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2.
Artigo em Inglês | MEDLINE | ID: mdl-32656094

RESUMO

As an emerging swine enteropathogenic coronavirus, porcine deltacoronavirus (PDCoV) not only causes serious diarrhea in suckling piglets but also possesses the potential for cross-species transmission, which has sparked growing interest when studying this emerging virus. We previously identified a novel accessory protein NS7a encoded by PDCoV; however, the function of NS7a was not resolved. In this study, we demonstrated that PDCoV NS7a is an interferon antagonist. Overexpression of NS7a notably inhibited Sendai virus (SeV)-induced interferon-ß (IFN-ß) production and the activation of IRF3 rather than NF-κB. NS7a also inhibited IFN-ß promoter activity induced by RIG-I, MDA5, MAVS, TBK1, and IKKε, which are key components of the RIG-I-like receptor (RLR) signaling pathway but not IRF3, the transcription factor downstream of TBK1/IKKε. Surprisingly, NS7a specifically interacts with IKKε but not with the closely related TBK1. Furthermore, NS7a interacts simultaneously with the kinase domain (KD) and the scaffold dimerization domain (SDD) of IKKε, competing with TRAF3, and IRF3 for binding to IKKε, leading to the reduction of RLR-mediated IFN-ß production. The interactions of TRAF3-IKKε and IKKε-IRF3 are also attenuated in PDCoV-infected cells. Taken together, our results demonstrate that PDCoV NS7a inhibits IFN-ß production by disrupting the association of IKKε with both TRAF3 and IRF3, revealing a new mechanism utilized by a PDCoV accessory protein to evade the host antiviral innate immune response.


Assuntos
Infecções por Coronavirus/metabolismo , Coronavirus/metabolismo , Quinase I-kappa B/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/antagonistas & inibidores , Fator 3 Associado a Receptor de TNF/metabolismo , Proteínas não Estruturais Virais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Coronavirus/genética , Coronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Células HEK293 , Humanos , Quinase I-kappa B/imunologia , Evasão da Resposta Imune , Fator Regulador 3 de Interferon/imunologia , Helicase IFIH1 Induzida por Interferon/metabolismo , Interferon beta/biossíntese , Interferon beta/imunologia , Receptores do Ácido Retinoico/metabolismo , Vírus Sendai/imunologia , Vírus Sendai/metabolismo , Transdução de Sinais , Suínos , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia
3.
Trials ; 21(1): 549, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32560745

