scholarly journals Adaptation of Pandemic H1N1 Influenza Viruses in Mice

2010 ◽  
Vol 84 (17) ◽  
pp. 8607-8616 ◽  
Author(s):  
Natalia A. Ilyushina ◽  
Alexey M. Khalenkov ◽  
Jon P. Seiler ◽  
Heather L. Forrest ◽  
Nicolai V. Bovin ◽  
...  
Keyword(s):  
Amino Acid ◽  
Pandemic Influenza ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Mouse Lung ◽  
Mammalian Host ◽  
Influenza A Viruses ◽  
Receptor Specificity ◽  
Viral Receptor

ABSTRACT The molecular mechanism by which pandemic 2009 influenza A viruses were able to sufficiently adapt to humans is largely unknown. Subsequent human infections with novel H1N1 influenza viruses prompted an investigation of the molecular determinants of the host range and pathogenicity of pandemic influenza viruses in mammals. To address this problem, we assessed the genetic basis for increased virulence of A/CA/04/09 (H1N1) and A/TN/1-560/09 (H1N1) isolates, which are not lethal for mice, in a new mammalian host by promoting their mouse adaptation. The resulting mouse lung-adapted variants showed significantly enhanced growth characteristics in eggs, extended extrapulmonary tissue tropism, and pathogenicity in mice. All mouse-adapted viruses except A/TN/1-560/09-MA2 grew faster and to higher titers in cells than the original strains. We found that 10 amino acid changes in the ribonucleoprotein (RNP) complex (PB2 E158G/A, PA L295P, NP D101G, and NP H289Y) and hemagglutinin (HA) glycoprotein (K119N, G155E, S183P, R221K, and D222G) controlled enhanced mouse virulence of pandemic isolates. HA mutations acquired during adaptation affected viral receptor specificity by enhancing binding to α2,3 together with decreasing binding to α2,6 sialyl receptors. PB2 E158G/A and PA L295P amino acid substitutions were responsible for the significant enhancement of transcription and replication activity of the mouse-adapted H1N1 variants. Taken together, our findings suggest that changes optimizing receptor specificity and interaction of viral polymerase components with host cellular factors are the major mechanisms that contribute to the optimal competitive advantage of pandemic influenza viruses in mice. These modulators of virulence, therefore, may have been the driving components of early evolution, which paved the way for novel 2009 viruses in mammals.

scholarly journals Improving pandemic influenza risk assessment

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Colin A Russell ◽  
Peter M Kasson ◽  
Ruben O Donis ◽  
Steven Riley ◽  
John Dunbar ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Sequence Data ◽  
Virus Genome ◽  
Influenza Viruses ◽  
Influenza Surveillance ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
Virus Genotype

Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response.

scholarly journals Plasticity of the Influenza Virus H5 HA Protein

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huihui Kong ◽  
David F. Burke ◽  
Tiago Jose da Silva Lopes ◽  
Kosuke Takada ◽  
Masaki Imai ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Mammalian Cells ◽  
Influenza A ◽  
Viral Antigen ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Highly Pathogenic ◽  
Antigenic Properties ◽  
Ha Protein

ABSTRACT Since the emergence of highly pathogenic avian influenza viruses of the H5 subtype, the major viral antigen, hemagglutinin (HA), has undergone constant evolution, resulting in numerous genetic and antigenic (sub)clades. To explore the consequences of amino acid changes at sites that may affect the antigenicity of H5 viruses, we simultaneously mutated 17 amino acid positions of an H5 HA by using a synthetic gene library that, theoretically, encodes all combinations of the 20 amino acids at the 17 positions. All 251 mutant viruses sequenced possessed ≥13 amino acid substitutions in HA, demonstrating that the targeted sites can accommodate a substantial number of mutations. Selection with ferret sera raised against H5 viruses of different clades resulted in the isolation of 39 genotypes. Further analysis of seven variants demonstrated that they were antigenically different from the parental virus and replicated efficiently in mammalian cells. Our data demonstrate the substantial plasticity of the influenza virus H5 HA protein, which may lead to novel antigenic variants. IMPORTANCE The HA protein of influenza A viruses is the major viral antigen. In this study, we simultaneously introduced mutations at 17 amino acid positions of an H5 HA expected to affect antigenicity. Viruses with ≥13 amino acid changes in HA were viable, and some had altered antigenic properties. H5 HA can therefore accommodate many mutations in regions that affect antigenicity. The substantial plasticity of H5 HA may facilitate the emergence of novel antigenic variants.

