Potential human adaptation mutation of influenza A(H5N1) virus, Canada.
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ABSTRACT:
SUBMITTER: Maurer-Stroh S
PROVIDER: S-EPMC4178386 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The role of the influenza virus polymerase complex in host range restriction has been well-studied and several host range determinants, such as the polymerase PB2-E627K and PB2-D701N mutations, have been identified. However, there may be additional, currently unknown, human adaptation polymerase mutations. Here, we used a database search of influenza virus H5N1 clade 1.1, clade 2.3.2.1 and clade 2.3.4 strains isolated from 2008-2012 in Southern China, Vietnam and Cambodia to identify polymerase adaptation mutations that had been selected in infected patients. Several of these mutations acted either alone or together to increase viral polymerase activity in human airway cells to levels similar to the PB2-D701N and PB2-E627K single mutations and to increase progeny virus yields in infected mouse lungs to levels similar to the PB2-D701N single mutation. In particular, specific mutations acted synergistically with the PB2-D701N mutation and showed synergistic effects on viral replication both in human airway cells and mice compared with the corresponding single mutations. Thus, H5N1 viruses in infected patients were able to acquire multiple polymerase mutations that acted cooperatively for human adaptation. Our findings give new insight into the human adaptation of AI viruses and help in avian influenza virus risk assessment.
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Project description:Highly pathogenic avian H5N1 influenza viruses remain a pandemic threat. Antiviral drugs such as neuraminidase (NA) inhibitors will be crucial for disease control in the event of a pandemic. Should drug-resistant H5N1 viruses develop, all defense strategies will be compromised. To determine the likelihood and mechanisms of emergence of NA inhibitor-resistant H5N1 variants in humans, we serially passaged two H5N1 viruses, A/Hong Kong/213/03 and A/Turkey/65-1242/06, in normal human bronchial epithelial (NHBE) cells in the presence of oseltamivir, zanamivir, or peramivir. To monitor the emergence of changes associated with the adaptation of H5N1 viruses to humans, we passaged the strains in the absence of drugs. Under pressure of each NA inhibitor, A/Turkey/65-1242/06 developed mutations in the hemagglutinin (HA) (H28R and P194L/T215I) and NA (E119A) proteins that reduced virus binding to ?2,3-sialyl receptor and NA activity. Oseltamivir pressure selected a variant of A/Hong Kong/213/03 virus with HA P194S mutation that decreased viral binding to ?2,6 receptor. Under peramivir pressure, A/Hong Kong/213/03 virus developed a novel NA mutation, R156K, that reduced binding to all three drugs, caused about 90% loss of NA activity, and compromised replication in NHBE cells. Both strains were eliminated in NHBE cells when they were cultivated in the absence of drugs. Here, we show for the first time that decreased NA activity mediated through NA inhibitors is essential for the adaptation of pandemic H5N1 influenza virus to humans. This ability of decreased NA activity to promote H5N1 infection underlines the necessity to optimize management strategies for a plausible H5N1 pandemic.
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Project description:Migratory birds have been implicated in the long-range spread of highly pathogenic avian influenza (HPAI) A virus (H5N1) from Asia to Europe and Africa. Although sampling of healthy wild birds representing a large number of species has not identified possible carriers of influenza virus (H5N1) into Europe, surveillance of dead and sick birds has demonstrated mute (Cygnus olor) and whooper (C. cygnus) swans as potential sentinels. Because of concerns that migratory birds could spread H5N1 subtype to the Western Hemisphere and lead to its establishment within free-living avian populations, experimental studies have addressed the susceptibility of several indigenous North American duck and gull species. We examined the susceptibility of Canada geese (Branta canadensis) to HPAI virus (H5N1). Large populations of this species can be found in periagricultural and periurban settings and thus may be of potential epidemiologic importance if H5N1 subtype were to establish itself in North American wild bird populations.