RESUMO

OBJECTIVES: There is little information about Coronavirus Disease 2019 (COVID-19) management for critically ill patients. Most of these patients develop acute respiratory distress syndrome (ARDS) due to excessive inflammatory response and the ensuing cytokine storm. Anti-inflammatory drugs including corticosteroids can be used to effectively reduce the effect of this cytokine storm and lung damage. However, corticosteroids can have side effects, so simultaneous administration of immunoglobulin (IV-IG) and interferon-beta can help manage treatment using corticosteroids. Therefore, we designed a trial to test our hypothesis that early administration of dexamethasone in combination with IV-IG and interferon-beta can reduce the effect of the cytokine storm in critically ill patients COVID-19. TRIAL DESIGN: A phase two multi-center randomized controlled trial (RCT) with three parallel arms (1:1:1 ratio). PARTICIPANTS: They will be hospitalized patients with severe COVID-19 who have positive RT-PCR test and have blood oxygen saturation levels (SpO2) less than 90% and respiratory rate higher than 24 per minute or have involvement of more than 50% of their lung when viewed using computed tomography (CT)-scan. The age range of patients will be 18-70 years old. EXCLUSION CRITERIA: the need for intubation; allergy, intolerance, or contraindication to any study drug including dexamethasone, IV-IG, and interferon-beta; pregnancy or lactation; known HIV positive or active hepatitis B or C. The study will be conducted in several hospitals of the Golestan province, Iran. INTERVENTION AND COMPARATOR: The study subjects will be randomly allocated to three treatment arms: two experimental groups (two arms: Intervention 1 and Intervention 2) and one Control Group, which will be matched for age and sex using frequency matching method. Each eligible patient in the control arm will receive the standard treatment for COVID-19 based on WHO guidelines and the Ministry of the Health and Medical Education (MOHME) of Iran. Each patient in the Intervention Group 1 will receive the standard treatment for COVID-19 and dexamethasone, at the first 24 hours' time of admission. The intervention begins with the administration of dexamethasone based on the SpO2 levels. If the level of SpO2 does not improve after 24 hours, IV-IG (400 mg/kg once daily for 5 days) and interferon-beta (7 doses every other day) will be prescribed along with dexamethasone administration. In Intervention Group 2, the administration of dexamethasone will be started within the first 24 hours' time of admission and will be continued for 48-72 hours and then the SpO2 level will be checked. Then, if the level of SpO2 has not improved after that time, IV-IG and interferon-beta will be prescribed as the same dosage as Group 1. If the percentages of the SpO2 level are between 85 and 90/ 80 and 85/ 75 and 80/ less than 75, the dosages will be 4 mg every 12 hours/ 4 mg every 8 hours/ 8 mg every 12 hours/ 8 mg every 8 hours, respectively. According to the WHO recommendation, all participants will have the best available supportive care with full monitoring. MAIN OUTCOMES: Primary: An increase in the SpO2 level to reach more than 90% in each case, which will be assessed by the oximeter. Secondary: The duration of hospital stays; intubation status and the percentage of patients who are free of mechanical ventilation; the mortality rates during hospitalization and one month after the admission time. RANDOMISATION: Participants will be allocated into either control or intervention groups with a 1:1:1 allocation ratio using a computer random number generator to generate a table of random numbers for simple randomization. BLINDING (MASKING): The project's principal investigator (PI) is unblinded. However, the PI will not analyse the data and interpret the results. An unblinded researcher (a pharmacist) will cover the drug's bottles with aluminium foil and prepare them interventions and control drugs in a syringe with a code so that patients are blinded. This person will have no patients contact. The staff and nurses, caring for the patients, will be unblinded for each study group due to the nature of this study. The staff that take outcome measurements will be blinded. The laboratory technicians will also be blinded as well as the statistical team. These study statisticians will have access to coded data and will analyse the data labelled as group X, group Y, and group Z. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The target sample size will be 105 critically ill COVID-19 patients, who will be allocated randomly to the three trial arms with 35 patients in each group. TRIAL STATUS: Recruitment is ongoing. The study began on April 18 2020 and will be completed June 19 2020. This summary describes protocol version 1; April 2 2020. TRIAL REGISTRATION: https://www.irct.ir/. Identifier: IRCT20120225009124N4 version 1; Registration date: April 2 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The full protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Adolescente , Adulto , Idoso , Dexametasona/administração & dosagem , Quimioterapia Combinada , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Interferon beta/administração & dosagem , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Oxigênio/sangue , Pandemias , Adulto Jovem
4.
Mult Scler Relat Disord ; 42: 102196, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32480326

RESUMO

BACKGROUND: The Coronavirus (COVID-19), (Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)) has been spreading worldwide since its first identification in China. It has been speculated that patients with comorbidities and elderly patients could be at high risk for the pandemic reasoned respiratory insufficiency and death. At first, it was thought that the patients who use immunmodulator therapy could be even at higher risks of disease complications. However, it has been also speculated about that using immunmodulators could be an advantage for the clinical prognosis. Therefore, several immunmodulators are currently being tested as potential treatment for COVID-19. METHODS: In this paper we report on a patient that has been treated with type 1 interferon for multiple sclerosis who developed COVID-19. RESULTS: Despite using immunmodulator, the symptoms of the patient at hospitalization were mild and he did not show elevated D-dimer, and there was no lymphopenia. He was discharged to home-quarantine with no symptoms. DISCUSSION: This report supports the idea of using type 1 interferon in the treatment could be effective in COVID-19 affected patients.


Assuntos
Infecções por Coronavirus/fisiopatologia , Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Adulto , Antibacterianos/uso terapêutico , Antimaláricos/uso terapêutico , Azitromicina/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/tratamento farmacológico , Tosse/etiologia , Humanos , Hidroxicloroquina/uso terapêutico , Tempo de Internação , Masculino , Esclerose Múltipla/complicações , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/tratamento farmacológico , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
7.
Arch Virol ; 165(7): 1557-1567, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32356187

