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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.

SUBMITTER: Thakar J

PROVIDER: S-EPMC4356402 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Aging-dependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination.

Thakar Juilee J Mohanty Subhasis S West A Phillip AP Joshi Samit R SR Ueda Ikuyo I Wilson Jean J Meng Hailong H Blevins Tamara P TP Tsang Sui S Trentalange Mark M Siconolfi Barbara B Park Koonam K Gill Thomas M TM Belshe Robert B RB Kaech Susan M SM Shadel Gerald S GS Kleinstein Steven H SH Shaw Albert C AC

Aging 20150101 1

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 def ...[more]

PMID: 25596819

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Project description:Background: Influenza is a global public health problem for its detrimental impact on human health. Annual vaccination is the most effective prevention of influenza infection. Identifying host genetic factors associated with the responsiveness to influenza vaccines can provide clues for developing more effective influenza vaccines. In this study, we aimed to explore whether the single nucleotide polymorphisms in BAT2 are associated with the antibody responses to influenza vaccines. Method: A nested case-control study was conducted in this research. 1968 healthy volunteers were enrolled and 1,582 of them from a Chinese Han population were eligible for further research. According to the hemagglutination inhibition titers of subjects against all influenza vaccine strains, a total of 227 low responders and 365 responders were included in the analysis. Six tag single nucleotide polymorphisms in the coding region of BAT2 were selected and genotyped using the MassARRAY technology platform. Univariable and multivariable analyses were conducted to evaluate the relationship between variants and antibody responses to influenza vaccination. Results: Multivariable logistic regression analysis showed that, compared with the BAT2 rs1046089GG genotype, the GA + AA genotype was correlated with decreased risk of low responsiveness to influenza vaccines after adjusting for gender and age (p = 1.12E-03, OR = .562, 95%CI: .398-.795). rs9366785 GA + AA genotype was associated with a higher risk of low responsiveness to influenza vaccination compared with the GG genotype (p = .003, OR = 1.854, 95%CI: 1.229-2.799). The haplotype consisting of BAT2 rs2280801-rs10885-rs1046089-rs2736158-rs1046080-rs9366785 CCAGAG was correlated with a higher level of antibody response to influenza vaccines compared with haplotype CCGGAG (p < .001, OR = .37, 95%CI: .23-.58). Conclusion: Genetic variants in BAT2 were statistically associated with the immune response to influenza vaccination among the Chinese population. Identifying these variants will provide clues for further research on novel broad-spectrum influenza vaccines, and improve the individualized influenza vaccination scheme.

Project description:Classical antiviral therapies target viral proteins and are consequently subject to resistance. To counteract this limitation, alternative strategies have been developed that target cellular factors. We hypothesized that such an approach could also be useful to identify broad-spectrum antivirals. The influenza A virus was used as a model for its viral diversity and because of the need to develop therapies against unpredictable viruses as recently underlined by the H1N1 pandemic. We proposed to identify a gene-expression signature associated with infection by different influenza A virus subtypes which would allow the identification of potential antiviral drugs with a broad anti-influenza spectrum of activity. We analyzed the cellular gene expression response to infection with five different human and avian influenza A virus strains and identified 300 genes as differentially expressed between infected and non-infected samples. The most 20 dysregulated genes were used to screen the connectivity map, a database of drug-associated gene expression profiles. Candidate antivirals were then identified by their inverse correlation to the query signature. We hypothesized that such molecules would induce an unfavorable cellular environment for influenza virus replication. Eight potential antivirals including ribavirin were identified and their effects were tested in vitro on five influenza A strains. Six of the molecules inhibited influenza viral growth. The new pandemic H1N1 virus, which was not used to define the gene expression signature of infection, was inhibited by five out of the eight identified molecules, demonstrating that this strategy could contribute to identifying new broad anti-influenza agents acting on cellular gene expression. The identified infection signature genes, the expression of which are modified upon infection, could encode cellular proteins involved in the viral life cycle. This is the first study showing that gene expression-based screening can be used to identify antivirals. Such an approach could accelerate drug discovery and be extended to other pathogens.

Dataset Information

Aging-dependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination.

Publications

Aging-dependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination.

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