Our goal is to understand how a successful vaccine induces long-term immunological memory and protective immunity in humans. To achieve this goal we have initiated a detailed cellular and molecular characterization of human immune responses induced by the yellow fever virus (YFV-17D) vaccine. This is one of our most efficacious vaccines and induces long-term immunity that lasts for decades. Also, since YFV-17D is a live attenuated vaccine and most of the U.S. population is not exposed to YFV-, this provides a unique opportunity to analyze antiviral responses in humans during the course of a primary infection and then to monitor the generation and maintenance of immune memory after resolution of the infection. One of the potential benefits of understanding how a successful vaccine induces long-term protective immunity is that this knowledge can be applied to improving other less effective vaccines and, more importantly, to develop new vaccines against emerging diseases. During the previous cycle of funding we have made substantial progress in characterizing human memory T and B cell responses not only to YFV but also after immunization with small pox and influenza vaccines. In this renewal application we will focus our studies on CDS T cells and examine the mechanisms that regulate human effector and memory CDS T cell differentiation. The following specific aims are proposed to achieve our goals: 1) To identify transcription factors that regulate naive to effector CDS Tee// differentiation. 2) To analyze the in vivo turnover of human YFV specific CDS T cells and to examine their homing potential. 3) To define the genomic and epigenetic changes that occur during human memory CDS T cell differentiation.These studies will will provide the first view of the transcriptional changes that occur following CDS T cell differentiation in humans and will provide unique markers that will enable identification, isolation, and characterization of the differentiated cell subsets. Examination of the epigenetic DMA methylation marks during the progression of the T cell response, as well as between CD8 T cells responding to acute versus chronic viral infections will provide a potential mechanistic view of how memory CDS T cell differentiation is globally regulated.

Public Health Relevance

YFV-17D is an ideal model to study memory T cell generation in the context of an acute viral infection.The underlying importance of this study is that the longitudinal analysis of YFV specific CDS T cells in vaccinees, offers a unique opportunity to track differentiation of highly functional and long-lived human memory CDS T cells and generate a signature that may be a benchmark for other vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI057266-10
Application #
8468620
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$403,338
Indirect Cost
$83,526
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Moore, James; Ahmed, Hasan; Jia, Jonathan et al. (2018) What Controls the Acute Viral Infection Following Yellow Fever Vaccination? Bull Math Biol 80:46-63
Li, Yinyin; Goronzy, Jörg J; Weyand, Cornelia M (2018) DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system. Exp Gerontol 105:118-127
Henry, Carole; Palm, Anna-Karin E; Krammer, Florian et al. (2018) From Original Antigenic Sin to the Universal Influenza Virus Vaccine. Trends Immunol 39:70-79
Goronzy, Jörg J; Hu, Bin; Kim, Chulwoo et al. (2018) Epigenetics of T cell aging. J Leukoc Biol 104:691-699
Watanabe, Ryu; Maeda, Toshihisa; Zhang, Hui et al. (2018) MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. Circ Res 123:700-715
Weyand, Cornelia M; Shen, Yi; Goronzy, Jorg J (2018) Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. Free Radic Biol Med 125:36-43
Wilson, Patrick C; Cobey, Sarah (2018) Characterization of the immunologic repertoire: A quick start guide. Immunol Rev 284:5-8
Buenrostro, Jason D; Corces, M Ryan; Lareau, Caleb A et al. (2018) Integrated Single-Cell Analysis Maps the Continuous Regulatory Landscape of Human Hematopoietic Differentiation. Cell 173:1535-1548.e16
Stamper, Christopher T; Wilson, Patrick C (2018) What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Is Affinity Maturation a Self-Defeating Process for Eliciting Broad Protection? Cold Spring Harb Perspect Biol 10:
Mezger, Anja; Klemm, Sandy; Mann, Ishminder et al. (2018) High-throughput chromatin accessibility profiling at single-cell resolution. Nat Commun 9:3647

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