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1.
Int J Nanomedicine ; 15: 661-674, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099358

RESUMO

Background: New approaches are urgently needed to fight influenza viral infection. Previous research has shown that zirconia nanoparticles can be used as anticancer materials, but their antiviral activity has not been reported. Here, we investigated the antiviral effect of zirconia (ZrO2) nanoparticles (NPs) against a highly pathogenic avian influenza virus. Materials and Methods: In this study, the antiviral effects of ZrO2 on H5N1 virus were assessed in vivo, and the molecular mechanism responsible for this protection was investigated. Results: Mice treated with 200 nm positively-charged NPs at a dose of 100 mg/kg showed higher survival rates and smaller reductions in weight. 200 nm ZrO2 activated mature dendritic cells and initially promoted the expression of cytokines associated with the antiviral response and innate immunity. In the lungs of H5N1-infected mice, ZrO2 treatment led to less pathological lung injury, significant reduction in influenza A virus replication, and overexpression of pro-inflammatory cytokines. Conclusion: This antiviral study using zirconia NPs shows protection of mice against highly pathogenic avian influenza virus and suggests strong application potential for this method, introducing a new tool against a wide range of microbial infections.


Assuntos
Antivirais/farmacologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Zircônio/farmacologia , Animais , Antivirais/química , Citocinas/metabolismo , Cães , Feminino , Imunidade Inata/efeitos dos fármacos , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Virus da Influenza A Subtipo H5N1/patogenicidade , Virus da Influenza A Subtipo H5N1/fisiologia , Células Madin Darby de Rim Canino , Camundongos Endogâmicos BALB C , Glicinas N-Substituídas/química , Glicinas N-Substituídas/farmacologia , Nanopartículas/química , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Tamanho da Partícula , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Replicação Viral/efeitos dos fármacos , Zircônio/química
2.
Emerg Microbes Infect ; 9(1): 78-87, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31894728

RESUMO

The H7N9 influenza virus has been circulating in China for more than six years. The neuraminidase (NA) has gained great concern for the development of antiviral drugs, therapeutic antibodies, and new vaccines. In this study, we screened seven mouse monoclonal antibodies (mAbs) and compared their protective effects against H7N9 influenza virus. The epitope mapping from escape mutants showed that all the seven mAbs could bind to the head region of the N9 NA close to the enzyme activity sites, and four key sites of N9 NA were reported for the first time. The mAbs D3 and 7H2 could simultaneously inhibit the cleavage of the sialic acid of fetuin protein with large molecular weight and NA-XTD with small molecule weight in the NA inhibition experiment, prevent the formation of virus plaque at a low concentration, and effectively protect the mice from the challenge of the lethal dose of H7N9 virus.


Assuntos
Anticorpos Monoclonais/química , Subtipo H7N9 do Vírus da Influenza A/imunologia , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Infecções por Orthomyxoviridae/prevenção & controle , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antígenos Virais , Domínio Catalítico , Linhagem Celular , Cães , Mapeamento de Epitopos , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/tratamento farmacológico
3.
Phytomedicine ; 67: 153150, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31958713