scholarly journals MOLECULAR AND GENETIC CHARACTERISTICS OF SURFACE AND NONSTRUCTURE PROTEINS OF PANDEMIC INFLUENZA VIRUSES A(H1N1)PDM09 IN 2015-2016 EPIDEMIC SEASON

2016 ◽  
Vol 72 (2) ◽  
pp. 44-48
Author(s):  
O. Smutko ◽  
L. Radchenko ◽  
A. Mironenko
Keyword(s):  
Amino Acid ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Phylogenetic Trees ◽  
Influenza Viruses ◽  
Amino Acid Substitutions ◽  
Ns1 Protein ◽  
Genetic Characteristics ◽  
Epidemic Season ◽  
Influenza A H1n1

The aim of the present study was identifying of molecular and genetic changes in hemaglutinin (HA), neuraminidase (NA) and non-structure protein (NS1) genes of pandemic influenza A(H1N1)pdm09 strains, that circulated in Ukraine during 2015-2016 epidemic season. Samples (nasopharyngeal swabs from patients) were analyzed using real-time polymerase chain reaction (RTPCR). Phylogenetic trees were constructed using MEGA 7 software. 3D structures were constructed in Chimera 1.11.2rc software. Viruses were collected in 2015-2016 season fell into genetic group 6B and in two emerging subgroups, 6B.1 and 6B.2 by gene of HA and NA. Subgroups 6B.1 and 6B.2 are defined by the following amino acid substitutions. In the NS1 protein were identified new amino acid substitutions D2E, N48S, and E125D in 2015-2016 epidemic season. Specific changes were observed in HA protein antigenic sites, but viruses saved similarity to vaccine strain. NS1 protein acquired substitution associated with increased virulence of the influenza virus.

scholarly journals PB2 Residue 271 Plays a Key Role in Enhanced Polymerase Activity of Influenza A Viruses in Mammalian Host Cells

2010 ◽  
Vol 84 (9) ◽  
pp. 4395-4406 ◽  
Author(s):  
Kendra A. Bussey ◽  
Tatiana L. Bousse ◽  
Emily A. Desmet ◽  
Baek Kim ◽  
Toru Takimoto
Keyword(s):  
Mammalian Cells ◽  
Influenza A ◽  
Virus Titer ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Host Cells ◽  
Mammalian Host ◽  
Influenza A Viruses ◽  
H5n1 Influenza ◽  
Avian Viruses

ABSTRACT The direct infection of humans with highly pathogenic avian H5N1 influenza viruses has suggested viral mutation as one mechanism for the emergence of novel human influenza A viruses. Although the polymerase complex is known to be a key component in host adaptation, mutations that enhance the polymerase activity of avian viruses in mammalian hosts are not fully characterized. The genomic comparison of influenza A virus isolates has identified highly conserved residues in influenza proteins that are specific to either human or avian viruses, including 10 residues in PB2. We characterized the activity of avian polymerase complexes containing avian-to-human mutations at these conserved PB2 residues and found that, in addition to the E627K mutation, the PB2 mutation T271A enhances polymerase activity in human cells. We confirmed the effects of the T271A mutation using recombinant WSN viruses containing avian NP and polymerase genes with wild-type (WT) or mutant PB2. The 271A virus showed enhanced growth compared to that of the WT in mammalian cells in vitro. The 271A mutant did not increase viral pathogenicity significantly in mice compared to that of the 627K mutant, but it did enhance the lung virus titer. Also, cell infiltration was more evident in lungs of 271A-infected mice than in those of the WT. Interestingly, the avian-derived PB2 of the 2009 pandemic H1N1 influenza virus has 271A. The characterization of the polymerase activity of A/California/04/2009 (H1N1) and corresponding PB2 mutants indicates that the high polymerase activity of the pandemic strain in mammalian cells is, in part, dependent on 271A. Our results clearly indicate the contribution of PB2 amino acid 271 to enhanced polymerase activity and viral growth in mammalian hosts.

scholarly journals Contemporary Seasonal Influenza A (H1N1) Virus Infection Primes for a More Robust Response To Split Inactivated Pandemic Influenza A (H1N1) Virus Vaccination in Ferrets

