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1.
Vet Microbiol ; 235: 234-242, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31383307

RESUMO

During 2012-2015, six H5N1 avian influenza viruses were isolated from domestic birds and the environment around Qinghai Lake. Phylogenetic analysis of HA genes revealed that A/chicken/Gansu/XG2/2012 (CK/GS/XG2/12) belonged to clade 2.3.2.1a, while A/environment/Qinghai/1/2013 (EN/QH/1/13), A/chicken/Qinghai/QH1/2015 (CK/QH/QH1/15), A/chicken/Qinghai/QH2/2015 (CK/QH/QH2/15), A/chicken/Qinghai/QH3/2015 (CK/QH/QH3/15), and A/goose/Qinghai/QH6/2015 (GS/QH/QH6/15) belonged to clade 2.3.2.1c. Further analysis of the internal genes of the isolates found that the PB2 gene of EN/QH/1/13 had 99.6% nucleotide identity with that of A/tiger/Jiangsu/1/2013 (H5N1), which clustered into an independent branch with PB2 from multiple subtypes. PB2, PB1, and M genes of CK/QH/QH3/15 were from H9N2, suggesting it was a reassortant of H5N1 and H9N2. Animal studies of three selected viruses revealed that CK/GS/XG2/12, EN/QH/1/13, and CK/QH/QH3/15 were highly lethal to chickens, with intravenous pathogenicity indexes (IVPIs) of 2.97, 2.81, and 3.00, respectively, and systemically replicated in chickens. In a mouse study, three selected H5N1 viruses were highly pathogenic to mice and readily replicated in the lungs, nasal turbinates, kidneys, spleens, and brains. Therefore, isolates in this study appear to be novel reassortants that were circulating at the interface of wild and domestic birds around Qinghai Lake and are lethal to chickens and mice. These data suggest that more extensive surveillance should be implemented, and matched vaccines should be chosen for the domestic birds in this area.


Assuntos
Animais Domésticos/virologia , Virus da Influenza A Subtipo H5N1/genética , Influenza Aviária/epidemiologia , Lagos/virologia , Células A549 , Animais , Galinhas/virologia , China/epidemiologia , Cães , Patos/virologia , Evolução Molecular , Feminino , Humanos , Virus da Influenza A Subtipo H5N1/patogenicidade , Vírus da Influenza A Subtipo H9N2/genética , Vírus da Influenza A Subtipo H9N2/patogenicidade , Influenza Aviária/mortalidade , Influenza Aviária/virologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Filogenia , Vírus Reordenados/genética , Vírus Reordenados/patogenicidade , Replicação Viral
2.
J Virol ; 92(11)2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29563291

RESUMO

Nonstructural protein 1 (NS1) of influenza A virus regulates innate immune responses via various mechanisms. We previously showed that a naturally occurring deletion (the EALQR motif) in the NS1 effector domain of an H5N1 swine-origin avian influenza virus impairs the inhibition of type I interferon (IFN) in chicken fibroblasts and attenuates virulence in chickens. Here we found that the virus bearing this deletion in its NS1 effector domain showed diminished inhibition of IFN-related cytokine expression and attenuated virulence in mice. We further showed that deletion of the EALQR motif disrupted NS1 dimerization, impairing double-stranded RNA (dsRNA) sequestration and competitive binding with RIG-I. In addition, the EALQR-deleted NS1 protein could not bind to TRIM25, unlike full-length NS1, and was less able to block TRIM25 oligomerization and self-ubiquitination, further impairing the inhibition of TRIM25-mediated RIG-I ubiquitination compared to that with full-length NS1. Our data demonstrate that the EALQR deletion prevents NS1 from blocking RIG-I-mediated IFN induction via a novel mechanism to attenuate viral replication and virulence in mammalian cells and animals.IMPORTANCE H5 highly pathogenic avian influenza viruses have infected more than 800 individuals across 16 countries, with an overall case fatality rate of 53%. Among viral proteins, nonstructural protein 1 (NS1) of influenza virus is considered a key determinant for type I interferon (IFN) antagonism, pathogenicity, and host range. However, precisely how NS1 modulates virus-host interaction, facilitating virus survival, is not fully understood. Here we report that a naturally occurring deletion (of the EALQR motif) in the NS1 effector domain of an H5N1 swine-origin avian influenza virus disrupted NS1 dimerization, which diminished the blockade of IFN induction via the RIG-I signaling pathway, thereby impairing virus replication and virulence in the host. Our study demonstrates that the EALQR motif of NS1 regulates virus fitness to attain a virus-host compromise state in animals and identifies this critical motif as a potential target for the future development of small molecular drugs and attenuated vaccines.