RESUMO

BACKGROUND: Influenza virus is one of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. Houttuynia cordata is a traditionally used medicinal plant for the treatment of pneumonia. Flavonoids are one of the major bioactive constituents of Houttuynia cordata. PURPOSE: This study was designed to investigate the therapeutic effect and mechanism of flavonoid glycosides from H. cordata on influenza A virus (IAV)-induced acute lung injury (ALI) in mice. METHODS: Flavonoids from H. cordata (HCF) were extracted from H. cordata and identified by high-performance liquid chromatography. Mice were infected intranasally with influenza virus H1N1 (A/FM/1/47). HCF (50, 100, or 200 mg/kg) or Ribavirin (100 mg/kg, the positive control) were administered intragastrically. Survival rates, life spans, weight losses, lung indexes, histological changes, inflammatory infiltration, and inflammatory markers in the lungs were measured. Lung virus titers and neuraminidase (NA) activities were detected. The expression of Toll-like receptors (TLRs) and levels of NF-κB p65 phosphorylation (NF-κB p65(p)) in the lungs were analysed. The effects of HCF on viral replication and TLR signalling were further evaluated in cells. RESULTS: HCF contained 78.5% flavonoid glycosides. The contents of rutin, hyperin, isoquercitrin, and quercitrin in HCF were 8.8%, 26.7%, 9.9% and 31.7%. HCF (50, 100 and 200 mg/kg) increased the survival rate and life span of mice infected with the lethal H1N1 virus. In H1N1-induced ALI, mice treated with HCF (50, 100 and 200 mg/kg) showed lesser weight loss and lower lung index than the model group. The lungs of HCF-treated ALI mice presented more intact lung microstructural morphology, milder inflammatory infiltration, and lower levels of monocyte chemotactic protein 1 (MCP-1), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α) and malondialdehyde (MDA) than in the model group. Further investigation revealed that HCF exerted antiviral and TLR-inhibitory effects in vivo and in vitro. HCF (50, 100 and 200 mg/kg) reduced lung H1N1 virus titers and inhibited viral NA activity in mice. HCF (100 and 200 mg/kg) elevated the levels of interferon-ß in lungs. HCF also decreased the expression of TLR3/4/7 and level of NF-κB p65(p) in lung tissues. In vitro experiments showed that HCF (50, 100 and 200 µg/ml) significantly inhibited viral proliferation and suppressed NA activity. In RAW 264.7 cells, TLR3, TLR4, and TLR7 agonist-stimulated cytokine secretion, NF-κB p65 phosphorylation, and nuclear translocation were constrained by HCF treatment. Furthermore, among the four major flavonoid glycosides in HCF, hyperin and quercitrin inhibited both viral replication and TLR signalling in cells. CONCLUSION: HCF significantly alleviated H1N1-induced ALI in mice, which were associated with its dual antiviral and anti-inflammatory effects via inhibiting influenzal NA activity and TLR signalling. among the four major flavonoid glycosides in HCF, hyperin and quercitrin played key roles in the therapeutic effect of HCF.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/virologia , Antivirais/farmacologia , Flavonoides/farmacologia , Houttuynia/química , Vírus da Influenza A Subtipo H1N1/patogenicidade , Lesão Pulmonar Aguda/metabolismo , Animais , Antivirais/química , Cães , Flavonoides/química , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/fisiologia , Células Madin Darby de Rim Canino , Camundongos Endogâmicos BALB C , Neuraminidase/metabolismo , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/metabolismo , Receptores Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Replicação Viral/efeitos dos fármacos
4.
Biomed Pharmacother ; 121: 109471, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31707346

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In recent years, Gegen Qinlian decoction (GQD) has been applied to treat influenza virus infection, and its clinical effectiveness has been shown. However, the potential mechanism by which GQD acts on influenza A virus (IAV) has not been fully elucidated. Traditional Chinese medicine (TCM) formulas are well known to have multiple targets and effects. Our previous experiments examined the mechanism by which TCM can be used to treat influenza from the perspective of the influenza immune mechanism. AIM OF THE STUDY: To explore the possible mechanism by which GQD affects mice infected with the FM1 strain of influenza virus. MATERIALS AND METHODS: Forty-eight C57BL/6 mice were divided randomly into four groups: a normal control (NG) group, an IAV infection (VG) group, an IAV + oseltamivir (30.44 mg/kg) treatment (VO) group, and an IAV + GQD (9.74 g/kg) treatment (VQ) group. We also grouped forty-eight Toll-like receptor 7 knockout (TLR7-/-) mice in the same manner. The pulmonary mRNA expression of TLR7, myeloid differentiation factor 88 (MyD88), and nuclear factor (NF)-κB p65 was measured by RT-qPCR, and the pulmonary protein expression of TLR7, MyD88, and NF-κB p65 was measured by western blot. The proportions of T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cells were measured by flow cytometry. RESULTS: IAV infection led to low body weights and high viral load. Compared with those in the NG group, the mRNA expression levels of TLR7, MyD88, and NF-κB p65 in the VG group were upregulated (P < 0.05). However, the mRNA and protein expression levels of TLR7, MyD88, and NF-κB p65 were lower in the VO and VQ groups than in the VG group (P < 0.05). IAV infection led to increased proportions of Th1/Th2 and Th17/Treg cells in the VG group. In the VO and VQ groups, both Th2 and Th1 cell numbers were increased, resulting in a lower Th1/Th2 proportion than that in the VG group. CONCLUSIONS: GQD downregulated the expression of some key TLR signalling pathway factors. GQD also affected the differentiation of CD4+ T cells, thereby exerting a protective systemic effect on influenza virus infection. In conclusion, GQD activated a balanced inflammatory response in the host to limit immune pathological injury and improve clinical and survival outcomes.


