Mortality from chronic infectious diseases, including Hepatitis C, HIV, and tuberculosis, remains a major problem among Veterans, making the development of new vaccines an important priority of biomedical research. Immunologic memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Traditional vaccination strategies are very effective at generating neutralizing antibodies against bacteria and viruses. However, a vaccine capable of generating robust T cell memory is still beyond our research, due, in part, to an incomplete understanding of the molecular basis for memory lymphocyte fate specification. Moreover, the molecular mechanisms underlying immune `exhaustion,' a state in which T cells are rendered ineffective during many chronic viral infections, remain incompletely understood. Thus, a fundamental understanding of how memory lymphocyte fate is specified, as well as what goes awry in the exhausted state, is a crucial first step in rational vaccine design for infectious diseases such as HIV, HCV, malaria, and tuberculosis. Our underlying hypothesis is that previously unappreciated molecular determinants control the specification of terminal effector and memory (TCM, TEM, and TRM) cell fates as well as the exhausted CD8+ T cell state. Our goal is to identify and validate these determinants using innovative multi-disciplinary approaches that include single-cell RNA sequencing, computational analyses, and immunological techniques.

Public Health Relevance

Complications from chronic infectious diseases contribute to significant morbidity and mortality in the Veteran population. Effector and memory T lymphocytes are cells of the immune system that provide protection against infections. Our goal is to understand how these cells are generated and how they function in response to different infections. These studies may help our efforts to improve vaccines.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX003424-01
Application #
9138080
Study Section
Infectious Diseases A (INFA)
Project Start
2016-10-01
Project End
2020-09-30
Budget Start
2016-10-01
Budget End
2017-09-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161