RESUMO

Caprine arthritis-encephalitis (CAE) is a chronic progressive infectious disease caused by caprine arthritis-encephalitis virus (CAEV) that seriously threatens the goat industry. Chronic infection and life-long multi-tissue inflammation are the typical features of the disease. Innate antiviral immunity is essential for the host defense system that rapidly recognizes and eliminates invading viruses. Interferon ß (IFN-ß) is important for innate immunity and regulates immunity against a broad spectrum of viruses. To investigate the details of the IFN-ß response to CAEV infection, the effects of six viral proteins and the molecular mechanisms by which they affect IFN-ß production were analyzed. Overexpression of DU and Vif promote virus proliferation and inhibit the production of IFN-ß. qRT-PCR and luciferase reporter assays showed that overexpression of Vif inhibits the expression of luciferase under the control of the ISRE, NF-κB or IFN-ß promoter but does not affect the expression of IFN-ß activated by IRF3, indicating that Vif negatively regulates IFN-ß production by affecting upstream signal transduction of IRF3. Amino acids 149-164 of Vif were found to be necessary for the inhibitory effect of IFN-ß production. Our results indicate that CAEV evades surveillance and clearance by intracellular innate immunity by downregulating IFN-ß production.


Assuntos
Vírus da Artrite-Encefalite Caprina/imunologia , Produtos do Gene vif/imunologia , Doenças das Cabras/imunologia , Interferon beta/imunologia , Infecções por Lentivirus/veterinária , Animais , Vírus da Artrite-Encefalite Caprina/genética , Produtos do Gene vif/genética , Doenças das Cabras/genética , Doenças das Cabras/virologia , Cabras , Interações Hospedeiro-Patógeno , Imunidade Inata , Interferon beta/genética , Infecções por Lentivirus/genética , Infecções por Lentivirus/imunologia , Infecções por Lentivirus/virologia , NF-kappa B/genética , NF-kappa B/imunologia
9.
Antiviral Res ; 179: 104811, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32360182

RESUMO

There is an urgent need to identify antivirals to curtail the COVID-19 pandemic. Herein, we report the sensitivity of SARS-CoV-2 to recombinant human interferons α and ß (IFNα/ß). Treatment with IFN-α or IFN-ß at a concentration of 50 international units (IU) per milliliter reduces viral titers by 3.4 log or over 4 log, respectively, in Vero cells. The EC50 of IFN-α and IFN-ß treatment is 1.35 IU/ml and 0.76 IU/ml, respectively, in Vero cells. These results suggest that SARS-CoV-2 is more sensitive than many other human pathogenic viruses, including SARS-CoV. Overall, our results demonstrate the potential efficacy of human Type I IFN in suppressing SARS-CoV-2 infection, a finding which could inform future treatment options for COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Interferon Tipo I/farmacologia , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Animais , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Imunidade Inata , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Recombinantes/farmacologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Células Vero , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
10.
Mult Scler Relat Disord ; 43: 102174, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32464584

RESUMO

BACKGROUND: SARS-CoV-2 viral infection causes COVID-19 that can result in severe acute respiratory distress syndrome (ARDS), which can cause significant mortality, leading to concern that immunosuppressive treatments for multiple sclerosis and other disorders have significant risks for both infection and ARDS. OBJECTIVE: To examine the biology that potentially underpins immunity to the SARS-Cov-2 virus and the immunity-induced pathology related to COVID-19 and determine how this impinges on the use of current disease modifying treatments in multiple sclerosis. OBSERVATIONS: Although information about the mechanisms of immunity are scant, it appears that monocyte/macrophages and then CD8 T cells are important in eliminating the SARS-CoV-2 virus. This may be facilitated via anti-viral antibody responses that may prevent re-infection. However, viral escape and infection of leucocytes to promote lymphopenia, apparent CD8 T cell exhaustion coupled with a cytokine storm and vascular pathology appears to contribute to the damage in ARDS. IMPLICATIONS: In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD8 T cells to limit protection against COVID-19. In addition, few block the formation of immature B cells within lymphoid tissue that will provide antibody-mediated protection from (re)infection. However, adjustments to dosing schedules may help de-risk the chance of infection further and reduce the concerns of people with MS being treated during the COVID-19 pandemic.


