# Project 3 - Zuniga

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $463,910

## Abstract

SUMMARY-PROJECT 3-ZUNIGA:
Tissue-resident memory (Trm) CD8+ T cells are a distinct subset of memory cells that provide an essential
frontline of defense against microbes at mucosal barriers and non-barrier tissues. Although Trm are now
recognized to play critical roles in host defense against acute infection, their function and molecular regulation
during persistent infections have been largely unexplored. This knowledge gap is fundamentally important
given that infection persists primarily in non-lymphoid tissues following chronic infection. As persistent
infections such as HIV, HCV and HBV are responsible for tremendous disease burden worldwide,
understanding immune regulation in non-lymphoid tissues will inform novel strategies to harness Trm against
chronic infections and tumors.
We propose innovative approaches to elucidate new mechanisms that specifically promote Trm exhaustion,
the progressive loss of effector functions, leading to persistent pathogen in tissues and enhancing susceptibility
to secondary infections. These studies will likely redefine current models of CD8+ T cell differentiation, fate and
function during persistent viral infection as the current understanding of T cell exhaustion is almost exclusively
based on studying circulating lymphocyte populations. Specifically, we will: (1) Decipher the unique molecular
regulation and heterogeneity of exhausted Trm using cutting-edge single-cell RNA-seq and small-cell-number
epigenetic methodologies combined with novel integrative computational analyses. Novel regulators of
exhausted Trm identified in these studies will be tested with high-throughput functional in vivo shRNA
screening. (2) Elucidate the mechanisms by which T-box transcription factors, T-bet and Eomes, and the
transcriptional repressor Ezh2 differentially operate to control Trm differentiation in acute and chronic infection.
(3) Investigate how non-canonical TGFβ signaling components regulate Trm development and exhaustion. Our
studies will leverage the data and expertise represented in the other Project and Core laboratories to define the
functional and molecular determinants of Trm differentiation, retention, and exhaustion, providing the
foundation with which to effectively manipulate this CD8+ T cell subset to combat chronic infectious diseases
and cancer where tumor infiltrating lymphocytes undergo exhaustion. As LCMV is a prototypic member of the
family arenaviridae, our work will also help explain T cell suppression caused by hemorrhagic fever
arenaviruses. Moreover, we anticipate that the basic knowledge on Trm regulation that will be gathered from
our studies will have broad implications for other immune-related diseases in which Trm have been shown to
play a pathogenic role, such as allergy and autoimmunity.

## Key facts

- **NIH application ID:** 9960427
- **Project number:** 5P01AI132122-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Elina I Zuniga
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,910
- **Award type:** 5
- **Project period:** 2018-07-17 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960427

## Citation

> US National Institutes of Health, RePORTER application 9960427, Project 3 - Zuniga (5P01AI132122-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9960427. Licensed CC0.

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