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.
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.
|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