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VA San Diego Healthcare System
California
Background and Innovation: Mortality from infectious diseases remains the second leading cause of death worldwide, a fact highlighted by 4 years of a global pandemic, making the understanding of host responses, development of new vaccines, and improving existing vaccines important priorities of biomedical research. Memory T cells mediate protection from reinfection with previously encountered pathogens, and a large number of these cells, termed tissue-resident memory cells (TRM), do not recirculate throughout the body, reside within tissues, and provide essential sentinel protection at body surfaces. Using a murine infection model that is well established in the field for studying CD8 TRM, this application will investigate the context- and tissue-specific roles of the transcription factor Foxo1. Conceptual innovations include the study of Foxo1, the role of which is poorly understood in TRM biology. Technical innovations include the use of numerous cutting- edge approaches, including Cellular Indexing of Transcriptomes and Epitopes (CITE-seq) which enables proteomic and transcriptomic (scRNA-seq) analyses in the same single-cells, to identify consequences of Foxo1-deficiency in TRM. Bioinformatic innovations include the application of Taiji, a state-of-the-art bioinformatic analysis algorithm integrating transcriptomic and epigenomic data, to reveal Foxo1-transcription factor networks and identify putative regulatory factors and pathways controlled by Foxo1. Significance and Impact to Veterans Healthcare: Infectious diseases have a substantial public health and economic burden on the Veteran population. These include diseases for which we have vaccines, such as SARS-CoV-2 and influenza, as well as diseases that we do not yet have vaccines for, such as Hepatitis C (HCV) and HIV. A major gap in knowledge is that current vaccines generate neutralizing antibodies but do not generate a robust memory T cell response, including TRM, which are crucial for optimal protection at barrier surfaces. Another gap in knowledge is a comprehensive molecular understanding of the tissue-specific requirements for the generation and persistence of TRM, which will be addressed by this project. This research will address the VHA/ORD research priority of exploring fundamental biologic principles in pre-clinical models with the ultimate goal of improving the well-being of the nation’s Veterans specifically in the area of infectious diseases. Path to translation/implementation: Current vaccination regimens aim to generate protective antibodies but do not generate TRM. A detailed understanding of regulatory programs and transcriptional networks that govern T cell adaptation to tissues and barrier sites must be gained in order to provide the foundation and rational scientific basis to develop “tissue-tailored” immune responses. In this way, immune cells that promote or regulate inflammation can be transcriptionally engineered for trafficking to, retention in, and function within a particular tissue. Next steps to move this research along the translational pathway will involve testing whether modulation of Foxo1-mediated pathways enhances vaccine-generated immune memory.