Assuntos
Antivirais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Infecções por Orthomyxoviridae/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Receptor 7 Toll-Like/metabolismo , Animais , Regulação para Baixo/efeitos dos fármacos , Feminino , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Infecções por Orthomyxoviridae/virologia , Oseltamivir/farmacologia , Linfócitos T/efeitos dos fármacos
5.
Biomed Pharmacother ; 121: 109652, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31734578

RESUMO

BACKGROUND: The aim of the present study was to investigate the synergistic effects and interactive mechanisms of Shufeng Jiedu Capsule (SFJDC) combined with oseltamivir in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) induced by the influenza A virus (IAV). METHODS: The extraction of SFJDC was analyzed by UHPLC/ESI Q-Orbitrap Mass Spectrometry. Human bronchial epithelial cells were isolated from COPD (DHBE) bronchial tissues, co-cultured with IAV for 24 h, and were subsequently treated with SFJDC and/or oseltamivir. Cell viability was detected by MTT assay. A rat model of COPD with IAV infection was established and treated with SFJDC and/or oseltamivir. Interleukin (IL)-1ß and IL-18 in serum and bronchoalveolar lavage fluid (BALF) were measured by ELISA. Additionally, mRNA and protein levels of NLRP3 inflammasome pathway were measured by quantitative real-time PCR and Western blotting, respectively. RESULTS: SFJDC and/or oseltamivir, at their optimal concentrations, had no significant cytotoxicity against DHBEs. The levels of NLRP3-inflammasome-associated components were significantly elevated after cells were inoculated with IAV, whereas the mRNA and protein levels of these components were significantly decreased after treatment with SFJDC and/or oseltamivir in vitro. Moreover, in vivo, the combination of SFJDC and oseltamivir improved survival rates, attenuated clinical symptoms, induced weight gain, alleviated lung damage, and significantly reduced IL-1ß and IL-18 levels in serum and BALF, as well as reduced the expression levels of NLRP3-associated components and viral titers in lung homogenates. CONCLUSION: SFJDC combined with oseltamivir treatment significantly attenuated IAV-induced airway inflammation and lung viral titers. Hence, our findings may provide a novel therapeutic strategy for IAV-induced respiratory infection.


Assuntos
Antivirais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Oseltamivir/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/virologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/virologia , Animais , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/virologia , Líquido da Lavagem Broncoalveolar/virologia , Linhagem Celular , Técnicas de Cocultura/métodos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/virologia , Influenza Humana/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/virologia , Masculino , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Carga Viral/efeitos dos fármacos
6.
Virol J ; 16(1): 163, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870450

RESUMO

BACKGROUND: Patchouli alcohol (PA) is a tricyclic sesquiterpene extracted from Pogostemonis Herba, which is a traditional Chinese medicine used for therapy of inflammatory diseases. Recent studies have shown that PA has various pharmacological activities, including anti-bacterial and anti-viral effects. METHODS: In this study, the anti-influenza virus (IAV) activities and mechanisms were investigated both in vitro and in vivo. The inhibitory effects of PA against IAV in vitro were evaluated by plaque assay and immunofluorescence assay. The neuraminidase inhibition assay, hemagglutination inhibition (HI) assay, and western blot assay were used to explore the anti-viral mechanisms. The anti-IAV activities in vivo were determined by mice pneumonia model and HE staining. RESULTS: The results showed that PA significantly inhibited different IAV strains multiplication in vitro, and may block IAV infection through inactivating virus particles directly and interfering with some early stages after virus adsorption. Cellular PI3K/Akt and ERK/MAPK signaling pathways may be involved in the anti-IAV actions of PA. Intranasal administration of PA markedly improved mice survival and attenuated pneumonia symptoms in IAV infected mice, comparable to the effects of Oseltamivir. CONCLUSIONS: Therefore, Patchouli alcohol has the potential to be developed into a novel anti-IAV agent in the future.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A/crescimento & desenvolvimento , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Administração Intranasal , Animais , Antivirais/administração & dosagem , Modelos Animais de Doenças , Pulmão/patologia , Camundongos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/patologia , Sesquiterpenos/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento
7.
Int J Mol Sci ; 20(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842256