2010 ◽  
Vol 17 (12) ◽  
pp. 1998-2006 ◽  
Author(s):  
Ali H. Ellebedy ◽  
Thomas P. Fabrizio ◽  
Ghazi Kayali ◽  
Thomas H. Oguin ◽  
Scott A. Brown ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Seasonal Influenza ◽  
H1n1 Virus ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Inactivated Vaccine ◽  
H1n1 Influenza Virus ◽  
Influenza A H1n1

ABSTRACT Human influenza pandemics occur when influenza viruses to which the population has little or no immunity emerge and acquire the ability to achieve human-to-human transmission. In April 2009, cases of a novel H1N1 influenza virus in children in the southwestern United States were reported. It was retrospectively shown that these cases represented the spread of this virus from an ongoing outbreak in Mexico. The emergence of the pandemic led to a number of national vaccination programs. Surprisingly, early human clinical trial data have shown that a single dose of nonadjuvanted pandemic influenza A (H1N1) 2009 monovalent inactivated vaccine (pMIV) has led to a seroprotective response in a majority of individuals, despite earlier studies showing a lack of cross-reactivity between seasonal and pandemic H1N1 viruses. Here we show that previous exposure to a contemporary seasonal H1N1 influenza virus and to a lesser degree a seasonal influenza virus trivalent inactivated vaccine is able to prime for a higher antibody response after a subsequent dose of pMIV in ferrets. The more protective response was partially dependent on the presence of CD8+ cells. Two doses of pMIV were also able to induce a detectable antibody response that provided protection from subsequent challenge. These data show that previous infection with seasonal H1N1 influenza viruses likely explains the requirement for only a single dose of pMIV in adults and that vaccination campaigns with the current pandemic influenza vaccines should reduce viral burden and disease severity in humans.

scholarly journals Resurrected ancestral influenza A viruses recapitulate the avian-to-mammalian adaptation of European avian-like swine influenza virus

2021 ◽  
Author(s):  
Wen Su ◽  
Rhodri Harfoot ◽  
Yvonne Su ◽  
Jennifer DeBeauchamp ◽  
Udayan Joseph ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Influenza A ◽  
Swine Influenza Virus ◽  
Swine Influenza ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Mammalian Host ◽  
Influenza A Viruses ◽  
Sequence Reconstruction

Abstract The emergence of a pandemic influenza virus may be better anticipated if we better understand the evolutionary steps taken by avian influenza viruses as they adapt to mammals. We used ancestral sequence reconstruction to resurrect viruses representing initial adaptive stages of the European avian-like H1N1 virus as it transitioned from avian to swine hosts. We demonstrate that efficient transmissibility in pigs was gained through stepwise adaptation after 1983. These time-dependent adaptations resulted in changes in hemagglutinin receptor binding specificity and increased viral polymerase activity. An NP-R351K mutation under strong positive selection increased the transmissibility of a reconstructed virus. The stepwise-adaptation of a wholly avian influenza virus to a mammalian host suggests a window where targeted intervention may have highest impact. Successful intervention will, however, require strategic coordination of surveillance and risk assessment activities to identify these adapting viruses and guide pandemic preparedness resources.

scholarly journals FluPhenotype—a one-stop platform for early warnings of the influenza A virus

2020 ◽  
Vol 36 (10) ◽  
pp. 3251-3253 ◽  
Author(s):  
Congyu Lu ◽  
Zena Cai ◽  
Yuanqiang Zou ◽  
Zheng Zhang ◽  
Wenjun Chen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amino Acid ◽  
Influenza A ◽  
Genetic Relationships ◽  
Influenza Viruses ◽  
Supplementary Information ◽  
Influenza A Viruses ◽  
One Stop ◽  
Related Amino Acid ◽  
Early Warnings

