunoregulatory effects, causing pathogenic damage and uncontrolled inflammatory responses. There are 13 human IFN-α subtypes that bind to the same receptor and induce different interferon-stimulated gene (ISG) expression, regulating various antiviral and immunoregulatory effects. The varying degrees of inflammatory regulations may raise concerns about the possible side effects to enlarge the inflammatory responses, exacerbating the severity of infection. Thus, the analysis of various IFN-α subtype induction during SARS-CoV-2 infection is necessary in exploring the mechanism of COVID-19 pathogenesis. This review summarizes the current understanding of IFN-α in the pathogenesis of respiratory virus diseases and IFN-α based clinical intervention used in SARS-CoV-2 infection and other respiratory virus diseases. Besides, new ideas in selecting suitable IFN-α subtypes or combinations as drug candidates for viral infection treatment will also be discussed.Key Points• IFN-α plays an important role in anti-viral and immunoregulatory effects in COVID-19 patients caused by SARS-CoV-2.• The uncontrolled inflammation and disease severity correlated to the diversity of IFN-α subtype induction.• Selecting suitable IFN-α subtypes or combinations as drug candidates will be beneficial for the treatment of patients with COVID-19.


Assuntos
COVID-19 , Antivirais/uso terapêutico , Humanos , Interferon-alfa/uso terapêutico , SARS-CoV-2
3.
Signal Transduct Target Ther ; 6(1): 189, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980808

RESUMO

Since the outbreak of coronavirus disease 2019 (COVID-19), it has become a global pandemic. The spike (S) protein of etiologic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specifically recognizes human angiotensin-converting enzyme 2 (hACE2) as its receptor, which is recently identified as an interferon (IFN)-stimulated gene. Here, we find that hACE2 exists on the surface of exosomes released by different cell types, and the expression of exosomal hACE2 is increased by IFNα/ß treatment. In particular, exosomal hACE2 can specifically block the cell entry of SARS-CoV-2, subsequently inhibit the replication of SARS-CoV-2 in vitro and ex vivo. Our findings have indicated that IFN is able to upregulate a viral receptor on the exosomes which competitively block the virus entry, exhibiting a potential antiviral strategy.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Exossomos/metabolismo , Interferon-alfa/farmacologia , Interferon beta/farmacologia , SARS-CoV-2/fisiologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/genética , Animais , Chlorocebus aethiops , Exossomos/genética , Exossomos/virologia , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Células Vero
4.
Immunopharmacol Immunotoxicol ; 43(3): 259-264, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34018464

RESUMO

Coronavirus disease 2019 (COVID-19) is associated with irreversible effects on vital organs, especially the respiratory and cardiac systems. While the immune system plays a key role in the survival of patients to viral infections, in COVID-19, there is a hyperinflammatory immune response evoked by all the immune cells, such as neutrophils, monocytes, and includes release of various cytokines, resulting in an exaggerated immune response, named cytokine storm. This severe, dysregulated immune response causes multi-organ damage, which eventually leads to high mortality. One of the most important components of hypersensitivity is immunoglobulin E (IgE), which plays a major role in susceptibility to respiratory infections and can lead to the activation of mast cells. There is also a negative association between IgE and IFN-α, which can reduce Toll-like receptor (TLR) nine receptor expression and TLR-7 signaling to disrupt IFN production. Moreover, anti-IgE drugs such as omalizumab reduces the severity and duration of COVID-19. In addition to its anti-IgE effect, omalizumab inhibits inflammatory cells such as neutrophils. Hence, blockade of IgE may have clinical utility as an immunotherapy for COVID-19.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/imunologia , Omalizumab/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Humanos , Imunoglobulina E/imunologia , Interferon-alfa/imunologia , Omalizumab/imunologia , Transdução de Sinais/imunologia , Receptor 7 Toll-Like/imunologia
5.
Talanta ; 230: 122338, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33934790