RESUMO

The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC50) for H1N1 and H1N1-H275Y were 33.6 µM and 32.8 µM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC50) of NC-5 was greater than 640 µM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.


Assuntos
Antivirais/farmacologia , Ácido Benzoico/farmacologia , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Ácido Benzoico/síntese química , Ácido Benzoico/química , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Replicação Viral/efeitos dos fármacos
8.
PLoS Pathog ; 15(11): e1007634, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31682641

RESUMO

Induction of vast transcriptional programs is a central event of innate host responses to viral infections. Here we report a transcriptional program with potent antiviral activity, driven by E74-like ETS transcription factor 1 (ELF1). Using microscopy to quantify viral infection over time, we found that ELF1 inhibits eight diverse RNA and DNA viruses after multi-cycle replication. Elf1 deficiency results in enhanced susceptibility to influenza A virus infections in mice. ELF1 does not feed-forward to induce interferons, and ELF1's antiviral effect is not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNA-seq revealed that the ELF1 transcriptional program is distinct from interferon signatures. Thus, ELF1 provides an additional layer of the innate host response, independent from the action of type I interferons.


Assuntos
Antivirais/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Vírus da Influenza A/imunologia , Interferon Tipo I/farmacologia , Proteínas Nucleares/metabolismo , Infecções por Orthomyxoviridae/imunologia , Fatores de Transcrição/metabolismo , Replicação Viral/imunologia , Células A549 , Animais , Feminino , Humanos , Imunidade Inata , Vírus da Influenza A/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Nucleares/genética , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Fosforilação , Fator de Transcrição STAT1 , Transdução de Sinais , Fatores de Transcrição/genética , Replicação Viral/efeitos dos fármacos
9.
Cell Host Microbe ; 26(6): 729-738.e4, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31757767

RESUMO

Influenza virus neuraminidase (NA) is a major target for small-molecule antiviral drugs. Antibodies targeting the NA surface antigen could also inhibit virus entry and egress to provide host protection. However, our understanding of the nature and range of target epitopes is limited because of a lack of human antibody structures with influenza neuraminidase. Here, we describe crystal and cryogenic electron microscopy (cryo-EM) structures of NAs from human-infecting avian H7N9 viruses in complex with five human anti-N9 antibodies, systematically defining several antigenic sites and antibody epitope footprints. These antibodies either fully or partially block the NA active site or bind to epitopes distant from the active site while still showing neuraminidase inhibition. The inhibition of antibodies to NAs was further analyzed by glycan array and solution-based NA activity assays. Together, these structural studies provide insights into protection by anti-NA antibodies and templates for the development of NA-based influenza virus vaccines and therapeutics.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Epitopos/ultraestrutura , Neuraminidase , Infecções por Orthomyxoviridae/tratamento farmacológico , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/ultraestrutura , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/ultraestrutura , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/ultraestrutura , Antivirais/imunologia , Microscopia Crioeletrônica , Epitopos/imunologia , Epitopos/metabolismo , Humanos , Subtipo H7N9 do Vírus da Influenza A/imunologia , Vacinas contra Influenza , Neuraminidase/química , Neuraminidase/ultraestrutura , Infecções por Orthomyxoviridae/prevenção & controle , Proteínas Virais/química , Proteínas Virais/ultraestrutura
10.
mBio ; 10(5)2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641082

