A central challenge for immune profiling, particularly for monitoring vaccine efficacy or disease progression, has been the identification of measurable parameters that can predict the outcome of an immune response. Given the heterogeneity of individual responses, we expect that the characteristic factors that define a healthy immune system, and its response to antigenic perturbations, are manifold rather than singular. We hypothesize that integrative analysis of data from individuals responding to vaccines or viral infections will allow for inference of causal chains of immunological processes associated with clinically defined outcomes (responsiveness, disease severity). Research Project 3 will focus on interrogating temporal behaviors of immune responses in diverse cohorts using novel single-cell techniques and mathematical methods. The application of time-series gene expression data to determine temporal gene expression patterns (SA1), single-cell analyses to determine intercellular influence networks(SA2),and multivariate statistical approaches (SA3) will generate models that describe the dynamic functional responses of the immune system, and identify sets of measurable predictors of clinical outcomes. This project involves a collaboration among four labs: The Xavier lab (MGH/Broad) and the Kleinstein lab (Yale) with expertise in bioinformatics and modeling approaches to innate and adaptive immunity, and the Love lab (MIT/Broad Institute) and the Lauffenburger lab (MIT/Broad) with expertise in microscale single-cell assays and mathematical algorithms to infer cellular networks. We will combine efforts 1) to integrate data on the diverse immune responses studied in this research program (vaccinations in healthy or aged persons, natural infections by viruses) and 2) to generate new network models based on comprehensive single-cell analyses. This project will leverage emerging approaches from engineering and computer science to improve detailed modeling of biological phenomena and provide feedback to refine experimental hypotheses in other areas of the program. The outcome of this research for health will be a set of comprehensive, integrated models for systemic immune responses that will inform vaccine design and improve the selection of biomarkers for clinical monitoring.

Public Health Relevance

Many studies have measured independent parameters as related to disease or the efficacy of treatment. While these studies have advanced analysis of immune responses to infection and vaccination, we still lack a cohesive approach to describe the coordinated and integrated immune system. This project will develop new methods to define immunological signatures within large sets of clinical data and to translate those signatures back to simple, predictive sets of parameters for routine clinical monitoring of immune responses

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-QV-I)
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Yale University
New Haven
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Murray, Kristy O; Garcia, Melissa N; Rahbar, Mohammad H et al. (2014) Survival analysis, long-term outcomes, and percentage of recovery up to 8 years post-infection among the Houston West Nile virus cohort. PLoS One 9:e102953
Yao, Yi; Liu, Rebecca; Shin, Min Sun et al. (2014) CyTOF supports efficient detection of immune cell subsets from small samples. J Immunol Methods 415:1-5
Olivieri, Fabiola; Procopio, Antonio Domenico; Montgomery, Ruth R (2014) Effect of aging on microRNAs and regulation of pathogen recognition receptors. Curr Opin Immunol 29:29-37
Vander Heiden, Jason A; Yaari, Gur; Uduman, Mohamed et al. (2014) pRESTO: a toolkit for processing high-throughput sequencing raw reads of lymphocyte receptor repertoires. Bioinformatics 30:1930-2
Zapata, Heidi J; Shaw, Albert C (2014) Aging of the human innate immune system in HIV infection. Curr Opin Immunol 29:127-36
Qian, Feng; Thakar, Juilee; Yuan, Xiaoling et al. (2014) Immune markers associated with host susceptibility to infection with West Nile virus. Viral Immunol 27:39-47
Lee, Naeun; Shin, Min Sun; Kang, Ki Soo et al. (2014) Human monocytes have increased IFN-?-mediated IL-15 production with age alongside altered IFN-? receptor signaling. Clin Immunol 152:101-10
Chattopadhyay, Pratip K; Gierahn, Todd M; Roederer, Mario et al. (2014) Single-cell technologies for monitoring immune systems. Nat Immunol 15:128-35
Gierahn, Todd M; Loginov, Denis; Love, J Christopher (2014) Crossword: a fully automated algorithm for the segmentation and quality control of protein microarray images. J Proteome Res 13:362-71
Goel, Gautam; Conway, Kara L; Jaeger, Martin et al. (2014) Multivariate inference of pathway activity in host immunity and response to therapeutics. Nucleic Acids Res 42:10288-306

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