title: Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice.
abstract: Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genome-wide association study evaluated the expression of single-nucleotide polymorphisms (SNPs) in the HO-1 gene and the response to influenza vaccination in healthy humans. HO-1-deficient mice had decreased survival after influenza infection compared to WT mice (median survival 5.5 vs. 6.5 d, P=0.016). HO-1-deficient mice had impaired production of antibody following influenza vaccination compared to WT mice (mean antibody titer 869 vs. 1698, P=0.02). One SNP in HO-1 and one SNP in the constitutively expressed isoform HO-2 were independently associated with decreased antibody production after influenza vaccination in healthy human volunteers (P=0.017 and 0.014, respectively). HO-1 deficient mice were paired with sex- and age-matched WT controls. HO-1 affects the immune response to both influenza infection and vaccination, suggesting that therapeutic induction of HO-1 expression may represent a novel adjuvant to enhance influenza vaccine effectiveness.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Cummins
authors.forename: Eric A
authors.initials: EA
authors.lastname: Weaver
authors.forename: Shannon M
authors.initials: SM
authors.lastname: May
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Croatt
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kennedy
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Poland
authors.forename: Michael A
authors.initials: MA
authors.lastname: Barry
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Badley
mesh_terms: D000375:Aging / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology; D007251:Influenza, Human / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014611:Vaccination
chemical_list: D000914:Antibodies, Viral; D017931:DNA Primers; D007252:Influenza Vaccines; D008565:Membrane Proteins; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse