Intracellular protein levels, subcellular localization, or activation state are reflective of a cell's functions. Some relevant cell populations are so rare as to make their isolation for standard biochemical analysis essentially impossible. We have previously shown that disease-driven, single-cell intrinsic events can have profound effects on phospho-signaling network architecture and this can be correlated to clinical outcomes. In the case of viral infection, it is unclear whether or not certain individuals possess immune characteristics that make them more or less susceptible to influenza infection. For instance, environmental or individual characteristics such as age and immune system health could have effects upon the immune system's response to viral challenge. We will document the signaling biology of the immune system at two levels of resolution. First, we will investigate and document the changes to immune signaling post-influenza infection of human PBMC in vitro. These studies allow for analysis of influenza infection and the changes that it creates in immune cell subsets at a single cell level. Second, we will study the signaling biology of PBMC in age-selected cohorts of healthy subjects, including monozygotic twins, given either of the two licensed influenza vaccines (TIV or LAIV). These studies provide a fuller understanding of how immune system changes in the young, the healthy adult, and the elderly individual might account for differing response patterns to alternative vaccine strategies and provide in-sights about influenza effects upon signaling behaviors of immune system cells.

Public Health Relevance

The age-driven differences we have already observed in signaling and the potent changes in the signaling of immune response profiles in PBMC infected with influenza, demonstrates this project will enhance our mechanistic understanding of influenza and its interaction with the immune system, and could identify new tools for clinical differential diagnosis. Such studies could provide means to measure responses to influenza infection and approaches to better manage influenza infection with vaccination or drug intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI057229-10
Application #
8508797
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$234,011
Indirect Cost
$66,318
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Krishnaswamy, Smita; Spitzer, Matthew H; Mingueneau, Michael et al. (2014) Systems biology. Conditional density-based analysis of T cell signaling in single-cell data. Science 346:1250689
Bendall, Sean C; Davis, Kara L; Amir, El-Ad David et al. (2014) Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development. Cell 157:714-25
Gaudillière, Brice; Fragiadakis, Gabriela K; Bruggner, Robert V et al. (2014) Clinical recovery from surgery correlates with single-cell immune signatures. Sci Transl Med 6:255ra131
Sen, Adrish; Rott, Lusijah; Phan, Nguyen et al. (2014) Rotavirus NSP1 protein inhibits interferon-mediated STAT1 activation. J Virol 88:41-53
Furman, David; Hejblum, Boris P; Simon, Noah et al. (2014) Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc Natl Acad Sci U S A 111:869-74
Sen, Nandini; Mukherjee, Gourab; Sen, Adrish et al. (2014) Single-cell mass cytometry analysis of human tonsil T cell remodeling by varicella zoster virus. Cell Rep 8:633-45
Pernas, Lena; Ramirez, Raymund; Holmes, Tyson H et al. (2014) Immune profiling of pregnant Toxoplasma-infected US and Colombia patients reveals surprising impacts of infection on peripheral blood cytokines. J Infect Dis 210:923-31
Bruggner, Robert V; Bodenmiller, Bernd; Dill, David L et al. (2014) Automated identification of stratifying signatures in cellular subpopulations. Proc Natl Acad Sci U S A 111:E2770-7
Chang, Serena; Kohrt, Holbrook; Maecker, Holden T (2014) Monitoring the immune competence of cancer patients to predict outcome. Cancer Immunol Immunother 63:713-9
Birnbaum, Michael E; Mendoza, Juan L; Sethi, Dhruv K et al. (2014) Deconstructing the peptide-MHC specificity of T cell recognition. Cell 157:1073-87

Showing the most recent 10 out of 64 publications