RESUMO

Influenza virus neuraminidase (NA) has been under intense study recently as a vaccine antigen, yet there remain unanswered questions regarding the immune response directed toward NA. Antibodies (Abs) that can inhibit NA activity have been shown to aid in the control of disease caused by influenza virus infection in humans and animal models, yet how and if interactions between the Fc portion of anti-NA Abs and Fcγ receptors (FcγR) contribute to protection has not yet been extensively studied. Herein, we show that poly- and monoclonal anti-NA IgG antibodies with NA inhibitory activity can control A(H1N1)pdm09 infection in the absence of FcγRs, but FcγR interaction aided in viral clearance from the lungs. In contrast, a mouse-human chimeric anti-NA IgG1 that was incapable of mediating NA inhibition (NI) solely relied on FcγR interaction to protect transgenic mice (with a humanized FcγR compartment) against A(H1N1)pdm09 infection. As such, this study suggests that NA-specific antibodies contribute to protection against influenza A virus infection even in the absence of NI activity and supports protection through multiple effector mechanisms.IMPORTANCE There is a pressing need for next-generation influenza vaccine strategies that are better able to manage antigenic drift and the cocirculation of multiple drift variants and that consistently improve vaccine effectiveness. Influenza virus NA is a key target antigen as a component of a next-generation vaccine in the influenza field, with evidence for a role in protective immunity in humans. However, mechanisms of protection provided by antibodies directed to NA remain largely unexplored. Herein, we show that antibody Fc interaction with Fcγ receptors (FcγRs) expressed on effector cells contributes to viral control in a murine model of influenza. Importantly, a chimeric mouse-human IgG1 with no direct antiviral activity was demonstrated to solely rely on FcγRs to protect mice from disease. Therefore, antibodies without NA enzymatic inhibitory activity may also play a role in controlling influenza viruses and should be of consideration when designing NA-based vaccines and assessing immunogenicity.


Assuntos
Anticorpos Antivirais/farmacologia , Anticorpos Antivirais/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Neuraminidase/imunologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/imunologia , Antivirais/imunologia , Feminino , Fragmentos Fc das Imunoglobulinas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/imunologia
11.
mBio ; 10(5)2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641086

RESUMO

The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. In vitro studies have confirmed that extreme virulence is an inherent property of this virus. Here, we utilized the macaque model for evaluating the efficacy of oseltamivir phosphate against the fully reconstructed 1918 influenza virus in a highly susceptible and relevant disease model. Our findings demonstrate that oseltamivir phosphate is effective in preventing severe disease in macaques but vulnerable to virus escape through emergence of resistant mutants, especially if given in a treatment regimen. Nevertheless, we conclude that oseltamivir would be highly beneficial to reduce the morbidity and mortality rates caused by a highly pathogenic influenza virus although it would be predicted that resistance would likely emerge with sustained use of the drug.IMPORTANCE Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.


Assuntos
Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/uso terapêutico , Animais , Macaca , Infecções por Orthomyxoviridae/virologia
12.
Am J Respir Cell Mol Biol ; 61(4): 537-540, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31573336
13.
J Dairy Sci ; 102(11): 9559-9569, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31495632