Abstract Motivation Newly emerging influenza viruses keep challenging global public health. To evaluate the potential risk of the viruses, it is critical to rapidly determine the phenotypes of the viruses, including the antigenicity, host, virulence and drug resistance. Results Here, we built FluPhenotype, a one-stop platform to rapidly determinate the phenotypes of the influenza A viruses. The input of FluPhenotype is the complete or partial genomic/protein sequences of the influenza A viruses. The output presents five types of information about the viruses: (i) sequence annotation including the gene and protein names as well as the open reading frames, (ii) potential hosts and human-adaptation-associated amino acid markers, (iii) antigenic and genetic relationships with the vaccine strains of different HA subtypes, (iv) mammalian virulence-related amino acid markers and (v) drug resistance-related amino acid markers. FluPhenotype will be a useful bioinformatic tool for surveillance and early warnings of the newly emerging influenza A viruses. Availability and implementation It is publicly available from: http://www.computationalbiology.cn : 18888/IVEW. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Molecular basis of mammalian transmissibility of avian H1N1 influenza viruses and their pandemic potential

2017 ◽  
Vol 114 (42) ◽  
pp. 11217-11222 ◽  
Author(s):  
Mark Zanin ◽  
Sook-San Wong ◽  
Subrata Barman ◽  
Challika Kaewborisuth ◽  
Peter Vogel ◽  
...  
Keyword(s):  
Genetic Markers ◽  
Nuclear Export ◽  
Influenza A ◽  
Nonstructural Protein ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Upper Respiratory Tract ◽  
Influenza A Viruses ◽  
Airborne Transmission ◽  
Nonstructural Protein 1

North American wild birds are an important reservoir of influenza A viruses, yet the potential of viruses in this reservoir to transmit and cause disease in mammals is not well understood. Our surveillance of avian influenza viruses (AIVs) at Delaware Bay, USA, revealed a group of similar H1N1 AIVs isolated in 2009, some of which were airborne-transmissible in the ferret model without prior adaptation. Comparison of the genomes of these viruses revealed genetic markers of airborne transmissibility in the Polymerase Basic 2 (PB2), PB1, PB1-F2, Polymerase Acidic-X (PA-X), Nonstructural Protein 1 (NS1), and Nuclear Export Protein (NEP) genes. We studied the role of NS1 in airborne transmission and found that NS1 mutants that were not airborne-transmissible caused limited tissue pathology in the upper respiratory tract (URT). Viral maturation was also delayed, evident as strong intranuclear staining and little virus at the mucosa. Our study of this naturally occurring constellation of genetic markers has provided insights into the poorly understood phenomenon of AIV airborne transmissibility by revealing a role for NS1 and characteristics of viral replication in the URT that were associated with airborne transmission. The transmissibility of these viruses further highlights the pandemic potential of AIVs in the wild bird reservoir and the need to maintain surveillance.

scholarly journals Evidence of Cross-Reactive Immunity to 2009 Pandemic Influenza A Virus in Workers Seropositive to Swine H1N1 Influenza Viruses Circulating in Italy

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e57576 ◽  
Author(s):  
Maria A. De Marco ◽  
Stefano Porru ◽  
Paolo Cordioli ◽  
Bruno M. Cesana ◽  
Ana Moreno ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Pandemic Influenza ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Influenza Viruses

scholarly journals Minor variants of swine H1N1 influenza viruses with enhanced polymerase activity and HA stability promote airborne transmission in ferrets

2021 ◽  
Author(s):  
Meng Hu ◽  
Jeremy Jones ◽  
Balaji Banoth ◽  
Chet R Ojha ◽  
Jeri Carol Crumpton ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Deep Sequencing ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Polymerase Activity ◽  
Protein Stabilization ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Airborne Transmission ◽  
Ha Protein

Understanding how animal influenza A viruses (IAVs) acquire airborne transmissibility in humans and ferrets is needed to prepare for and respond to pandemics. Previously, we showed that hemagglutinin (HA) protein stabilization promotes replication and airborne transmission in ferrets using swine H1N1 gamma strains P4 and G15 (Hu et al. 2020). Here, we show that a combination of enhanced polymerase activity and HA stability is necessary for efficient airborne transmission in ferrets and that minor variants containing both properties are quickly selected. P4 and G15 were found to have decreased polymerase activity and relatively poor HA stability, respectively. Polymerase-enhancing variant PA-S321 was selected in half of P4 isolates that airborne-transmitted in ferrets. HA-stabilizing variant HA1-S210 was selected in all G15-inoculated ferrets and was transmitted. With an efficient polymerase and a stable HA, purified G15-HA1-S210 had earlier and higher peak titers in inoculated ferrets and was recovered at a higher frequency after airborne transmission than P4 and G15. Pandemic risk-assessment studies may benefit from deep sequencing capable of identifying minor variants with human-adapted traits.

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