The influenza virus and its variants remains a serious public health threat in both developing and developed counties, accounting for ~35,000 deaths and hundreds of thousands hospitalized in the US alone in an average year. In this renewal application from the Cooperative Center for Human Immunology at Stanford University, we wish to leverage our considerable experience in analyzing the influenza vaccine response to address some fundamental questions and hypotheses regarding how the human immune system responds to influenza vaccination or infection. We also wish to continue advancing immune monitoring technologies relevant to analyzing the human immune response, such Cytometry by Time-Of-Flight, or CyTOF, combinatorial peptide-MHC tetramers and new TCR and BCR repertoire and gene expression analysis methods that open up entirely new areas of investigation and ways to test hypotheses. The general theme of our proposal is to address specific questions regarding how the human immune system develops and changes in young children, adolescents and young adults. While there are considerable challenges in monitoring the immune responses of infants and young children, new technologies, many of them developed here at Stanford, now make some very fundamental questions feasible to address. These include testing hypotheses about memory phenotype T cells, and of flu-specific effector and memory CD4+ T cells (PI), the influence of innate immune factors and CD4+ T cells on influenza virus infection in a novel ex vivo system (P2), the development of the immunoglobulin, T cell receptor and NK repertoires in response to vaccination in different age groups from our twin cohort (P3), and advancing the capabilities of the CyTOF instrument (P4). These efforts will be very ably supported by our Administrative (A), Pilot (B), Clinical (C), Human Immune Monitoring (D), Genomics (E) and Bioinformatics (F) Cores. Most of these cores have been in place for four or more years and have provided vital and state-of the-art support for the research activities of the group. We are entering into an exciting period of time for human immunology and we think that the Stanford team will continue to be extremely productive.

Public Health Relevance

Influenza virus is a category C priority human pathogen that represents an ongoing and serious public health threat world-wide. In this proposal we seek to understand the fundamental processes with which the human immune system responds to vaccination and combats influenza infection. We are particularly focused on how this immunity develops in children and adolescents compared to adults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI057229-15
Application #
9461457
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Ramachandra, Lakshmi
Project Start
2003-09-30
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
15
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Bukhari, Syed Ahmad Chan; O'Connor, Martin J; Martínez-Romero, Marcos et al. (2018) The CAIRR Pipeline for Submitting Standards-Compliant B and T Cell Receptor Repertoire Sequencing Studies to the National Center for Biotechnology Information Repositories. Front Immunol 9:1877
Azad, Tej D; Donato, Michele; Heylen, Line et al. (2018) Inflammatory macrophage-associated 3-gene signature predicts subclinical allograft injury and graft survival. JCI Insight 3:
Leipold, Michael D; Obermoser, Gerlinde; Fenwick, Craig et al. (2018) Comparison of CyTOF assays across sites: Results of a six-center pilot study. J Immunol Methods 453:37-43
Sibener, Leah V; Fernandes, Ricardo A; Kolawole, Elizabeth M et al. (2018) Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding. Cell 174:672-687.e27
Ju, Chia-Hsin; Blum, Lisa K; Kongpachith, Sarah et al. (2018) Plasmablast antibody repertoires in elderly influenza vaccine responders exhibit restricted diversity but increased breadth of binding across influenza strains. Clin Immunol 193:70-79
Sweeney, Timothy E; Perumal, Thanneer M; Henao, Ricardo et al. (2018) A community approach to mortality prediction in sepsis via gene expression analysis. Nat Commun 9:694
Davis, Mark M; Tato, Cristina M (2018) Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? Seeing the Forest Rather than a Few Trees. Cold Spring Harb Perspect Biol 10:
Gee, Marvin H; Han, Arnold; Lofgren, Shane M et al. (2018) Antigen Identification for Orphan T Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes. Cell 172:549-563.e16
Keeffe, Jennifer R; Van Rompay, Koen K A; Olsen, Priscilla C et al. (2018) A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. Cell Rep 25:1385-1394.e7
Wagar, Lisa E; DiFazio, Robert M; Davis, Mark M (2018) Advanced model systems and tools for basic and translational human immunology. Genome Med 10:73

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