Assuntos
Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/imunologia , Interferon Tipo I/imunologia , Proteínas não Estruturais Virais/genética , Células A549 , Animais , Linhagem Celular Tumoral , Embrião de Galinha , Proteínas de Ligação a DNA/metabolismo , Feminino , Células HEK293 , Humanos , Imunidade Inata/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica/genética , Domínios Proteicos/genética , Deleção de Sequência/genética , Células THP-1 , Fatores de Transcrição/metabolismo , Ubiquitinação , Células Vero , Proteínas não Estruturais Virais/metabolismo
3.
J Virol ; 91(12)2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28404845

RESUMO

H5N6 avian influenza virus (AIV) has posed a potential threat to public health since its emergence in China in 2013. To understand the evolution and emergence of H5N6 AIV in the avian population, we performed molecular surveillance of live poultry markets (LPMs) in Wugang Prefecture, Hunan Province, in central China, during 2014 and 2015. Wugang Prefecture is located on the Eastern Asian-Australian migratory bird flyway, and a human death due to an H5N6 virus was reported in the prefecture on 21 November 2016. In total, we sampled and sequenced the complete genomes of 175 H5N6 AIVs. Notably, our analysis revealed that H5N6 AIVs contain at least six genotypes arising from segment reassortment, including a rare variant that possesses an HA gene derived from H5N1 clade 2.3.2 and a novel NP gene that has its origins with H7N3 viruses. In addition, phylogenetic analysis revealed that genetically similar H5N6 AIVs tend to cluster according to their geographic regions of origin. These results help to reveal the evolutionary behavior of influenza viruses prior to their emergence in humans.IMPORTANCE The newly emerged H5N6 influenza A virus has caused more than 10 human deaths in China since 2013. In November 2016, a human death due to an H5N6 virus, in Wugang Prefecture, Hunan Province, was confirmed by the WHO. To better understand the evolution and emergence of H5N6 viruses, we surveyed live poultry markets (LPMs) in Wugang Prefecture before the reported human death, with a focus on revealing the diversity and genomic origins of H5N6 in birds during 2014 and 2015. In general, H5N6 viruses in this region were most closely related to H5N1 clade 2.3.4.4, with the exception of one virus with an HA gene derived from clade 2.3.2 such that it represents a novel reassortant. Clearly, the ongoing surveillance of LPMs is central to monitoring the emergence of pathogenic influenza viruses.


Assuntos
Aves/virologia , Evolução Molecular , Genoma Viral , Vírus da Influenza A/genética , Influenza Aviária/epidemiologia , Influenza Aviária/virologia , Animais , China/epidemiologia , Monitoramento Epidemiológico , Variação Genética , Genótipo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Influenza Humana/virologia , Filogenia , Aves Domésticas/virologia , RNA Viral/genética , Vírus Reordenados
4.
Arch Virol ; 162(5): 1349-1353, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28116526

RESUMO

In this study, we analyzed the genome of a H10N5 influenza virus from wild birds. This virus was identified as a novel reassortant virus with internal genes from multiple subtypes and of distinct origins. After sequential passage in mice, mouse-adapted viruses bearing mutations PB2-E627K and HA-G218E were generated. These viruses caused dramatic body weight loss and death, and also replicated in mouse brain, suggesting that the pathogenicity of low pathogenic H10N5 in chickens can be enhanced after passage in mammals. Our data imply that H10N5 viruses might be a potential risk to human health therefore it is important to undertake continued surveillance and biosecurity evaluation of these viruses.


