# Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $453,462

## Abstract

Project Summary
Natural killer (NK) cells are lymphocytes of the immune system that can detect and kill virally infected cells.
Epidemiological studies have shown that immunosuppressed (e.g. cancer, organ transplant, AIDS) patients
and newborns display an enhanced risk for health complications associated with human cytomegalovirus
(HCMV) infection that can be life-threating. Previous work has shown that mouse cytomegalovirus (MCMV)
infection in mice can accurately model HCMV infection, and demonstrated that NK cells are critical for the
control of MCMV. Furthermore, NK cells have been shown to have properties of the adaptive immune system
such as recall responses, antigen-specificity, and clonal expansion in mice, macaques, and humans. Although
our work has made significant progress into elucidating how autophagy and mitophagy lead to the generation
of memory NK cells and the survival of proliferating lymphocytes, the upstream regulatory elements of these
fundamental biological processes remain poorly understood in lymphocytes in vivo. Our long-term goals seek
to identify the relevant transcriptional signals that induce autophagy, mitophagy, and survival of memory NK
cells following viral infection. In RNA-sequencing experiments, we have identified Trp73 (p73) as a
transcription factor selectively enriched in memory NK cells following murine cytomegalovirus (MCMV)
infection. Further experimental validation by qRT-PCR revealed that two dominant isoforms of Trp73 in mice
(TAp73 and ΔNp73) display distinct temporal expression patterns in NK cells during MCMV infection.
Importantly, the roles of p73 transcriptional isoforms in lymphocyte responses to viral infection in vivo are
unknown. Our exciting preliminary findings suggest that ΔNp73 is transiently induced in effector NK cells and is
required for clonal expansion and generation of memory NK cells. In contrast, TAp73 expression is sustained
in effector and memory NK cells and is dispensable for effector NK proliferation, but critical for the survival and
generation of memory NK cells. In Aim 1, we will determine whether TAp73 influences autophagic removal of
dysfunctional mitochondria in NK cells to promote the survival of effector NK cells as they transition to memory
cells using cutting-edge autophagy and metabolism assays. In Aim 2, we will determine whether ΔNp73 leads
to the proliferation of effector NK cells through repression of p53 to shield NK cells from apoptosis or relieve
cell cycle repression. In Aim 3, we will perform RNA and ChIP-sequencing experiments to determine the gene
targets of p73 in effector NK cells using genomic analyses. In summary, the proposed studies included in this
R01 proposal will contribute to our basic understanding of how primary cells induce mitophagy in vivo, while
also contributing to novel clinical strategies to enhance the use of adaptive NK cell responses for immunization
against infectious disease.

## Key facts

- **NIH application ID:** 10596995
- **Project number:** 5R01AI145997-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Timothy E O'Sullivan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $453,462
- **Award type:** 5
- **Project period:** 2019-05-06 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596995

## Citation

> US National Institutes of Health, RePORTER application 10596995, Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection (5R01AI145997-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10596995. Licensed CC0.

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