title: What Lies Beneath: Antibody Dependent Natural Killer Cell Activation by Antibodies to Internal Influenza Virus Proteins.
abstract: The conserved internal influenza proteins nucleoprotein (NP) and matrix 1 (M1) are well characterised for T cell immunity, but whether they also elicit functional antibodies capable of activating natural killer (NK) cells has not been explored. We studied NP and M1-specific ADCC activity using biochemical, NK cell activation and killing assays with plasma from healthy and influenza-infected subjects. Healthy adults had antibodies to M1 and NP capable of binding dimeric FcγRIIIa and activating NK cells. Natural symptomatic and experimental influenza infections resulted in a rise in antibody dependent NK cell activation post-infection to the hemagglutinin of the infecting strain, but changes in NK cell activation to M1 and NP were variable. Although antibody dependent killing of target cells infected with vaccinia viruses expressing internal influenza proteins was not detected, opsonising antibodies to NP and M1 likely contribute to an antiviral microenvironment by stimulating innate immune cells to secrete cytokines early in infection. We conclude that effector cell activating antibodies to conserved internal influenza proteins are common in healthy and influenza-infected adults. Given the significance of such antibodies in animal models of heterologous influenza infection, the definition of their importance and mechanism of action in human immunity to influenza is essential.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Hillary A
authors.initials: HA
authors.lastname: Vanderven
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ana-Sosa-Batiz
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Sinthujan
authors.initials: S
authors.lastname: Jegaskanda
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; Seqirus Ltd, Parkville, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Rockman
authors.affiliation: WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Karen
authors.initials: K
authors.lastname: Laurie
authors.affiliation: WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Barr
authors.affiliation: La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, Bundoora, Australia.
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Burnet Institute, Melbourne, Australia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Wines
authors.affiliation: Burnet Institute, Melbourne, Australia.
authors.forename: P Mark
authors.initials: PM
authors.lastname: Hogarth
authors.affiliation: Jenner Institute, Oxford University, Oxford, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Lambe
authors.affiliation: Jenner Institute, Oxford University, Oxford, UK.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Parsons
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; Melbourne Sexual Health Centre, Department of Infectious Diseases, Alfred Health, Central Clinical School, Monash University, Melbourne, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Parkville, Australia. Electronic address: skent@unimelb.edu.au.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kent
mesh_terms: D000914:Antibodies, Viral / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D016022:Case-Control Studies; D002460:Cell Line; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D007251:Influenza, Human / Q000175:diagnosis / Q000276:immunology* / Q000821:virology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D009975:Orthomyxoviridae / Q000276:immunology*; D011485:Protein Binding; D055503:Protein Multimerization; D017452:Receptors, IgG / Q000737:chemistry / Q000378:metabolism; D012720:Severity of Illness Index; D019562:Viral Load; D014764:Viral Proteins / Q000276:immunology* / Q000378:metabolism; D017201:Virus Shedding
chemical_list: D000914:Antibodies, Viral; C496124:FCGR3A protein, human; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D017452:Receptors, IgG; D014764:Viral Proteins
keywords: Antibody dependent cellular cytotoxicity; Hemagglutinin; Influenza; Matrix protein 1; Natural killer cells; Nucleoprotein