Assuntos
Doenças das Aves/virologia , Aves/virologia , Hemaglutininas Virais/genética , Influenza Aviária/virologia , Vírus Reordenados/classificação , Vírus Reordenados/genética , Animais , Animais Selvagens/virologia , Embrião de Galinha , Feminino , Marcadores Genéticos/genética , Camundongos , Camundongos Endogâmicos BALB C , Vírus Reordenados/isolamento & purificação
5.
Virology ; 496: 131-137, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27310357

RESUMO

We have previously reported that phosphoinositide-specific phospholipase γ1 (PLC-γ1) signaling is activated by influenza virus H1N1 infection and mediates efficient viral entry in human epithelial cells. In this study, we show that H1N1 also activates PLCγ-1 signaling in human promonocytic cell line -derived macrophages. Surprisingly, the activated PLCγ-1 signaling is not important for viral replication in macrophages, but is involved in the virus-induced inflammatory responses. PLC-γ1-specific inhibitor U73122 strongly inhibits the H1N1 virus-induced NF-κB signaling, blocking the up-regulation of TNF-α, IL-6, MIP-1α, and reactive oxidative species. In a positive feedback loop, IL-1ß and TNF-α activate the PLCγ-1 signaling in both epithelial and macrophage cell lines. In summary, we have shown for the first time that the PLCγ-1 signaling plays an important role in the H1N1-induced inflammatory responses. Our study suggests that targeting the PLCγ-1 signaling is a potential antiviral therapy against H1N1 by inhibiting both viral replication and excessive inflammation.


Assuntos
Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/metabolismo , Influenza Humana/virologia , Fosfolipase C gama/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Estrenos/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/virologia , NF-kappa B/metabolismo , Fosfolipase C gama/antagonistas & inibidores , Pirrolidinonas/farmacologia , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Células U937
6.
Sci Rep ; 6: 25549, 2016 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-27151540

RESUMO

Multiple infections of avian influenza viruses (AIVs) in poultry or wild birds contribute to the continued evolution of H5 subtype viruses in nature and provide potential recombination of AIVs of different origins. In this study, we carried out surveillance of AIVs in ducks, geese and the environment of a community in Hunan province, China, from 2014-2015. We isolated multiple co-circulated AIVs including H3N2, H3N8, and H5N6, and, most importantly, a novel reassortant: H3N6. Phylogenetic analyses suggest that H3N6 is highly likely derived from H5N6, which has recently been shown to have zoonotic potential with human infections. Studies with mammalian cell lines and a mouse model indicate that four selected AIVs of duck or goose origin can infect MDCK and A549 cells but have low pathogenicity in mice. We propose that a potential co-circulation of multiple subtypes including H5N6 in local area may result in the production of novel subtypes such as H3N6 by gene reassortment.


Assuntos
Microbiologia Ambiental , Vírus da Influenza A/classificação , Vírus da Influenza A/isolamento & purificação , Influenza Aviária/epidemiologia , Influenza Aviária/virologia , Vírus Reordenados/classificação , Vírus Reordenados/isolamento & purificação , Animais , Linhagem Celular , China/epidemiologia , Modelos Animais de Doenças , Cães , Patos , Evolução Molecular , Gansos , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/patogenicidade , Camundongos , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Filogenia , Vírus Reordenados/genética , Vírus Reordenados/patogenicidade , Análise de Sequência de DNA , Virulência
7.
Infect Genet Evol ; 36: 462-466, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26296602

RESUMO

Novel H5N6 influenza A viruses have infected birds and human beings and caused four human clinical cases in China since 2014. The pig, as a mixing vessel, plays an important role for influenza virus reassortment and transmission. Towards this, routine surveillance for swine influenza in Guangdong province was conducted in 2014. In this study, we reported the biological characterization of two H5N6 influenza viruses isolated from healthy pigs in Guangdong province. Genetic analysis indicates that the two viruses are reassortants of 2.3.4.4 H5N1 and H6N6 avian influenza viruses with a high similarity to duck and human H5N6 influenza viruses isolated from Guangdong province. The data from chicken and mouse experiments show that the viruses are highly pathogenic in chickens and result in a systemic infection, and replicate in the mouse lung accompanying with a clinical inflammatory pathology. The results of the study demonstrate that the two H5N6 influenza viruses isolated from swine are the avian-originated viruses and have not adapted to swine population yet. However, they might keep evolving and pose a potential risk to public health and the continued surveillance of swine influenza should be strengthened.


Assuntos
Genótipo , Vírus da Influenza A/classificação , Vírus da Influenza A/fisiologia , Influenza Aviária/virologia , Infecções por Orthomyxoviridae/virologia , Vírus Reordenados , Animais , Galinhas , Feminino , Genes Virais , Vírus da Influenza A/isolamento & purificação , Camundongos , Infecções por Orthomyxoviridae/patologia , Filogenia , Suínos , Fatores de Virulência/genética , Replicação Viral/genética
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