title: The soft palate is an important site of adaptation for transmissible influenza viruses.
abstract: Influenza A viruses pose a major public health threat by causing seasonal epidemics and sporadic pandemics. Their epidemiological success relies on airborne transmission from person to person; however, the viral properties governing airborne transmission of influenza A viruses are complex. Influenza A virus infection is mediated via binding of the viral haemagglutinin (HA) to terminally attached α2,3 or α2,6 sialic acids on cell surface glycoproteins. Human influenza A viruses preferentially bind α2,6-linked sialic acids whereas avian influenza A viruses bind α2,3-linked sialic acids on complex glycans on airway epithelial cells. Historically, influenza A viruses with preferential association with α2,3-linked sialic acids have not been transmitted efficiently by the airborne route in ferrets. Here we observe efficient airborne transmission of a 2009 pandemic H1N1 (H1N1pdm) virus (A/California/07/2009) engineered to preferentially bind α2,3-linked sialic acids. Airborne transmission was associated with rapid selection of virus with a change at a single HA site that conferred binding to long-chain α2,6-linked sialic acids, without loss of α2,3-linked sialic acid binding. The transmissible virus emerged in experimentally infected ferrets within 24 hours after infection and was remarkably enriched in the soft palate, where long-chain α2,6-linked sialic acids predominate on the nasopharyngeal surface. Notably, presence of long-chain α2,6-linked sialic acids is conserved in ferret, pig and human soft palate. Using a loss-of-function approach with this one virus, we demonstrate that the ferret soft palate, a tissue not normally sampled in animal models of influenza, rapidly selects for transmissible influenza A viruses with human receptor (α2,6-linked sialic acids) preference.
authors.affiliation: Laboratory of infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Seema S
authors.initials: SS
authors.lastname: Lakdawala
authors.affiliation: Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Singapore-MIT Alliance for Research and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Akila
authors.initials: A
authors.lastname: Jayaraman
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland 20850, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Halpin
authors.affiliation: Laboratory of infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Lamirande
authors.affiliation: Laboratory of infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Shih
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland 20850, USA.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Stockwell
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland 20850, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Lin
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland 20850, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Simenauer
authors.affiliation: Laboratory of infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Hanson
authors.affiliation: Laboratory of infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Leatrice
authors.initials: L
authors.lastname: Vogel
authors.affiliation: Laboratory of infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Myeisha
authors.initials: M
authors.lastname: Paskel
authors.affiliation: Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Minai
authors.affiliation: Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Moore
authors.affiliation: Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Marlene
authors.initials: M
authors.lastname: Orandle
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland 20850, USA.
authors.forename: Suman R
authors.initials: SR
authors.lastname: Das
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland 20850, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Wentworth
authors.affiliation: Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Singapore-MIT Alliance for Research and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Ram
authors.initials: R
authors.lastname: Sasisekharan
authors.affiliation: Laboratory of infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kanta
authors.initials: K
authors.lastname: Subbarao
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005260:Female; D005289:Ferrets / Q000821:virology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D009976:Orthomyxoviridae Infections / Q000635:transmission / Q000821:virology; D010160:Palate, Soft / Q000737:chemistry / Q000378:metabolism* / Q000821:virology*; D011991:Receptors, Virus / Q000378:metabolism*; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism / Q000821:virology; D012641:Selection, Genetic / Q000235:genetics; D012794:Sialic Acids / Q000737:chemistry / Q000378:metabolism; D013552:Swine / Q000821:virology
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus; D012794:Sialic Acids