RESUMEN
The influenza A virus (IAV) nonstructural protein 1 (NS1) contributes to disease pathogenesis through the inhibition of host innate immune responses. Dendritic cells (DCs) release interferons (IFNs) and proinflammatory cytokines and promote adaptive immunity upon viral infection. In order to characterize the strain-specific effects of IAV NS1 on human DC activation, we infected human DCs with a panel of recombinant viruses with the same backbone (A/Puerto Rico/08/1934) expressing different NS1 proteins from human and avian origin. We found that these viruses induced a clearly distinct phenotype in DCs. Specifically, viruses expressing NS1 from human IAV (either H1N1 or H3N2) induced higher levels of expression of type I (IFN-α and IFN-ß) and type III (IFN-λ1 to IFNλ3) IFNs than viruses expressing avian IAV NS1 proteins (H5N1, H7N9, and H7N2), but the differences observed in the expression levels of proinflammatory cytokines like tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6) were not significant. In addition, using imaging flow cytometry, we found that human and avian NS1 proteins segregate based on their subcellular trafficking dynamics, which might be associated with the different innate immune profile induced in DCs by viruses expressing those NS1 proteins. Innate immune responses induced by our panel of IAV recombinant viruses were also characterized in normal human bronchial epithelial cells, and the results were consistent with those in DCs. Altogether, our results reveal an increased ability of NS1 from avian viruses to antagonize innate immune responses in human primary cells compared to the ability of NS1 from human viruses, which could contribute to the severe disease induced by avian IAV in humans.IMPORTANCE Influenza A viruses (IAVs) cause seasonal epidemics which result in an important health and economic burden. Wild aquatic birds are the natural host of IAV. However, IAV can infect diverse hosts, including humans, domestic poultry, pigs, and others. IAVs circulating in animals occasionally cross the species barrier, infecting humans, which results in mild to very severe disease. In some cases, these viruses can acquire the ability to be transmitted among humans and initiate a pandemic. The nonstructural 1 (NS1) protein of IAV is an important antagonist of the innate immune response. In this study, using recombinant viruses and primary human cells, we show that NS1 proteins from human and avian hosts show intrinsic differences in the modulation of the innate immunity in human dendritic cells and epithelial cells, as well as different cellular localization dynamics in infected cells.
Asunto(s)
Células Epiteliales/inmunología , Interacciones Huésped-Patógeno/genética , Inmunidad Innata , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H5N1 del Virus de la Influenza A/genética , Proteínas no Estructurales Virales/genética , Animales , Aves , Células Dendríticas/inmunología , Células Dendríticas/virología , Perros , Células Epiteliales/virología , Regulación de la Expresión Génica , Especificidad del Huésped , Interacciones Huésped-Patógeno/inmunología , Humanos , Subtipo H1N1 del Virus de la Influenza A/clasificación , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/clasificación , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A/inmunología , Subtipo H5N1 del Virus de la Influenza A/clasificación , Subtipo H5N1 del Virus de la Influenza A/inmunología , Subtipo H7N2 del Virus de la Influenza A/clasificación , Subtipo H7N2 del Virus de la Influenza A/genética , Subtipo H7N2 del Virus de la Influenza A/inmunología , Subtipo H7N9 del Virus de la Influenza A/clasificación , Subtipo H7N9 del Virus de la Influenza A/genética , Subtipo H7N9 del Virus de la Influenza A/inmunología , Interferón-alfa/genética , Interferón-alfa/inmunología , Interferón beta/genética , Interferón beta/inmunología , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Células de Riñón Canino Madin Darby , Filogenia , Cultivo Primario de Células , Virus Reordenados/genética , Virus Reordenados/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Proteínas no Estructurales Virales/clasificación , Proteínas no Estructurales Virales/inmunologíaAsunto(s)
Pollos , Subtipo H7N2 del Virus de la Influenza A/genética , Subtipo H7N2 del Virus de la Influenza A/aislamiento & purificación , Subtipo H7N9 del Virus de la Influenza A/genética , Gripe Aviar/virología , Virus Reordenados/genética , Virus Reordenados/aislamiento & purificación , Animales , Antígenos Virales/genética , Antígenos Virales/inmunología , China , Inmunoensayo , Subtipo H7N2 del Virus de la Influenza A/clasificación , Subtipo H7N2 del Virus de la Influenza A/patogenicidad , Gripe Aviar/inmunología , Filogenia , Virus Reordenados/clasificación , Virus Reordenados/patogenicidad , Análisis de Secuencia de ADN , Proteínas Virales/genética , Proteínas Virales/inmunología , VirulenciaRESUMEN
During December 2016-February 2017, influenza A viruses of the H7N2 subtype infected ≈500 cats in animal shelters in New York, NY, USA, indicating virus transmission among cats. A veterinarian who treated the animals also became infected with feline influenza A(H7N2) virus and experienced respiratory symptoms. To understand the pathogenicity and transmissibility of these feline H7N2 viruses in mammals, we characterized them in vitro and in vivo. Feline H7N2 subtype viruses replicated in the respiratory organs of mice, ferrets, and cats without causing severe lesions. Direct contact transmission of feline H7N2 subtype viruses was detected in ferrets and cats; in cats, exposed animals were also infected via respiratory droplet transmission. These results suggest that the feline H7N2 subtype viruses could spread among cats and also infect humans. Outbreaks of the feline H7N2 viruses could, therefore, pose a risk to public health.