RESUMO

Antiviral neuraminidase inhibitors, such as oseltamivir, zanamivir, and peramivir, are widely used for treatment of influenza virus infection. We reported previously that oseltamivir inhibits the viral growth cycle, ameliorates symptoms, and reduces viral antigen quantities. Suppressed viral antigen production, however, induces a reduction of acquired antiviral humoral immunity, and increases the incidence of re-infection rate in the following year. To achieve effective treatment of influenza virus infection, it is necessary to overcome these adverse effects of antiviral neuraminidase inhibitors. Feeding of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus (L. bulgaricus) OLL1073R-1 is reported to have immune-stimulatory effects on influenza virus infection in mice and humans. In the present study, we assessed the effect of feeding L. bulgaricus OLL1073R-1 yogurt cultures (YC) on local and systemic humoral immune responses, which were suppressed by oseltamivir treatment, in mice infected with influenza A virus. Yogurt culture (1.14 × 108 cfu/0.4 mL per mouse per day) or sterile water (vehicle) was administered by intragastric gavage for 35 d. At d 22, influenza A virus/Puerto Rico/8/34 (H1N1) (PR8; 0.5 pfu/15 µL per mouse) was instilled intranasally, followed immediately by oral administration of oseltamivir (50 µg/100 µL per mouse, twice daily) or 5% methylcellulose (100 µL/mouse) as a vehicle for 13 d. Titers of anti-PR8-specific IgG and IgA in serum and mucosal secretory IgA (S-IgA) and IgG in bronchoalveolar lavage fluid (BALF) were analyzed by ELISA at 14 d after infection. Oseltamivir significantly suppressed the induction of anti-PR8-specific IgG and IgA in serum and S-IgA and IgG in BALF after infection. Feeding YC mildly but significantly stimulated production of PR8-specific IgA in serum, S-IgA in BALF, and IgG in serum without changing the IgG2a:IgG1 ratio. We analyzed the neutralizing activities against PR8 in serum and BALF and found that oseltamivir also reduced protective immunity, and YC feeding abrogated this effect. The immune-stimulatory tendency of YC on anti-PR8-specific IgA and IgG titers in serum and BALF was also detected in mice re-infected with PR8, but the effect was insignificant, unlike the effect of YC in the initial infection.


Assuntos
Antivirais/uso terapêutico , Imunidade Humoral/efeitos dos fármacos , Lactobacillus delbrueckii , Neuraminidase/antagonistas & inibidores , Infecções por Orthomyxoviridae/imunologia , Oseltamivir/uso terapêutico , Probióticos/uso terapêutico , Proteínas Virais/antagonistas & inibidores , Ração Animal , Animais , Antivirais/efeitos adversos , Antivirais/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Lactobacillus delbrueckii/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/dietoterapia , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/efeitos adversos , Oseltamivir/antagonistas & inibidores , Iogurte
14.
Chin J Nat Med ; 17(9): 650-662, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31526500

RESUMO

Ge Gen Decoction (GGD), a Traditional Chinese Medicine prescription, is mainly used to treat infectious respiratory diseases and can relieve the symptoms of influenza A virus (IAV) infection. However, the underlying mechanism of GGD against IAV infection remains unclear. In this study, we found that GGD had moderate anti-IAV activity in vitro. GGD was more effective when given before the viral infection and targeted the viral attachment and replication stages rather than the internalization stage. In vivo, GGD treatment reduced thevirus titers of lung tissue significantly and improved the survival rate, lung index, and pulmonary histopathological changes in H1N1-infected mice. We observed the changes in several key immuno-related indexes in GGD administrated H1N1-infected mice with anti-IAV drug oseltamivir phosphate as the control. GGD treatment decreased the expression of TNF-α and improved Th1/Th2 immune balance to reduce the excessive immune response in H1N1-infected mice. Besides, the expression of the toll-like receptor 7 signaling pathway in H1N1-infected mice decreased after GGD treatment. Our results showed that GGD has anti-IAV activity and can modulate the immune system to relieve lung inflammation.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Vírus da Influenza A/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/imunologia , Animais , Antivirais/administração & dosagem , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Citocinas/metabolismo , Cães , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Feminino , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A/fisiologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Células Madin Darby de Rim Canino , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos ICR , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Oseltamivir/administração & dosagem , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Equilíbrio Th1-Th2/efeitos dos fármacos , Receptor 7 Toll-Like/metabolismo , Ligação Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
15.
Influenza Other Respir Viruses ; 13(6): 564-573, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31541519

