#Globular Head-Displayed Conserved #Influenza #H1 #Hemagglutinin #Stalk #Epitopes Confer Protection against Heterologous #H1N1 Virus (PLoS One, abstract)

[Source: PLoS One, full page: (LINK). Abstract, edited.]

Open Access / Peer-reviewed / Research Article

Globular Head-Displayed Conserved Influenza H1 Hemagglutinin Stalk Epitopes Confer Protection against Heterologous H1N1 Virus

Miriam Klausberger, Rupert Tscheliessnig, Silke Neff, Raffael Nachbagauer, Teddy John Wohlbold, Monika Wilde, Dieter Palmberger, Florian Krammer, Alois Jungbauer, Reingard Grabherr

PLOS / Published: April 18, 2016 / http://dx.doi.org/10.1371/journal.pone.0153579

 

Abstract

Significant genetic variability in the head region of the influenza A hemagglutinin, the main target of current vaccines, makes it challenging to develop a long-lived seasonal influenza prophylaxis. Vaccines based on the conserved hemagglutinin stalk domain might provide broader cross-reactive immunity. However, this region of the hemagglutinin is immunosubdominant to the head region. Peptide-based vaccines have gained much interest as they allow the immune system to focus on relevant but less immunogenic epitopes. We developed a novel influenza A hemagglutinin-based display platform for H1 hemagglutinin stalk peptides that we identified in an epitope mapping assay using human immune sera and synthetic HA peptides. Flow cytometry and competition assays suggest that the identified stalk sequences do not recapitulate the epitopes of already described broadly neutralizing stalk antibodies. Vaccine constructs displaying 25-mer stalk sequences provided up to 75% protection from lethal heterologous virus challenge in BALB/c mice and induced antibody responses against the H1 hemagglutinin. The developed platform based on a vaccine antigen has the potential to be either used as stand-alone or as prime-vaccine in combination with conventional seasonal or pandemic vaccines for the amplification of stalk-based cross-reactive immunity in humans or as platform to evaluate the relevance of viral peptides/epitopes for protection against influenza virus infection.

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Citation: Klausberger M, Tscheliessnig R, Neff S, Nachbagauer R, Wohlbold TJ, Wilde M, et al. (2016) Globular Head-Displayed Conserved Influenza H1 Hemagglutinin Stalk Epitopes Confer Protection against Heterologous H1N1 Virus. PLoS ONE 11(4): e0153579. doi:10.1371/journal.pone.0153579

Editor: Stephen J. Turner, Monash University, Australia, AUSTRALIA

Received: November 11, 2015; Accepted: March 31, 2016; Published: April 18, 2016

Copyright: © 2016 Klausberger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: MK and MW received funding from the Austrian Science Foundation FWF Doctoral program BioToP-Molecular Technology of Proteins W1224 and DP also was funded by the FWF (P 25092-B13). RT was funded by the Austrian Centre of Industrial Biotechnology (ACIB). ACIB is a non-profit research centre supported by the Federal Ministry of Economy, Family and Youth (BMWJF), the Federal Ministry of Traffic, Innovation and Technology (BMVIT), the Syrian Business Promotion Agency SFG, the Standortagentur Tirol and ZIT – Technology Agency of the City of Vienna through the COMET-Funding Program managed by the Austrian Research Promotion Agency FFG. FK was supported by an Erwin Schrödinger fellowship (J 3232) from the Austrian Science Fund. This work was partially supported by NIH (National Institutes of Health) program project grant 1P01AI097092-01A1 and PATH (Program for Appropriate Technology in Health). The Austrian Centre of Industrial Biotechnology provided support in the form of salaries for authors [RT], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.

Competing interests: Rupert Tscheliessnig was funded by and is employed by the Austrian Centre of Industrial Biotechnology. The Icahn School of Medicine at Mount Sinai together with the University of Natural Resources and Life Sciences has filed a patent on the mentioned display system for influenza epitopes (influenza virus vaccines and uses thereof; application no. 62180405). There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Keywords: Research; Abstracts; H1N1; Seasonal Influenza; Pandemic Influenza; Vaccines.