Assuntos
Betacoronavirus/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Imunossupressores/uso terapêutico , Linfopenia/imunologia , Esclerose Múltipla/terapia , Pneumonia Viral/imunologia , Alemtuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Antivirais/imunologia , Cladribina/uso terapêutico , Crotonatos/uso terapêutico , Desprescrições , Fumarato de Dimetilo/uso terapêutico , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Evasão da Resposta Imune/imunologia , Imunidade Inata/imunologia , Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Macrófagos/imunologia , Monócitos/imunologia , Natalizumab/uso terapêutico , Pandemias , Síndrome do Desconforto Respiratório do Adulto/imunologia , Toluidinas/uso terapêutico
11.
Am J Transplant ; 20(7): 1849-1858, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32301155

RESUMO

The clinical characteristics, management, and outcome of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after solid organ transplant (SOT) remain unknown. We report our preliminary experience with 18 SOT (kidney [44.4%], liver [33.3%], and heart [22.2%]) recipients diagnosed with COVID-19 by March 23, 2020 at a tertiary-care center at Madrid. Median age at diagnosis was 71.0 ± 12.8 years, and the median interval since transplantation was 9.3 years. Fever (83.3%) and radiographic abnormalities in form of unilateral or bilateral/multifocal consolidations (72.2%) were the most common presentations. Lopinavir/ritonavir (usually associated with hydroxychloroquine) was used in 50.0% of patients and had to be prematurely discontinued in 2 of them. Other antiviral regimens included hydroxychloroquine monotherapy (27.8%) and interferon-ß (16.7%). As of April 4, the case-fatality rate was 27.8% (5/18). After a median follow-up of 18 days from symptom onset, 30.8% (4/13) of survivors developed progressive respiratory failure, 7.7% (1/13) showed stable clinical condition or improvement, and 61.5% (8/13) had been discharged home. C-reactive protein levels at various points were significantly higher among recipients who experienced unfavorable outcome. In conclusion, this frontline report suggests that SARS-CoV-2 infection has a severe course in SOT recipients.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Transplante de Órgãos , Pneumonia Viral/complicações , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Transplantados , Idoso , Antivirais/administração & dosagem , Betacoronavirus , Combinação de Medicamentos , Feminino , Febre , Humanos , Hidroxicloroquina/administração & dosagem , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Interferon beta/administração & dosagem , Lopinavir/administração & dosagem , Masculino , Pessoa de Meia-Idade , Pandemias , Radiografia Torácica , Estudos Retrospectivos , Ritonavir/administração & dosagem , Espanha/epidemiologia
12.
Physiol Genomics ; 52(5): 217-221, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32275178
13.
Mol Immunol ; 121: 195-203, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32298923

RESUMO

Cells recognize virus nucleic acid by pattern recognition receptors (PRRs), virus involve in the activation of signaling cascade of variable adaptor proteins, TANK-binding kinase1(TBK1)/ inhibitor of nuclear factor kappa-B kinase subunit epsilon(IKKi) complex, IκB kinase(IKKs) to trigger activation of transcription factor, interferon regulatory factor 3/7(IRF3/7), ultimately, leading to the production of type I interferon and exert anti-viral effects. In this study, E3 ubiquitin ligase ankyrin repeat and SOCS box-containing 8(ASB8) interacted with TBK1/IKKi and phosphorylation modification of ASB8 at site of Ser17 to further strengthen its ubiquitination activity were verified. Conversely, phosphorylated ASB8 accelerate K48-linked ubiquitination and degradation of TBK1/IKKi, which further reduces phosphorylation level of IRF3 and inhibits production of IFN-ß. At the same time, a new bridge molecule Leucine-rich repeat containing protein 10B(LRRC10B) upregulated after viral infection are involved in the formation and interaction with ASB8-TBK1/IKKi complex was reported. Our study reveals a new mechanism of ubiquitin ligase ASB8 modulating antiviral innate immunity by altering stability of TBK1/IKKi kinase complex.