RESUMO

BACKGROUND: Bioaerosol sampling devices are necessary for the characterization of infectious bioaerosols emitted by naturally-infected hosts with acute respiratory virus infections. Assessment of these devices under multiple experimental conditions will provide insight for device use. OBJECTIVES: The primary objective of this study was to assess and compare bioaerosol sampling devices using a) an in vitro, environmentally-controlled artificial bioaerosol system at a range of different RH conditions and b) an in vivo bioaerosol system of influenza virus-infected ferrets under controlled environmental conditions. Secondarily, we also sought to examine the impact of NSAIDs on bioaerosol emission in influenza virus-infected ferrets to address its potential as a determinant of bioaerosol emission. METHODS: We examined the performance of low and moderate volume bioaerosol samplers for the collection of viral RNA and infectious influenza virus in vitroand in vivo using artificial bioaerosols and the ferret model of influenza virus infection. The following samplers were tested: the polytetrafluoroethylene filter (PTFE filter), the 2-stage National Institute of Occupational Safety and Health cyclone sampler (NIOSH cyclone sampler) and the 6-stage viable Andersen impactor (Andersen impactor). RESULTS: The PTFE filter and NIOSH cyclone sampler collected similar amounts of viral RNA and infectious virus from artificially-generated aerosols under a range of relative humidities (RH). Using the ferret model, the PTFE filter, NIOSH cyclone sampler and the Andersen impactor collected up to 3.66 log10 copies of RNA/L air, 3.84 log10 copies of RNA/L air and 6.09 log10 copies of RNA/L air respectively at peak recovery. Infectious virus was recovered from the PTFE filter and NIOSH cyclone samplers on the peak day of viral RNA recovery. CONCLUSION: The PTFE filter and NIOSH cyclone sampler are useful for influenza virus RNA and infectious virus collection and may be considered for clinical and environmental settings.


Assuntos
Aerossóis , Microbiologia do Ar , Vírus da Influenza A/isolamento & purificação , Infecções por Orthomyxoviridae/transmissão , Manejo de Espécimes/instrumentação , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Modelos Animais de Doenças , Furões , Umidade , Vírus da Influenza A/genética , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Tamanho da Partícula , RNA Viral/análise
16.
J Antibiot (Tokyo) ; 72(10): 759-768, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31300721

RESUMO

The pandemic influenza 2009 (A(H1N1)pdm09) virus currently causes seasonal and annual epidemic outbreaks. The widespread use of anti-influenza drugs such as neuraminidase and matrix protein 2 (M2) channel inhibitors has resulted in the emergence of drug-resistant influenza viruses. In this study, we aimed to determine the anti-influenza A(H1N1)pdm09 virus activity of azithromycin, a re-positioned macrolide antibiotic with potential as a new anti-influenza candidate, and to elucidate its underlying mechanisms of action. We performed in vitro and in vivo studies to address this. Our in vitro approaches indicated that progeny virus replication was remarkably inhibited by treating viruses with azithromycin before infection; however, azithromycin administration after infection did not affect this process. We next investigated the steps inhibited by azithromycin during virus invasion. Azithromycin did not affect attachment of viruses onto the cell surface, but blocked internalization into host cells during the early phase of infection. We further demonstrated that azithromycin targeted newly budded progeny virus from the host cells and inactivated their endocytic activity. This unique inhibitory mechanism has not been observed for other anti-influenza drugs, indicating the potential activity of azithromycin before and after influenza virus infection. Considering these in vitro observations, we administered azithromycin intranasally to mice infected with A(H1N1)pdm09 virus. Single intranasal azithromycin treatment successfully reduced viral load in the lungs and relieved hypothermia, which was induced by infection. Our findings indicate the possibility that azithromycin could be an effective macrolide for the treatment of human influenza.


Assuntos
Antivirais/farmacologia , Azitromicina/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Células A549 , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Antivirais/administração & dosagem , Azitromicina/administração & dosagem , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Humanos , Pulmão/virologia , Camundongos , Infecções por Orthomyxoviridae/tratamento farmacológico , Resultado do Tratamento , Carga Viral , Liberação de Vírus/efeitos dos fármacos
17.
Mar Drugs ; 17(6)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234532