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1918 #Influenza #RBD #variants bind and replicate in primary #human #airway #cells regardless of receptor specificity (Virology, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Virology. 2016 Apr 7;493:238-246. doi: 10.1016/j.virol.2016.03.025. [Epub ahead of print]

1918 Influenza receptor binding domain variants bind and replicate in primary human airway cells regardless of receptor specificity.

Davis AS1, Chertow DS2, Kindrachuk J3, Qi L4, Schwartzman LM4, Suzich J2, Alsaaty S3, Logun C3, Shelhamer JH3, Taubenberger JK5.

 

Author information: 1Viral Pathogenesis and Evolution Section, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States; Diagnostic Medicine and Pathobiology, Kansas State University College of Veterinary Medicine, Manhattan, KS, United States. 2Viral Pathogenesis and Evolution Section, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States; Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, United States. 3Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, United States. 4Viral Pathogenesis and Evolution Section, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States. 5Viral Pathogenesis and Evolution Section, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States. Electronic address: taubenbergerj@niaid.nih.gov.

 

Abstract

The 1918 influenza pandemic caused ~50 million deaths. Many questions remain regarding the origin, pathogenicity, and mechanisms of human adaptation of this virus. Avian-adapted influenza A viruses preferentially bind α2,3-linked sialic acids (Sia) while human-adapted viruses preferentially bind α2,6-linked Sia. A change in Sia preference from α2,3 to α2,6 is thought to be a requirement for human adaptation of avian influenza viruses. Autopsy data from 1918 cases, however, suggest that factors other than Sia preference played a role in viral binding and entry to human airway cells. Here, we evaluated binding and entry of five 1918 influenza receptor binding domain variants in a primary human airway cell model along with control avian and human influenza viruses. We observed that all five variants bound and entered cells efficiently and that Sia preference did not predict entry of influenza A virus to primary human airway cells evaluated in this model.

Published by Elsevier Inc.

KEYWORDS: Hemagglutinin; Influenza A virus; Pandemic; Receptor binding

PMID: 27062579 [PubMed – as supplied by publisher]

Keywords: Research; Abstracts; Pandemic Influenza; Spanish Flu; H1N1.

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#Identification of Low- and High-Impact #Hemagglutinin #AminoAcid #Substitutions That Drive Antigenic #Drift of #Influenza A(#H1N1) Viruses (PLoS Pathog., abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]

Open Access / Peer-reviewed / Research Article

Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses

William T. Harvey, Donald J. Benton, Victoria Gregory, James P. J. Hall, Rodney S. Daniels, Trevor Bedford, Daniel T. Haydon, Alan J. Hay, John W. McCauley, Richard Reeve

PLOS  / Published: April 8, 2016 / http://dx.doi.org/10.1371/journal.ppat.1005526

 

Abstract

Determining phenotype from genetic data is a fundamental challenge. Identification of emerging antigenic variants among circulating influenza viruses is critical to the vaccine virus selection process, with vaccine effectiveness maximized when constituents are antigenically similar to circulating viruses. Hemagglutination inhibition (HI) assay data are commonly used to assess influenza antigenicity. Here, sequence and 3-D structural information of hemagglutinin (HA) glycoproteins were analyzed together with corresponding HI assay data for former seasonal influenza A(H1N1) virus isolates (1997–2009) and reference viruses. The models developed identify and quantify the impact of eighteen amino acid substitutions on the antigenicity of HA, two of which were responsible for major transitions in antigenic phenotype. We used reverse genetics to demonstrate the causal effect on antigenicity for a subset of these substitutions. Information on the impact of substitutions allowed us to predict antigenic phenotypes of emerging viruses directly from HA gene sequence data and accuracy was doubled by including all substitutions causing antigenic changes over a model incorporating only the substitutions with the largest impact. The ability to quantify the phenotypic impact of specific amino acid substitutions should help refine emerging techniques that predict the evolution of virus populations from one year to the next, leading to stronger theoretical foundations for selection of candidate vaccine viruses. These techniques have great potential to be extended to other antigenically variable pathogens.