Assuntos
Quinase I-kappa B/metabolismo , Interferon beta/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Células HEK293 , Células HeLa , Humanos , Quinase I-kappa B/imunologia , Imunidade Inata , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 7 de Interferon/metabolismo , Interferon beta/imunologia , Fosforilação/imunologia , Proteínas Serina-Treonina Quinases/imunologia , RNA Interferente Pequeno/metabolismo , Serina/metabolismo , Transdução de Sinais/imunologia , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/imunologia , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação/imunologia
14.
PLoS Pathog ; 16(4): e1008483, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32330200

RESUMO

Pathogenic hantaviruses, genus Orthohantaviridae, are maintained in rodent reservoirs with zoonotic transmission to humans occurring through inhalation of rodent excreta. Hantavirus disease in humans is characterized by localized vascular leakage and elevated levels of circulating proinflammatory cytokines. Despite the constant potential for deadly zoonotic transmission to humans, specific virus-host interactions of hantaviruses that lead to innate immune activation, and how these processes impart disease, remain unclear. In this study, we examined the mechanisms of viral recognition and innate immune activation of Hantaan orthohantavirus (HTNV) infection. We identified the RIG-I-like receptor (RLR) pathway as essential for innate immune activation, interferon (IFN) production, and interferon stimulated gene (ISG) expression in response to HTNV infection in human endothelial cells, and in murine cells representative of a non-reservoir host. Our results demonstrate that innate immune activation and signaling through the RLR pathway depends on viral replication wherein the host response can significantly restrict replication in target cells in a manner dependent on the type 1 interferon receptor (IFNAR). Importantly, following HTNV infection of a non-reservoir host murine model, IFNAR-deficient mice had higher viral loads, increased persistence, and greater viral dissemination to lung, spleen, and kidney compared to wild-type animals. Surprisingly, this response was MAVS independent in vivo. Innate immune profiling in these tissues demonstrates that HTNV infection triggers expression of IFN-regulated cytokines early during infection. We conclude that the RLR pathway is essential for recognition of HTNV infection to direct innate immune activation and control of viral replication in vitro, and that additional virus sensing and innate immune response pathways of IFN and cytokine regulation contribute to control of HTNV in vivo. These results reveal a critical role for innate immune regulation in driving divergent outcomes of HTNV infection, and serve to inform studies to identify therapeutic targets to alleviate human hantavirus disease.


Assuntos
Proteína DEAD-box 58/imunologia , Infecções por Hantavirus/imunologia , Hantavirus/fisiologia , Interferon Tipo I/imunologia , Replicação Viral/fisiologia , Animais , Chlorocebus aethiops , Citocinas/imunologia , Citocinas/metabolismo , Proteína DEAD-box 58/metabolismo , RNA Helicases DEAD-box/metabolismo , Células Endoteliais/metabolismo , Hantavirus/imunologia , Hantavirus/metabolismo , Hantavirus/patogenicidade , Infecções por Hantavirus/metabolismo , Infecções por Hantavirus/virologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Interferon beta/metabolismo , Camundongos , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais/imunologia , Células Vero
15.
Drug Discov Ther ; 14(2): 67-72, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32336723

RESUMO

The virus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is currently affecting more than 200 countries and territories worldwide. It has been declared as pandemic by World Health Organization (WHO) and the whole world is suffering from corona virus disease 2019 (COVID-19). Currently, no treatment for SARS-CoV-2 are approved because of lack of evidence, but a number of clinical trials are in process and we are expecting fruitful results very soon. This review focuses on various approaches of treatment and few of the most recent clinical trials carried out in this field.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Cloroquina/uso terapêutico , Ensaios Clínicos como Assunto , Infecções por Coronavirus/tratamento farmacológico , Darunavir/uso terapêutico , Combinação de Medicamentos , Humanos , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Indóis/uso terapêutico , Interferon-alfa/uso terapêutico , Interferon beta/uso terapêutico , Lopinavir/uso terapêutico , Pandemias , Pirazinas/uso terapêutico , Ritonavir/uso terapêutico
16.
Georgian Med News ; (298): 84-88, 2020 Jan.
Artigo em Russo | MEDLINE | ID: mdl-32141856

RESUMO

About 30-40% of multiple sclerosis (MS) patients treated with interferon-beta (IFN-ß) develop neutralizing antibodies (NABs) to IFN-ß. NABs reduce bioavailability of IFN-ß, which leads to a decrease in the therapy effectiveness. The introduction of IFN-ß induce production of several proteins, which are used as markers of the therapy effectiveness. In this study, we assessed the prognostic significance of MS activity biomarkers in relation to the clinical data of MS patients treated with IFN-ß. The study involved 30 MS patients receiving IFN-ß. The average duration of therapy was 3.5 (3.4-5.3) years. The study showed the prevalence of NAbs formation in MS patients was 13% of cases, a year later - 30%. The level of viperin in patients without exacerbations during the observation period was lower than in patients with exacerbations. The study revealed the prognostic significance of viperin in relation to the frequency of exacerbations: viperin concentration above 0.2 ng / ml is a risk factor for exacerbation of MS. The results of this study suggest that viperin concentration in the serum could be used a prognostic marker in MS patients treated with interferons.