RESUMO

CONTEXT: Seaweed metabolites (fucoidans, carrageenans, ulvans, lectins, and polyphenols) are biologically active compounds that target proteins or genes of the influenza virus and host components that are necessary for replication and reproduction of the virus. OBJECTIVE: This review gathers the information available in the literature regarding to the useful properties of seaweeds metabolites as potential agents for the prevention and therapy of influenza infection. MATERIALS AND METHODS: The sources of scientific literature were found in various electronic databases (i.e., PubMed, Web of Science, and ScienceDirect) and library search. The retrospective search depth is 25 years. RESULTS: Influenza is a serious medical and social problem for humanity. Recently developed drugs are quite effective against currently circulating influenza virus strains, but their use can lead to the selection of resistant viral strains. In this regard, new therapeutic approaches and drugs with a broad spectrum of activity are needed. Metabolites of seaweeds fulfill these requirements. This review presents the results of in vitro and in vivo experimental and clinical studies about the effectiveness of these compounds in combating influenza infection and explains the necessity of their use as a potential basis for the creation of new drugs with a broad spectrum of activity.


Assuntos
Antivirais/metabolismo , Antivirais/farmacologia , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/prevenção & controle , Alga Marinha/metabolismo , Animais , Carragenina/metabolismo , Carragenina/farmacologia , Humanos , Polifenóis/metabolismo , Polifenóis/farmacologia , Estudos Retrospectivos
18.
J Microbiol Biotechnol ; 29(8): 1184-1192, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31154753

RESUMO

The influenza A virus is a highly infectious respiratory pathogen that sickens many people with respiratory disease annually. To prevent outbreaks of this viral infection, an understanding of the characteristics of virus-host interaction and development of an anti-viral agent is urgently needed. The influenza A virus can infect mammalian species including humans, pigs, horses and seals. Furthermore, this virus can switch hosts and form a novel lineage. This so-called zoonotic infection provides an opportunity for virus adaptation to the new host and leads to pandemics. Most influenza A viruses express proteins that antagonize the antiviral defense of the host cell. The non-structural protein 1 (NS1) of the influenza A virus is the most important viral regulatory factor controlling cellular processes to modulate host cell gene expression and double-stranded RNA (dsRNA)-mediated antiviral response. This review focuses on the influenza A virus NS1 protein and outlines current issues including the life cycle of the influenza A virus, structural characterization of the influenza A virus NS1, interaction between NS1 and host immune response factor, and design of inhibitors resistant to the influenza A virus.


Assuntos
Vírus da Influenza A/genética , Proteínas não Estruturais Virais/genética , Sequência de Aminoácidos , Animais , Antivirais/farmacologia , Regulação Viral da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Vírus da Influenza A/fisiologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/prevenção & controle , Conformação Proteica , RNA de Cadeia Dupla/genética , RNA de Cadeia Dupla/isolamento & purificação , Proteínas não Estruturais Virais/metabolismo , Replicação Viral
19.
Pharmazie ; 74(5): 265-269, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31109395

RESUMO

A series of new matrinic derivatives with an 11-adamantyl group were designed, synthesized and evaluated for their anti-influenza A H3N2 activities, based on the privileged structure strategy.SAR analysis indicated that introduction of an 11-adamantyl by ester linker might be helpful for the activity. Among them, compound 7b exhibited promising anti-H3N2 activities with IC50 value of 5.14 µM, slightly better than that of amantadine. Its activity was further confirmed at the protein level. In primary mechanism, compound 7b could inhibit virus replication cycle at early stage by targeting M2 protein, consistent with that of amantadine. This study represents a successful application of combined strategy of privileged amantadine segment for further structural optimization and development of a new class of anti-influenza agents.


Assuntos
Alcaloides/química , Amantadina/análogos & derivados , Antivirais/síntese química , Antivirais/farmacologia , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Quinolizinas/química , Alcaloides/farmacologia , Animais , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Quinolizinas/farmacologia , Relação Estrutura-Atividade
20.
PLoS One ; 14(5): e0217307, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31107922

RESUMO

Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Modelos Animais de Doenças , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Feminino , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunocompetência , Hospedeiro Imunocomprometido , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/fisiologia , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Camundongos Endogâmicos BALB C , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Oseltamivir/farmacologia , Oxazinas/administração & dosagem , Piridinas/administração & dosagem , Tiepinas/administração & dosagem , Triazinas/administração & dosagem , Replicação Viral/efeitos dos fármacos
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