Author Summary

Influenza A viruses are characterized by rapid antigenic drift: structural changes in B-cell epitopes that facilitate escape from pre-existing immunity. Consequently, seasonal influenza continues to impose a major burden on human health. Accurate quantification of the antigenic impact of specific amino acid substitutions is a pre-requisite for predicting the fitness and evolutionary outcome of variant viruses. Using assays to attribute antigenic variation to amino acid sequence changes we identify substitutions that contribute to antigenic drift and quantify their impact. We show that substitutions identified as low-impact are a critical component of virus antigenic evolution and by including these, as well as the high-impact substitutions often focused on, the accuracy of predicting antigenic phenotypes of emerging viruses from genotype is doubled.

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Citation: Harvey WT, Benton DJ, Gregory V, Hall JPJ, Daniels RS, Bedford T, et al. (2016) Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses. PLoS Pathog 12(4): e1005526. doi:10.1371/journal.ppat.1005526

Editor: Scott E. Hensley, The Wistar Institute, UNITED STATES

Received: August 19, 2015; Accepted: March 4, 2016; Published: April 8, 2016

Copyright: © 2016 Harvey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Sequences are available from GISAID—http://platform.gisaid.org—and the assay data underpinning this publication (and the GISAID accession numbers of the viruses used) are available from the associated data deposition at doi:10.5525/gla.researchdata.289.

Funding: This research was supported by the Medical Research Council under programme number U117512723 (WTH, VG, DJB, RSD, AJH, JWM) and grant MR/J50032X/1 (WTH), the Wellcome Trust grant number 083224 (JPJH), NIH grant U54GM111274 (TB), and by the Biotechnology and Biological Sciences Research Council Institute Strategic Programme on Livestock Viral Diseases at The Pirbright Institute (RR), grant BB/H009175/1 (RR), and grant BB/E010326/1 (DTH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Research; Abstracts; Seasonal Influenza; H1N1.

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Selective #Bottlenecks Shape #Evolutionary #Pathways Taken during #Mammalian #Adaptation of a 1918-like #Avian #Influenza #Virus (Cell Host Microbe, abstract)

[Source: Cell Host & Microbe, full page: (LINK). Abstract, edited.]

Selective Bottlenecks Shape Evolutionary Pathways Taken during Mammalian Adaptation of a 1918-like Avian Influenza Virus [      ]

Louise H. Moncla, Gongxun Zhong, Chase W. Nelson, Jorge M. Dinis, James Mutschler, Austin L. Hughes, Tokiko Watanabe, Yoshihiro Kawaoka, Thomas C. Friedrich

Published: February 10, 2016 / DOI: http://dx.doi.org/10.1016/j.chom.2016.01.011

 

Highlights

–| HA diversification arising during initial ferret adaption of avian flu virus is maintained

–| Low-frequency transmissible polymerase variants arise subsequently

–| Transmission bottleneck selects specific HA variants

–| Mammalian transmission can evolve through multiple genetic pathways

 

Summary

Avian influenza virus reassortants resembling the 1918 human pandemic virus can become transmissible among mammals by acquiring mutations in hemagglutinin (HA) and polymerase. Using the ferret model, we trace the evolutionary pathway by which an avian-like virus evolves the capacity for mammalian replication and airborne transmission. During initial infection, within-host HA diversity increased drastically. Then, airborne transmission fixed two polymerase mutations that do not confer a detectable replication advantage. In later transmissions, selection fixed advantageous HA1 variants. Transmission initially involved a “loose” bottleneck, which became strongly selective after additional HA mutations emerged. The stringency and evolutionary forces governing between-host bottlenecks may therefore change throughout host adaptation. Mutations occurred in multiple combinations in transmitted viruses, suggesting that mammalian transmissibility can evolve through multiple genetic pathways despite phenotypic constraints. Our data provide a glimpse into avian influenza virus adaptation in mammals, with broad implications for surveillance on potentially zoonotic viruses.