RESUMO

Interferons are important biomolecules in human immune system. Cytokine interferon alpha (IFN-α), a type I interferon, is one of the major components of the innate immune response involved in autoimmune diseases. Thus, the analysis of interferons is of great importance for both biological and pharmaceutical purposes. In this work, an IFN-α specific plastic antibody is prepared via boronate affinity oriented surface imprinting. By combing with the magnetic nanoparticles, the imprinted material exhibits several advantages, including strong affinity (Kd: 75.2 nM), high specificity (cross reactivity<25%), excellent efficiency (imprinting efficiency: 44.1%), tolerance to interferences, and easy manipulation. By employing the prepared imprinted material as sorbent for selective enrichment of IFN-α, a good linearity is achieved in the range of 50 ng/mL-10 µg/mL, and the detection and quantifcation limits are 10 ng/mL and 50 ng/mL respectively. The recoveries of this approach are found within 75.8%-82.2% with relative standard deviations of 6.4-9.7%. Furthermore, the IFN-α in spiked human serum is analyzed with acceptable reliability (recovery: 77.3%, RSD: 7.9%). Because of these highly desirable properties, the IFN-α specific plastic antibody can find more applications in medical and pharmaceutical industry.


Assuntos
Impressão Molecular , Humanos , Interferon-alfa , Magnetismo , Plásticos , Reprodutibilidade dos Testes
6.
Front Immunol ; 12: 635018, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936047

RESUMO

Objective: Bacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares. Methods: Normal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated. Results: CD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection). Conclusion: Entheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.


Assuntos
Artrite Psoriásica/complicações , COVID-19/complicações , Células Dendríticas/metabolismo , Interferon-alfa/metabolismo , Janus Quinases/antagonistas & inibidores , Adjuvantes Imunológicos/farmacologia , Adulto , Idoso , COVID-19/genética , COVID-19/metabolismo , Biologia Computacional , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Imiquimode/farmacologia , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Oligonucleotídeos/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Transcriptoma , Fator de Necrose Tumoral alfa/metabolismo
7.
Zool Res ; 42(3): 350-353, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-33998182

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has become an unprecedented global health emergency. At present, SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research. Here, we showed that northern pig-tailed macaques ( Macaca leonina, NPMs) supported SARS-CoV-2 replication. Furthermore, compared with rhesus macaques, NPMs showed rapid viral clearance in lung tissues, nose swabs, throat swabs, and rectal swabs, which may be due to higher expression of interferon (IFN)-α in lung tissue. However, the rapid viral clearance was not associated with good outcome. In the second week post infection, NPMs developed persistent or even more severe inflammation and body injury compared with rhesus macaques. These results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Macaca nemestrina , SARS-CoV-2/imunologia , Animais , Modelos Animais de Doenças , Interferon-alfa/análise , Interleucina-1beta/análise , Interleucina-6/análise , Pulmão/imunologia , Pulmão/virologia , Nariz/virologia , Faringe/virologia , RNA Viral/análise , Reto/virologia , SARS-CoV-2/genética
8.
Vet J ; 271: 105648, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33840487

RESUMO

Interferons (IFNs) are cytokines that play an important role in the immune response of animals and humans. A number of studies reviewed here have evaluated the use of human, canine and feline IFNs as treatments for infectious, inflammatory and neoplastic disease in dogs and cats. Recombinant canine IFN-γ is deemed an efficacious therapy for canine atopic dermatitis. Recombinant feline IFN-ω is effective against canine parvoviral enteritis and has also been recommended for canine atopic dermatitis. Based on limited evidence, recombinant canine IFN-α could be a topical treatment option for dogs with gingivitis and keratoconjunctivitis sicca. Conclusive evidence is lacking for other diseases and large randomised controlled trials are needed before IFNs can be recommended for other indications.


Assuntos
Doenças do Gato/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Interferons/uso terapêutico , Animais , Gatos , Cães , Gengivite/tratamento farmacológico , Humanos , Infecções/tratamento farmacológico , Infecções/veterinária , Inflamação/tratamento farmacológico , Inflamação/veterinária , Interferon-alfa/uso terapêutico , Ceratoconjuntivite Seca/tratamento farmacológico , Ceratoconjuntivite Seca/veterinária , Neoplasias/tratamento farmacológico , Neoplasias/veterinária , Proteínas Recombinantes/uso terapêutico , Viroses/tratamento farmacológico , Viroses/veterinária
9.
Eur Rev Med Pharmacol Sci ; 25(8): 3325-3337, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33928620

RESUMO

Since the reports in Wuhan (China), in December 2019, of the first cluster of cases of pneumonia caused by the new Coronavirus called 2019-nCoV or SARS-CoV-2, there has been a pandemic spread of the infection. By now, we have no specific therapy to counteract this emergency. The latest epidemiological data suggest that children are just as likely as adults to get infected by the virus. Most of them show mild clinical pictures or are completely asymptomatic, but there is an increased risk for severe disease in infancy (<12 months of age) and in children with underlying medical conditions. In this article, research achievements on the treatment of pediatric SARS-CoV-2 infection are examined.