Asunto(s)
Enfermedades de los Gatos/virología , Subtipo H7N2 del Virus de la Influenza A/genética , Infecciones por Orthomyxoviridae/veterinaria , Animales , Enfermedades de los Gatos/epidemiología , Gatos , Femenino , Hurones , Humanos , Subtipo H7N2 del Virus de la Influenza A/clasificación , Subtipo H7N2 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/epidemiología , Gripe Humana/transmisión , Gripe Humana/virología , Ratones Endogámicos BALB C , Ciudad de Nueva York/epidemiología , Infecciones por Orthomyxoviridae/virología , Filogenia , Cultivo de VirusRESUMEN
An outbreak of influenza A(H7N2) virus in cats in a shelter in New York, NY, USA, resulted in zoonotic transmission. Virus isolated from the infected human was closely related to virus isolated from a cat; both were related to low pathogenicity avian influenza A(H7N2) viruses detected in the United States during the early 2000s.
Asunto(s)
Enfermedades de los Gatos/epidemiología , Brotes de Enfermedades , Genoma Viral , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Subtipo H7N2 del Virus de la Influenza A/genética , Gripe Aviar/epidemiología , Zoonosis/epidemiología , Animales , Antígenos Virales/química , Antígenos Virales/genética , Antígenos Virales/metabolismo , Sitios de Unión , Aves , Enfermedades de los Gatos/transmisión , Enfermedades de los Gatos/virología , Gatos , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Vivienda para Animales , Humanos , Subtipo H7N2 del Virus de la Influenza A/clasificación , Subtipo H7N2 del Virus de la Influenza A/aislamiento & purificación , Gripe Aviar/transmisión , Gripe Aviar/virología , Modelos Moleculares , New York/epidemiología , Polisacáridos/química , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Receptores Virales/química , Receptores Virales/genética , Receptores Virales/metabolismo , Veterinarios , Zoonosis/transmisión , Zoonosis/virologíaRESUMEN
The number of human avian H7N9 influenza infections has been increasing in China. Understanding their antigenic and serologic relationships is crucial for developing diagnostic tools and vaccines. Here, we evaluated the cross-reactivities and neutralizing activities among H7 subtype influenza viruses and between H7N9 and heterosubtype influenza A viruses. We found strong cross-reactivities between H7N9 and divergent H7 subtypic viruses, including H7N2, H7N3, and H7N7. Antisera against H7N2, H7N3, and H7N7 could also effectively neutralize two distinct H7N9 strains. Two-way cross-reactivities exist within group 2, including H3 and H4, whereas one-way cross-reactivities were found across other groups, including H1, H10, H9, and H13. Our data indicate that the hemaglutinins from divergent H7 subtypes may facilitate the development of vaccines for distinct H7N9 infections. Moreover, serologic diagnoses for H7N9 infections need to consider possible interference from the cross-reactivity of H7N9 with other subtype influenza viruses.
Asunto(s)
Anticuerpos Antivirales/sangre , Hemaglutininas Virales/inmunología , Sueros Inmunes/química , Gripe Aviar/prevención & control , Gripe Humana/prevención & control , Animales , Aves/inmunología , Aves/virología , Protección Cruzada , Reacciones Cruzadas , Perros , Hemaglutininas Virales/química , Humanos , Subtipo H7N2 del Virus de la Influenza A/química , Subtipo H7N2 del Virus de la Influenza A/clasificación , Subtipo H7N2 del Virus de la Influenza A/inmunología , Subtipo H7N3 del Virus de la Influenza A/química , Subtipo H7N3 del Virus de la Influenza A/clasificación , Subtipo H7N3 del Virus de la Influenza A/inmunología , Subtipo H7N7 del Virus de la Influenza A/química , Subtipo H7N7 del Virus de la Influenza A/clasificación , Subtipo H7N7 del Virus de la Influenza A/inmunología , Subtipo H7N9 del Virus de la Influenza A/química , Subtipo H7N9 del Virus de la Influenza A/clasificación , Subtipo H7N9 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/biosíntesis , Gripe Aviar/sangre , Gripe Aviar/inmunología , Gripe Aviar/virología , Gripe Humana/sangre , Gripe Humana/inmunología , Gripe Humana/virología , Células de Riñón Canino Madin Darby , FilogeniaRESUMEN
Because pigs have respiratory epitheliums which express both α2-3 and α2-6 linked sialic acid as receptors to influenza A viruses, they are regarded as mixing vessel for the generation of pandemic influenza viruses through genetic reassortment. A H7N2 influenza virus (A/swine/KU/16/2001) was isolated from pig lungs collected from the slaughterhouse. All eight genes of the influenza virus were sequenced and phylogenetic analysis indicated that A/swine/KU/16/2001 originated in Hong Kong and genetic reassortment had occurred between the avian H7N2 and H5N3 influenza viruses. The first isolation of H7 influenza virus in pigs provides the opportunity for genetic reassortment of influenza viruses with pandemic potential and emphasizes the importance of surveillance for atypical swine influenza viruses.