Received: July 6, 2015; Received in revised form: October 26, 2015; Accepted: January 25, 2016; Published: February 10, 2016

© 2016 Elsevier Inc. Published by Elsevier Inc. All rights reserved.

Keywords: Research; Abstracts; Avian Influenza; Pandemic Influenza; H1N1; Spanish Flu.

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Integrated #Omics #Analysis of #Pathogenic Host Responses during #Pandemic #H1N1 #Influenza #Virus Infection: The Crucial Role of Lipid Metabolism (Cell Host Microbe, abstract)

[Source: Cell Host & Microbe, full page: (LINK). Abstract, edited.]

Integrated Omics Analysis of Pathogenic Host Responses during Pandemic H1N1 Influenza Virus Infection: The Crucial Role of Lipid Metabolism [      ]

Jennifer Tisoncik-Go, David J. Gasper, Jennifer E. Kyle, Amie J. Eisfeld, Christian Selinger, Masato Hatta, Juliet Morrison, Marcus J. Korth, Erika M. Zink, Young-Mo Kim, Athena A. Schepmoes, Carrie D. Nicora, Samuel O. Purvine, Karl K. Weitz, Xinxia Peng, Richard R. Green, Susan C. Tilton, Bobbie-Jo Webb-Robertson, Katrina M. Waters, Thomas O. Metz, Richard D. Smith, Yoshihiro Kawaoka, M. Suresh, Laurence Josset, Michael G. Katze,

Published: February 10, 2016 / DOI: http://dx.doi.org/10.1016/j.chom.2016.01.002

 

Highlights

–| Conducted lipidomic, metabolomic, and proteomic profiling of virus-infected ferrets

–| 1918 and CA04 viruses produce different histologic lesions and metabolic changes

–| Integrated omics analysis shows dynamic host responses in respiratory immunity

–| Proinflammatory lipid precursors correlate with influenza virus pathogenesis

 

Summary

Pandemic influenza viruses modulate proinflammatory responses that can lead to immunopathogenesis. We present an extensive and systematic profiling of lipids, metabolites, and proteins in respiratory compartments of ferrets infected with either 1918 or 2009 human pandemic H1N1 influenza viruses. Integrative analysis of high-throughput omics data with virologic and histopathologic data uncovered relationships between host responses and phenotypic outcomes of viral infection. Proinflammatory lipid precursors in the trachea following 1918 infection correlated with severe tracheal lesions. Using an algorithm to infer cell quantity changes from gene expression data, we found enrichment of distinct T cell subpopulations in the trachea. There was also a predicted increase in inflammatory monocytes in the lung of 1918 virus-infected animals that was sustained throughout infection. This study presents a unique resource to the influenza research community and demonstrates the utility of an integrative systems approach for characterization of lipid metabolism alterations underlying respiratory responses to viruses.

Keywords: Research; Abstracts; Pandemic Influenza; H1N1; Spanish Flu.

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Novel triple-reassortant #H1N1 #swine #influenza #viruses in #pigs in Tianjin, Northern #China (Vet Microbiol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Vet Microbiol. 2016 Feb 1;183:85-91. doi: 10.1016/j.vetmic.2015.12.006. Epub 2015 Dec 12.

Novel triple-reassortant H1N1 swine influenza viruses in pigs in Tianjin, Northern China. [      ]

Sun YF1, Wang XH2, Li XL1, Zhang L1, Li HH1, Lu C1, Yang CL1, Feng J1, Han W1, Ren WK1, Tian XX1, Tong GZ2, Wen F2, Li ZJ2, Gong XQ2, Liu XM2, Ruan BY2, Yan MH3, Yu H4.