Assuntos
Antivirais/uso terapêutico , COVID-19/terapia , Fatores Imunológicos/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Adolescente , Fatores Etários , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticoagulantes/uso terapêutico , COVID-19/tratamento farmacológico , Portador Sadio , Criança , Pré-Escolar , Cloroquina/uso terapêutico , Terapia de Substituição Renal Contínua , Combinação de Medicamentos , Oxigenação por Membrana Extracorpórea , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Recém-Nascido , Interferon-alfa/uso terapêutico , Lopinavir/uso terapêutico , Oseltamivir/uso terapêutico , Receptores de Superfície Celular/uso terapêutico , Respiração Artificial , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , SARS-CoV-2 , Índice de Gravidade de Doença , Trombose/prevenção & controle
10.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805426

RESUMO

Myeloproliferative neoplasms (MPNs) are a group of disorders characterized by clonal expansion of abnormal hematopoietic stem cells leading to hyperproliferation of one or more myeloid lineages. The main complications in MPNs are high risk of thrombosis and progression to myelofibrosis and leukemia. MPN patients with high risk scores are treated by hydroxyurea (HU), interferon-α, or ruxolitinib, a tyrosine kinase inhibitor. Polycythemia vera (PV) is an MPN characterized by overproduction of red blood cells (RBCs). ABCG2 is a member of the ATP-binding cassette superfamily transporters known to play a crucial role in multidrug resistance development. Proteome analysis showed higher ABCG2 levels in PV RBCs compared to RBCs from healthy controls and an additional increase of these levels in PV patients treated with HU, suggesting that ABCG2 might play a role in multidrug resistance in MPNs. In this work, we explored the role of ABCG2 in the transport of ruxolitinib and HU using human cell lines, RBCs, and in vitro differentiated erythroid progenitors. Using stopped-flow analysis, we showed that HU is not a substrate for ABCG2. Using transfected K562 cells expressing three different levels of recombinant ABCG2, MPN RBCs, and cultured erythroblasts, we showed that ABCG2 potentiates ruxolitinib-induced cytotoxicity that was blocked by the ABCG2-specific inhibitor KO143 suggesting ruxolitinib intracellular import by ABCG2. In silico modeling analysis identified possible ruxolitinib-binding site locations within the cavities of ABCG2. Our study opens new perspectives in ruxolitinib efficacy research targeting cell types depending on ABCG2 expression and polymorphisms among patients.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Eritrócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Policitemia Vera/tratamento farmacológico , Pirazóis/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Simulação por Computador , Dicetopiperazinas/farmacologia , Eritrócitos/efeitos dos fármacos , Células Eritroides/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Hidroxiureia/metabolismo , Hidroxiureia/farmacologia , Interferon-alfa/farmacologia , Células K562 , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Fosfatidilserinas/metabolismo , Policitemia Vera/sangue , Policitemia Vera/patologia , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacocinética
11.
Crit Care ; 25(1): 140, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33845874