Assuntos
Interferon beta/farmacologia , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Anticorpos/análise , Anticorpos/sangue , Anticorpos Neutralizantes , Biomarcadores/análise , Biomarcadores/sangue , República da Geórgia/epidemiologia , Humanos , Interferon beta/efeitos adversos , Interferon beta/uso terapêutico , Esclerose Múltipla/sangue , Esclerose Múltipla/epidemiologia , Prevalência , Prognóstico , Resultado do Tratamento
17.
Mol Immunol ; 121: 136-143, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32200171

RESUMO

The innate immune system is activated upon virus invasion of a host cell by recognizing viral component, such as dsRNA through specific receptors, resulting in the production of type- I IFNs, which confer an antiviral state within the invaded as well as surrounding cells. In the present study, fibroblast, monocyte and macrophage cells derived from water Buffalo (Bubalus bubalis) were exposed to a synthetic dsRNA analogue, poly I:C to mimic viral invasion in each cell type. Recognition of poly I:C through cytosolic helicase receptors RIG-I and MDA5 molecule lead to the activation of the RLR pathway, subsequently activating the MAVS-IRF3/7 cascade and the production of antiviral effector molecule like IFNß and ISGs. Within the different cell types, we identified variability in RLR receptor and IFNß expression after poly I:C administration. Fibroblasts responded quickly and strongly with IFNß production, followed by macrophages and monocytes. Despite absolute expression variability among different cell types the expression trend of RLRs pathway genes were similar. Length of poly I:C molecule also influence IFNß expression in response of RLR pathway. Short (LMW) poly I:C induce stronger IFN-ß expression in myeloid (macrophage and monocyte) cells. In contrast long (HMW) poly I:C preferably elicit higher IFNß expression in non-myeloid (fibroblast) cell. Therefore, MDA5 and RIG-1 plays an indispensable role in eliciting antiviral response in non- immune (fibroblast) host cell. Thus, stimulation of RLR pathway with suitable and potentially cell-type specific agonist molecules successfully elicit antiviral state in the host animal, with fibroblasts conferring a stronger antiviral state compared with the monocytes and macrophages.


Assuntos
Búfalos/imunologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Poli I-C/farmacologia , Animais , Células Cultivadas , Proteína DEAD-box 58/imunologia , Proteína DEAD-box 58/metabolismo , Resistência à Doença/imunologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Interferon beta/imunologia , Interferon beta/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
18.
Can J Microbiol ; 66(7): 435-445, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32191844

RESUMO

Pneumolysin (Ply) is a major virulence factor of Streptococcus pneumoniae. Ply-induced interferon-ß (IFN-ß) expression in host macrophages has been shown to be due to the accumulation of mitochondrial deoxyribonucleic acid (mtDNA) in the cytoplasm during S. pneumoniae infection. Our findings extend this work to show human bronchial epithelial cells that reside at the interface of inflammatory injury, BEAS-2B, adapt to local cues by altering mitochondrial states and releasing excess mtDNA. The results in this research showed that purified Ply induced the expression of IFN-ß in human epithelial cells, which was accompanied by mitochondrial damage both in vivo and in vitro. The observations also were supported by the increased mtDNA concentrations in the bronchial lavage fluid of mice infected with S. pneumoniae. In summary, our study demonstrated that Ply triggered the production of IFN-ß in epithelial cells, and this response was mediated by mtDNA released from Ply-damaged mitochondria. It displayed an impressive modulation of IFN-ß response to S. pneumoniae in epithelial cells.