Author information: 1Tianjin Animal Husbandry and Veterinary Research Institute, Tianjin 300381,China. 2Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China. 3Tianjin Animal Husbandry and Veterinary Research Institute, Tianjin 300381,China. Electronic address: yanmh81971@126.com. 4Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China. Electronic address: haiyu_008@126.com.

 

Abstract

Pigs are susceptible to both human and avian influenza viruses and therefore have been proposed to be mixing vessels for the generation of pandemic influenza viruses through reassortment. In this study, for the first time, we report the isolation and genetic analyses of three novel triple-reassortant H1N1 swine influenza viruses from pigs in Tianjin, Northern China. Phylogenetic analysis showed that these novel viruses contained genes from the 2009 pandemic H1N1 (PB2, PB1, PA and NP), Eurasian swine (HA, NA and M) and triple-reassortant swine (NS) lineages. This indicated that the reassortment among the 2009 pandemic H1N1, Eurasian swine and triple-reassortant swine influenza viruses had taken place in pigs in Tianjin and resulted in the generation of new viruses. Furthermore, three human-like H1N1, two classical swine H1N1 and two Eurasian swine H1N1 viruses were also isolated during the swine influenza virus surveillance from 2009 to 2013, which indicated that multiple genetic lineages of swine H1N1 viruses were co-circulating in the swine population in Tianjin, China. The emergence of novel triple-reassortant H1N1 swine influenza viruses may be a potential threat to human health and emphasizes the importance of further continuous surveillance.

Copyright © 2015 Elsevier B.V. All rights reserved.

KEYWORDS: Novel ressortant H1N1 influenza virus; Phylogenetic analysis; Swine influenza

PMID: 26790939 [PubMed – in process]

Keywords: Research; Abstracts; H1N1; Swine Influenza; Reassortant Strain; Pigs; China.

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Characterization of #Viral #Load, Viability and #Persistence of #Influenza A #Virus in #Air and on #Surfaces of #Swine Production #Facilities

[Source: PLoS One, full page: (LINK). Abstract, edited.]

Open Access / Peer-reviewed / Research Article

Characterization of Viral Load, Viability and Persistence of Influenza A Virus in Air and on Surfaces of Swine Production Facilities [      ][      ]

Victor Neira,  Peter Rabinowitz,  Aaron Rendahl,  Blanca Paccha,  Shawn G. Gibbs,  Montserrat Torremorell

Published: January 12, 2016 / DOI: 10.1371/journal.pone.0146616

 

Abstract

Indirect transmission of influenza A virus (IAV) in swine is poorly understood and information is lacking on levels of environmental exposure encountered by swine and people during outbreaks of IAV in swine barns. We characterized viral load, viability and persistence of IAV in air and on surfaces during outbreaks in swine barns. IAV was detected in pigs, air and surfaces from five confirmed outbreaks with 48% (47/98) of oral fluid, 38% (32/84) of pen railing and 43% (35/82) of indoor air samples testing positive by IAV RT-PCR. IAV was isolated from air and oral fluids yielding a mixture of subtypes (H1N1, H1N2 and H3N2). Detection of IAV RNA from air was sustained during the outbreaks with maximum levels estimated between 7 and 11 days from reported onset. Our results indicate that during outbreaks of IAV in swine, aerosols and surfaces in barns contain significant levels of IAV potentially representing an exposure hazard to both swine and people.

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Citation: Neira V, Rabinowitz P, Rendahl A, Paccha B, Gibbs SG, Torremorell M (2016) Characterization of Viral Load, Viability and Persistence of Influenza A Virus in Air and on Surfaces of Swine Production Facilities. PLoS ONE 11(1): e0146616. doi:10.1371/journal.pone.0146616

Editor: Xiang-Jin Meng, Virginia Polytechnic Institute and State University, UNITED STATES

Received: September 17, 2015; Accepted: December 18, 2015; Published: January 12, 2016

Copyright: © 2016 Neira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper.

Funding: Funding was provided by the National Pork Board. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Research; Abstracts; Swine Influenza; Pigs; H1N1; H1N2; H3N2.

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