RESUMO

BACKGROUND: Since the onset of the pandemic, only few studies focused on longitudinal immune monitoring in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) whereas their hospital stay may last for several weeks. Consequently, the question of whether immune parameters may drive or associate with delayed unfavorable outcome in these critically ill patients remains unsolved. METHODS: We present a dynamic description of immuno-inflammatory derangements in 64 critically ill COVID-19 patients including plasma IFNα2 levels and IFN-stimulated genes (ISG) score measurements. RESULTS: ARDS patients presented with persistently decreased lymphocyte count and mHLA-DR expression and increased cytokine levels. Type-I IFN response was initially induced with elevation of IFNα2 levels and ISG score followed by a rapid decrease over time. Survivors and non-survivors presented with apparent common immune responses over the first 3 weeks after ICU admission mixing gradual return to normal values of cellular markers and progressive decrease of cytokines levels including IFNα2. Only plasma TNF-α presented with a slow increase over time and higher values in non-survivors compared with survivors. This paralleled with an extremely high occurrence of secondary infections in COVID-19 patients with ARDS. CONCLUSIONS: Occurrence of ARDS in response to SARS-CoV2 infection appears to be strongly associated with the intensity of immune alterations upon ICU admission of COVID-19 patients. In these critically ill patients, immune profile presents with similarities with the delayed step of immunosuppression described in bacterial sepsis.


Assuntos
COVID-19/sangue , Estado Terminal , Unidades de Terapia Intensiva/tendências , Interferon-alfa/sangue , Síndrome do Desconforto Respiratório/sangue , Adulto , Idoso , Biomarcadores/sangue , COVID-19/epidemiologia , COVID-19/imunologia , Estado Terminal/epidemiologia , Feminino , Hospitalização/tendências , Humanos , Imunidade/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/imunologia
12.
Clin Drug Investig ; 41(4): 391-404, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33725322

RESUMO

BACKGROUND AND OBJECTIVES: Ropeginterferon alfa-2b is a novel monopegylated recombinant interferon alfa-2b for the treatment of patients with polycythemia vera. The objectives of this study were to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of ropeginterferon alfa-2b in healthy Japanese subjects compared with Caucasian subjects. METHODS: In this multicenter, parallel-group phase I study, a cohort consisting of six Japanese and six Caucasian subjects was designated to receive a single subcutaneous dose of ropeginterferon alfa-2b (100, 200, 300, and 450 µg). Pharmacokinetic and pharmacodynamic parameters, and immunogenicity were evaluated. Safety was assessed throughout the study. RESULTS: Cohort 4 (450-µg dose) was not initiated because the primary objective of this study was achieved based on the three completed cohorts. A total of 36 enrolled subjects (18 Japanese and 18 Caucasian) in three cohorts were included in the safety, pharmacokinetic, and pharmacodynamic analysis sets. Ropeginterferon alfa-2b exposure in terms of the area under the serum concentration-time curve (AUC) from time zero extrapolated to infinity and the AUC from time zero to the time of the last quantifiable concentration was approximately 1.7-fold and two-fold higher in Japanese subjects than in Caucasian subjects, respectively. Across the same dose range, the maximum serum concentration was approximately 1.25-fold higher in Japanese subjects than in Caucasian subjects. The time to reach the median maximum serum concentration was similar between ethnicities (approximately 96-111 h). The terminal half-life was 48-57 h in Japanese subjects and 31-75 h in Caucasian subjects. The slope of the relationship between dose and drug exposure was greater than 1 in both ethnicities. The dose-dependent induction of beta-2 microglobulin and neopterin expression was observed in both ethnicities, and the two groups showed similar pharmacodynamic parameters. At the end of the study, 22.2% of Japanese subjects and 11.1% of Caucasian subjects developed anti-ropeginterferon alfa-2b-binding antibodies. The neutralizing capacity of these antibodies was not tested. Ropeginterferon alfa-2b up to 300 µg was safe and well tolerated, with no unexpected safety findings based on previous experiences with ropeginterferon alfa-2b and other forms of interferon. CONCLUSIONS: Ropeginterferon alfa-2b exposure was higher in Japanese subjects than in Caucasian subjects. The increase in ropeginterferon alfa-2b exposure was greater than the dose proportion in the dose range of 100-300 µg. Ropeginterferon alfa-2b was safe and well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03546465, registered on 6 June, 2018.


