The genetic variability and Individual variations in immune status dictate responses to vaccinations, infections, and contribute to disease severity. The sequencing of the human genome and generation of the Haplotype Map now enables a mechanistic understanding of how genetic variation influences human immune responses. Yet manifold non-genetic factors also interact to maintain the healthy immune system, and complex analysis will be required to form predictions for its response to perturbations. Here, we will employ systems approaches and novel, high throughput and high-fidelity technologies such as multiplexed gene expression, automated multidimensional flow cytometry, and integrated single-cell assays in nanowells to quantitatively assess leukocyte function to ultimately identify the molecular signatures defining individual immune responses. We will address immune profiles in three related studies. In Research Project 1, we will develop immunologic signatures of influenza vaccine responsiveness and determine the effect of aging and functional status on these signatures. We will identify gene signatures and biological pathways that can distinguish between strong and weak immune responses to vaccination and that predict effective responses. In Research Project 2, we will investigate resistance to flaviviral infections using West Nile virus, and hepatitis C virus;through analysis of responses in patients from stratified cohorts, we will establish correlations between gene expression, immune cell responses and clinical outcome. In Research Project 3, we will generate mathematical models that detect connectivity and predict dynamic functional responses of the immune system. This approach will link data collected on both populations and individuals using multivariate statistical approaches to integrate cohort-wide data including genome wide association studies and novel single-cell analyses to assess immune responsiveness in relationship to genetic variation. Our functional systems immunology approach will allow us to define baseline human immune signatures following viral infection and vaccination along with deviations from this baseline, with the goal of identifying future targets for intervention and establishing sets of biomarkers that predict responses to vaccination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI089992-03
Application #
8292000
Study Section
Special Emphasis Panel (ZAI1-QV-I (M2))
Program Officer
Dong, Gang
Project Start
2011-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$2,837,004
Indirect Cost
$840,039
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Yao, Yi; Montgomery, Ruth R (2016) Role of Immune Aging in Susceptibility to West Nile Virus. Methods Mol Biol 1435:235-47
Montgomery, Ruth R (2016) High standards for high dimensional investigations. Cytometry A 89:886-888
Das, Rituparna; Loughran, Kerry; Murchison, Charles et al. (2016) Association between high expression macrophage migration inhibitory factor (MIF) alleles and West Nile virus encephalitis. Cytokine 78:51-4
Montgomery, Ruth R; Murray, Kristy O (2015) Risk factors for West Nile virus infection and disease in populations and individuals. Expert Rev Anti Infect Ther 13:317-25
Strauss-Albee, Dara M; Fukuyama, Julia; Liang, Emily C et al. (2015) Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility. Sci Transl Med 7:297ra115
Mohanty, Subhasis; Joshi, Samit R; Ueda, Ikuyo et al. (2015) Prolonged proinflammatory cytokine production in monocytes modulated by interleukin 10 after influenza vaccination in older adults. J Infect Dis 211:1174-84
Qian, Feng; Goel, Gautam; Meng, Hailong et al. (2015) Systems immunology reveals markers of susceptibility to West Nile virus infection. Clin Vaccine Immunol 22:6-16
Qian, Feng; Montgomery, Ruth R (2015) Imaging Immunosenescence. Methods Mol Biol 1343:97-106
Thakar, Juilee; Mohanty, Subhasis; West, A Phillip et al. (2015) Aging-dependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination. Aging (Albany NY) 7:38-52
Tsioris, Konstantinos; Gupta, Namita T; Ogunniyi, Adebola O et al. (2015) Neutralizing antibodies against West Nile virus identified directly from human B cells by single-cell analysis and next generation sequencing. Integr Biol (Camb) 7:1587-97

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