title: Aging-dependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination.
abstract: To elucidate gene expression pathways underlying age-associated impairment in influenza vaccine response, we screened young (age 21-30) and older (age≥65) adults receiving influenza vaccine in two consecutive seasons and identified those with strong or absent response to vaccine, including a subset of older adults meeting criteria for frailty. PBMCs obtained prior to vaccination (Day 0) and at day 2 or 4, day 7 and day 28 post-vaccine were subjected to gene expression microarray analysis. We defined a response signature and also detected induction of a type I interferon response at day 2 and a plasma cell signature at day 7 post-vaccine in young responders. The response signature was dysregulated in older adults, with the plasma cell signature induced at day 2, and was never induced in frail subjects (who were all non-responders). We also identified a mitochondrial signature in young vaccine responders containing genes mediating mitochondrial biogenesis and oxidative phosphorylation that was consistent in two different vaccine seasons and verified by analyses of mitochondrial content and protein expression. These results represent the first genome-wide transcriptional profiling analysis of age-associated dynamics following influenza vaccination, and implicate changes in mitochondrial biogenesis and function as a critical factor in human vaccine responsiveness.
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.|Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA.|Department of Biostatistics and Computational Biology, University of Rochester, Rochester NY 14642, USA.
authors.forename: Juilee
authors.initials: J
authors.lastname: Thakar
authors.affiliation: Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Subhasis
authors.initials: S
authors.lastname: Mohanty
authors.affiliation: Department of Pathology and Genetics, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: A Phillip
authors.initials: AP
authors.lastname: West
authors.affiliation: Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Samit R
authors.initials: SR
authors.lastname: Joshi
authors.affiliation: Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Ueda
authors.affiliation: Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Wilson
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hailong
authors.initials: H
authors.lastname: Meng
authors.affiliation: Center for Vaccine Development, Saint Louis University, St. Louis, MO 63104, USA.
authors.forename: Tamara P
authors.initials: TP
authors.lastname: Blevins
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Sui
authors.initials: S
authors.lastname: Tsang
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Trentalange
authors.affiliation: Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Siconolfi
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Koonam
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Gill
authors.affiliation: Center for Vaccine Development, Saint Louis University, St. Louis, MO 63104, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Belshe
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.affiliation: Department of Pathology and Genetics, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.|Interdepartmental Program in Computational Biology and Bioinformatics, Yale School of Medicine, New Haven, CT 06520, USA.|Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.affiliation: Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicince, New Haven, CT 06520, USA.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D055106:Genome-Wide Association Study; D006801:Humans; D007252:Influenza Vaccines / Q000008:administration & dosage*; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000187:drug effects / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation / Q000187:drug effects; D012621:Seasons; D013997:Time Factors; D016896:Treatment Outcome; D014611:Vaccination; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D007252:Influenza Vaccines