Assuntos
Antivirais/administração & dosagem , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Policitemia Vera/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Adulto Jovem
13.
J Virol ; 95(12)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33762411

RESUMO

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a betacoronavirus that causes vomiting and wasting disease and/or encephalomyelitis in suckling pigs. This study characterized PHEV infection, pathogenesis, and immune response in cesarean-derived, colostrum-deprived (CDCD) neonatal pigs. Infected animals developed mild respiratory, enteric, and neurological clinical signs between 2 to 13 days postoronasal inoculation (dpi). PHEV did not produce viremia, but virus shedding was detected in nasal secretions (1 to 10 dpi) and feces (2 to 7 dpi) by reverse transcriptase quantitative PCR (RT-qPCR). Viral RNA was detected in all tissues except liver, but the detection rate and RT-qPCR threshold cycle (CT ) values decreased over time. The highest concentration of virus was detected in inoculated piglets necropsied at 5 dpi in turbinate and trachea, followed by tonsils, lungs, tracheobronchial lymph nodes, and stomach. The most representative microscopic lesions were gastritis lymphoplasmacytic, moderate, multifocal, with perivasculitis, and neuritis with ganglia degeneration. A moderate inflammatory response, characterized by increased levels of interferon alpha (IFN-α) in plasma (5 dpi) and infiltration of T lymphocytes and macrophages were also observed. Increased plasma levels of interleukin-8 (IL-8) were detected at 10 and 15 dpi, coinciding with the progressive resolution of the infection. Moreover, a robust antibody response was detected by 10 dpi. An ex vivo air-liquid CDCD-derived porcine respiratory cells culture (ALI-PRECs) system showed virus replication in ALI-PRECs and cytopathic changes and disruption of ciliated columnar epithelia, thereby confirming the tracheal epithelia as a primary site of infection for PHEV.IMPORTANCE Among the ∼46 virus species in the family Coronaviridae, many of which are important pathogens of humans and 6 of which are commonly found in pigs, porcine hemagglutinating encephalomyelitis remains one of the least researched. The present study provided a comprehensive characterization of the PHEV infection process and immune responses using CDCD neonatal pigs. Moreover, we used an ex vivo ALI-PRECs system resembling the epithelial lining of the tracheobronchial region of the porcine respiratory tract to demonstrate that the upper respiratory tract is a primary site of PHEV infection. This study provides a platform for further multidisciplinary studies of coronavirus infections.


Assuntos
Betacoronavirus 1/imunologia , Infecções por Coronavirus/imunologia , Interferon-alfa/imunologia , Interleucina-8/imunologia , Doenças dos Suínos/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular , Infecções por Coronavirus/patologia , Infecções por Coronavirus/veterinária , Especificidade de Órgãos/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suínos , Doenças dos Suínos/patologia , Linfócitos T/patologia , Linfócitos T/virologia
14.
J Nat Med ; 75(3): 602-611, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33755912

RESUMO

Human respiratory syncytial virus (RSV) is highly contagious and the leading cause of severe respiratory tract illness in infants, elderly, and immunocompromised individuals. Toll-like receptor 7 (TLR7), a pattern recognition receptor recognising the ssRNA of RSV, activates proinflammatory pathways and triggers secretion of interferons (IFNs). On the one hand, the inflammatory responses help clear out virus. On the other hand, they lead to severe lung damage. Banlangen is a traditional Chinese herbal medicine commonly prescribed for respiratory virus infection treatment, but the mechanisms of action and active components remain largely unknown. In the present study, we investigated the effects of the main active components of total alkaloids from banlangen (epigoitrin, indole-3-carboxaldehyde, indole-3-acetonitrile and 4-methoxyindole-3-acetonitrile) on the RSV-induced inflammatory responses in mouse macrophage cells (RAW264.7). Our results demonstrated that RSV-induced IFN-α excessive secretion was moderately inhibited by indole-3-carboxaldehyde through downregulation of mRNA expression in a dose-dependent manner, in comparison, the inhibitory effects of ribavirin were too strong. Furthermore, we revealed that indole-3-carboxaldehyde suppressed transcription of IFN-α by inhibiting RSV-induced TLR7 expression in RAW264.7 cells. Additionally, indole-3-carboxaldehyde inhibited RSV-induced NF-κB signalling activation in a TLR7-MyD88-dependent manner. Together, our findings suggest that indole-3-carboxaldehyde inhibited RSV-induced inflammatory injury by moderate regulation of TLR7 signaling pathway and did not significantly affect the viral clearance competence of the innate immune system.