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Project description:BackgroundVery little is known regarding the persistence of highly pathogenic avian influenza H5N1 viruses in natural settings during outbreaks in tropical countries, although environmental factors may well play a role in the persistence and in the transmission of H5N1 virus.ObjectiveTo investigate various environmental compartments surrounding outbreak areas as potential sources for H5N1 virus transmission.MethodsEnvironmental specimens were collected following outbreaks of avian influenza in Cambodia between April 2007 and February 2010. The methods used to concentrate H5N1 virus from water samples were based either on agglutination of the virus with chicken red blood cells or on adsorption on glass wool, followed by an elution-concentration step. An elution-concentration method was used for mud specimens. All samples that tested positive by real-time RT-PCRs (qRT-PCRs) targeting the HA5, M and NA1 genes were inoculated into embryonated hen eggs for virus isolation.ResultsOf a total of 246 samples, 46 (19%) tested positive for H5N1 by qRT-PCRs. Viral RNA was frequently detected in dust, mud and soil samples from the farms' environment (respectively, 46%, 31% and 15%). Samples collected from ponds gave a lower proportion of positive samples (6%) as compared to those collected from the farms (24%). In only one sample, infectious virus particles were successfully isolated.ConclusionDuring H5N1 virus outbreaks, numerous environmental samples surrounding outbreak areas are contaminated by the virus and may act as potential sources for human and/or animal contamination.
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Project description:U.S. H5N1 clade 2.3.4.4b immediate releases related to emergence and spread in dairy cattle
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Project description:The continuing pandemic threat posed by avian influenza A/H5N1 viruses calls for improved insights into their evolution during human infection. We performed whole genome deep sequencing of respiratory specimens from 44 H5N1-infected individuals from Indonesia and found substantial within-host viral diversity. At nearly 30% of genome positions multiple amino acids were observed within or across samples, including positions implicated in aerosol transmission between ferrets. Amino acid variants detected our cohort were often found more frequently in available H5N1 sequences of human than avian isolates. We additionally identified previously unreported amino acid variants and multiple variants that increased in proportion over time in available sequential samples. Given the importance of the polymerase complex for host adaptation, we tested 121 amino acid variants found in the PB2, PB1 and PA subunits for their effects on polymerase activity in human cells. We identified multiple single amino acid variants in all three polymerase subunits that substantially increase polymerase activity including some with effects comparable to that of the widely recognized adaption and virulence marker PB2-E627 K. These results indicate highly dynamic evolutionary processes during human H5N1 virus infection and the potential existence of previously undocumented adaptive pathways.
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Project description:Laboratory-confirmed cases of subclinical infection with avian influenza A(H5N1) virus in humans are rare, and the true number of these cases is unknown. We describe the identification of a laboratory-confirmed subclinical case in a woman during an influenza A(H5N1) contact investigation in northern Vietnam.
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Project description:BackgroundInfluenza A virus (IAV) belongs to the Orthomyxoviridae family. IAV causes a highly contagious respiratory disease in humans that exacts severe economic losses globally. The virus uses strategies developed to exploit and subvert cellular proteins and pathways to increase its own replication and to inhibit antiviral immune response.ResultsA/bar-headed goose/Qinghai/1/2005 (A/QH) was able to infect A549 and 293 T cells, with a high infection rate for A549 cells. To identify host cellular responses of human cells to influenza infection, differentially expressed genes (DEGs) between AIV-infected groups and uninfected controls were identified using RNA-sequencing. The DEGs were annotated by Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analyses, which revealed that the DEGs were mainly linked to cellular function and metabolic processes, while the cellular function that is probably associated with host cellular response of human cells, including defense response to virus and protein modification. All the DEGs and pathways were possibly involved in the response to IAV invasion.ConclusionsThe global transcriptome analysis results revealed that sensitive genes and pathways of the cells were infected with the influenza virus and provided further evidence to investigate the complicated relationship between IAV and host cells.
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