Assuntos
Citosol/metabolismo , DNA Mitocondrial/metabolismo , Interferon beta/metabolismo , Mitocôndrias/efeitos dos fármacos , Estreptolisinas/toxicidade , Animais , Proteínas de Bactérias/toxicidade , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/microbiologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Streptococcus pneumoniae/patogenicidade
19.
PLoS Pathog ; 16(3): e1008294, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32210476

RESUMO

Mycobacterium abscessus (MAB) is a rapidly growing mycobacterium (RGM), and infections with this pathogen have been increasing worldwide. Recently, we reported that rough type (MAB-R) but not smooth type (MAB-S) strains enhanced type 1 interferon (IFN-I) secretion via bacterial phagosome escape, contributing to increased virulence. Here, we sought to investigate the role of mitochondrial oxidative stress in bacterial survival, IFN-I secretion and NLRP3 inflammasome activation in MAB-infected murine macrophages. We found that live but not heat-killed (HK) MAB-R strains increased mitochondrial ROS (mtROS) and increased release of oxidized mitochondrial DNA (mtDNA) into the cytosol of murine macrophages compared to the effects of live MAB-S strains, resulting in enhanced NLRP3 inflammasome-mediated IL-1ß and cGAS-STING-dependent IFN-I production. Treatment of the infected macrophages with mtROS-modulating agents such as mito-TEMPO or cyclosporin A reduced cytosolic oxidized mtDNA, which inhibited the MAB-R strain-induced production of IL-1ß and IFN-I. The reduced cytosolic oxidized mtDNA also inhibited intracellular growth of MAB-R strains via cytosolic escape following phagosomal rupture and via IFN-I-mediated cell-to-cell spreading. Moreover, our data showed that mtROS-dependent IFN-I production inhibited IL-1ß production, further contributing to MAB-R intracellular survival in murine macrophages. In conclusion, our data indicated that MAB-R strains enhanced IFN-I and IL-1ß production by inducing mtROS as a pathogen-associated molecular pattern (PAMP). These events also enhance bacterial survival in macrophages and dampen inflammation, which contribute to the pathogenesis of MAB-R strains.


Assuntos
Inflamassomos/imunologia , Macrófagos/imunologia , Infecções por Mycobacterium não Tuberculosas/imunologia , Mycobacterium abscessus/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Humanos , Inflamassomos/genética , Interferon beta/genética , Interferon beta/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Mitocôndrias/metabolismo , Infecções por Mycobacterium não Tuberculosas/genética , Infecções por Mycobacterium não Tuberculosas/metabolismo , Infecções por Mycobacterium não Tuberculosas/microbiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
20.
PLoS Pathog ; 16(3): e1008435, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32210480

RESUMO

A striking feature of human visceral leishmaniasis (VL) is chronic inflammation in the spleen and liver, and VL patients present increased production levels of multiple inflammatory mediators, which contribute to tissue damage and disease severity. Here, we combined an experimental model with the transcriptional profile of human VL to demonstrate that the TLR4-IFN-ß pathway regulates the chronic inflammatory process and is associated with the asymptomatic form of the disease. Tlr4-deficient mice harbored fewer parasites in their spleen and liver than wild-type mice. TLR4 deficiency enhanced the Th1 immune response against the parasite, which was correlated with an increased activation of dendritic cells (DCs). Gene expression analyses demonstrated that IRF1 and IFN-ß were expressed downstream of TLR4 after infection. Accordingly, IRF1- and IFNAR-deficient mice harbored fewer parasites in the target organs than wild-type mice due to having an increased Th1 immune response. However, the absence of TLR4 or IFNAR increased the serum transaminase levels in infected mice, indicating the presence of liver damage in these animals. In addition, IFN-ß limits IFN-γ production by acting directly on Th1 cells. Using RNA sequencing analysis of human samples, we demonstrated that the transcriptional signature for the TLR4 and type I IFN (IFN-I) pathways was positively modulated in asymptomatic subjects compared with VL patients and thus provide direct evidence demonstrating that the TLR4-IFN-I pathway is related to the nondevelopment of the disease. In conclusion, our results demonstrate that the TLR4-IRF1 pathway culminates in IFN-ß production as a mechanism for dampening the chronic inflammatory process and preventing immunopathology development.


Assuntos
Fator Regulador 1 de Interferon/imunologia , Interferon beta/imunologia , Leishmania infantum/imunologia , Leishmaniose Visceral/imunologia , Células Th1/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Fator Regulador 1 de Interferon/genética , Interferon beta/genética , Leishmaniose Visceral/genética , Leishmaniose Visceral/patologia , Camundongos , Camundongos Knockout , Células Th1/patologia , Receptor 4 Toll-Like/genética
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