Assuntos
Antivirais/farmacologia , Indóis/farmacologia , Macrófagos/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Vírus Sincicial Respiratório Humano , Transdução de Sinais , Receptor 7 Toll-Like/metabolismo , Alcaloides/farmacologia , Animais , Regulação para Baixo , Medicamentos de Ervas Chinesas/farmacologia , Interferon-alfa/metabolismo , Camundongos , Células RAW 264.7 , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/metabolismo
15.
Int J Infect Dis ; 105: 516-521, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33713817

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of pegylated interferon alfa-2b (PEG IFN-α2b) along with the standard of care (SOC) in subjects with moderate COVID-19. METHODS: In this phase 2, randomized, open-label study, adult subjects aged ≥18 years with RT-PCR confirmed COVID-19 with moderate symptoms were randomized in a 1:1 to receive PEG IFN-α2b plus SOC, or SOC alone. The primary endpoint was improvement in clinical status on day 15, measured by the WHO 7-point ordinal scale. RESULTS: Forty subjects were randomized to PEG IFN-α2b plus SOC (n = 20) and SOC (n = 20). Overall, 19 (95.00%) subjects in PEG IFN-α2b plus SOC had achieved clinical improvement on day 15 compared to 13 (68.42%) subjects in SOC (p < 0.05). Overall, 80% and 95% of subjects in the PEG IFN-α2b plus SOC group had a negative RT-PCR result on day 7 and day 14, respectively, compared to 63% and 68% in the SOC group. Adverse events (AEs) were reported for eleven subjects in the PEG IFN-α2b plus SOC group and eight subjects in the SOC group. All reported AEs were mild. CONCLUSION: The significant improvement in clinical status on day 15 is likely due to faster viral reduction compared to SOC with the PEG IFN-α2b treated moderate COVID-19 subjects showing a difference as early as day seven and becoming significant by day 14.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , SARS-CoV-2 , Adulto , Idoso , Feminino , Humanos , Interferon alfa-2/efeitos adversos , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico
16.
Front Immunol ; 12: 648004, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33767713

RESUMO

Background: Deficient interferon responses have been proposed as one of the relevant mechanisms prompting severe manifestations of COVID-19. Objective: To evaluate the interferon (IFN)-α levels in a cohort of COVID-19 patients in relation to severity, evolution of the clinical manifestations and immune/inflammatory profile. Methods: This is prospective study recruiting consecutive hospitalized patients with respiratory failure associated with SARS-COV-2 infection and matched controls. After enrollment, patients were assessed every 7 ± 2 days for additional 2 consecutive visits, for a total of 21 days. The severity of the clinical condition was ranked based on the level of respiratory support required. At each time-point blood samples were obtained to assess immune cells and mediators by multiplex immunoassay. Results: Fifty-four COVD-19 and 11 control patients matched for severity were enrolled. At recruitment, lower levels of blood IFN-α were found in COVID-19 patients compared to controls (3.8-fold difference, p < 0.01). Improvements in COVID-19 severity were paralleled by a significant increase of blood IFN-α levels. A significant increase in blood IFN-α was found over the study period in survivors (70% of the study population). A similar trend was found for blood IFN-ß with IFN-ß levels below the threshold of detectability in a substantial proportion of subjects. Significantly higher values of blood lymphocytes and lower levels of IL-10 were found at each time point in patients who survived compared to patients who died. In patients who clinically improved and survived during the study, we found an inverse association between IL-10 and IFN-α levels. Conclusion: The study identifies a blood immune profile defined by deficient IFN-α levels associated with increased IL-10 expression in patients progressing to severe/life threatening COVID-19 conditions, suggesting the involvement of immunological pathways that could be target of pharmacological intervention. Clinical Trial Registration: ClinicalTrials.gov identifier NCT04343053.


Assuntos
COVID-19/sangue , Mediadores da Inflamação/sangue , Interferon-alfa/sangue , Idoso , Biomarcadores/sangue , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/virologia , Estudos de Casos e Controles , Feminino , Hospitalização , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença
17.
Rev Bras Enferm ; 74Suppl 1(Suppl 1): e20200662, 2021.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33681959

RESUMO

OBJECTIVE: to map the knowledge about the clinical findings, treatment and outcome of newborns and children infected with COVID-19. METHODS: a scoping review with search of eight databases and electronic search engine in April 2020. RESULTS: the 12 studies analyzed showed that the main clinical findings in this population were nasal congestion, fever, respiratory distress, diarrhea, fatigue, dry cough, increased C-reactive protein, leukopenia, lymphopenia, thrombocytopenia, elevated procalcitonin, bilateral ground-glass opacity, pulmonary consolidation, and pneumonia. Antivirals, respiratory support, immunomodulatory therapy, glucocorticoids, antibiotics and alpha interferon were used as treatment. The presence of a cure with hospital discharge is present in most cases. FINAL CONSIDERATIONS: most patients required hospitalization, but it evolved to cure. This study provided a greater scientific basis by showing clinical findings, treatment, and outcomes in neopediatric patients with COVID-19.


Assuntos
Antivirais/uso terapêutico , COVID-19/diagnóstico , COVID-19/terapia , Imunomodulação , Terapia Intensiva Neonatal/psicologia , Terapia Intensiva Neonatal/estatística & dados numéricos , Avaliação de Sintomas/estatística & dados numéricos , Antibacterianos/uso terapêutico , Brasil/epidemiologia , COVID-19/epidemiologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Lactente , Recém-Nascido , Interferon-alfa/uso terapêutico , Masculino , SARS-CoV-2
18.
Medicine (Baltimore) ; 100(11): e24949, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33725966

RESUMO

ABSTRACT: Currently, no effective prognostic model of clear cell renal cell carcinoma (ccRCC) based on immune cell infiltration has been developed. Recent studies have identified 6 immune groups (IS) in 33 solid tumors. We aimed to characterize the expression pattern of IS in ccRCC and evaluate the potential in predicting patient prognosis. The clinical information, immune subgroup, somatic mutation, copy number variation, and methylation score of patients with TCGA ccRCC cohort were downloaded from UCSC Xena for further analysis. The most dominant IS in ccRCC was the inflammatory subgroup (immune C3) (86.5%), regardless of different pathological stages, pathological grades, and genders. In the C3 subgroup, stage IV (69.1%) and grade 4 (69.9%) were the least presented. Survival analysis showed that the IS could effectively predict the overall survival (OS) (P < .0001) and disease-specific survival (DSS) (P < .0001) of ccRCC alone, of which group C3 (OS, HR = 2.3, P < .001; DSS, HR = 2.84, P < .001) exhibited the best prognosis. Among the most frequently mutated ccRCC genes, only VHL and PBRM1 were found to be common in the C3 group. The homologous recombination deficiency score was also lower. High heterogeneity was observed in immune cells and immunoregulatory genes of IS. Notably, CD4+ memory resting T cells were highly infiltrating, regulatory T cells (Treg) showed low infiltration, and most immunoregulatory genes (such as CX3CL1, IFNA2, TLR4, SELP, HMGB1, and TNFRSF14) were highly expressed in the C3 subgroup than in other subgroups. Enrichment analysis showed that adipogenesis, apical junction, hypoxia, IL2 STAT5 signaling, TGF-beta signaling, and UV response DN were activated, whereas E2F targets, G2M checkpoint, and MYC targets V2 were downregulated in the C3 group. Immune classification can more accurately classify ccRCC patients and predict OS and DSS. Thus, IS-based classification may be a valuable tool that enables individualized treatment of patients with ccRCC.


Assuntos
Carcinoma de Células Renais/classificação , Imunofenotipagem/métodos , Neoplasias Renais/classificação , Subpopulações de Linfócitos/imunologia , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/mortalidade , Quimiocina CX3CL1 , Variações do Número de Cópias de DNA/imunologia , Proteínas de Ligação a DNA , Regulação Neoplásica da Expressão Gênica/imunologia , Proteína HMGB1 , Humanos , Interferon-alfa , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Metilação , Mutação/imunologia , Gradação de Tumores , Estadiamento de Neoplasias , Selectina-P , Valor Preditivo dos Testes , Prognóstico , Membro 14 de Receptores do Fator de Necrose Tumoral , Transdução de Sinais/imunologia , Análise de Sobrevida , Receptor 4 Toll-Like , Fatores de Transcrição , Proteína Supressora de Tumor Von Hippel-Lindau
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