# Defining the regulation of mitochondrial bioenergetics during virus infection

> **NIH NIH F31** · PRINCETON UNIVERSITY · 2022 · $46,752

## Abstract

PROJECT SUMMARY/ABSTRACT.
Human cytomegalovirus (HCMV) is a ß-herpesvirus that infects over 50% of the world’s population and
establishes lifelong infection in individuals. HCMV infection is a major concern in individuals with impaired or
naïve immune systems, as it can lead to a range of diseases, including deafness, respiratory disease, and organ
failure. Additionally, HCMV has garnered increased interest in recent years due to its implication in the
emergence and progression of chronic diseases, such as cardiovascular disease and cancer. A striking feature
of HCMV infection is the global rewiring of cellular metabolism for the increased production of biosynthetic
precursors and energy for replication. The dysregulation of cellular metabolism during HCMV infection is
necessary for its replication and has been linked to many of its pathologies, including its oncomodulatory
capacity. However, we currently lack an understanding of the mechanisms underlying the metabolic alterations
observed during infection. We recently discovered that the mitochondrial enzyme sirtuin 4 (SIRT4) is a potent
antiviral factor during HCMV infection. Furthermore, we established SIRT4 as the first known mammalian cellular
lipoamidase, removing the essential posttranslational modification lipoylation from the pyruvate dehydrogenase
complex. This discovery points to SIRT4 as a critical regulator of cellular metabolism, but how SIRT4 exerts its
antiviral function remains unknown. I hypothesize that SIRT4 functions in host defense during HCMV infection
by opposing viral-induced changes in cellular metabolism. Further supporting the critical role of SIRT4 in antiviral
response, I discovered that HCMV has acquired a mechanism to suppress its functions. My preliminary results
demonstrate that SIRT4 is targeted for inhibition by the previously uncharacterized viral protein, pUL13. In my
proposal, I will address both sides of this virus-host interplay. In Aim 1, a combination of molecular virology,
microscopy, proteomics and metabolomics will be used to define SIRT4-mediated mechanisms of defense
against HCMV infection. I will determine which specific SIRT4 enzymatic activities are required for antiviral
response. In Aim 2, I will uncover how pUL13 inhibits SIRT4, as well as characterize its function in regulating
cellular metabolism and mitochondrial bioenergetics. As a long-term objective, elucidating the functional
interaction between SIRT4 and pUL13 can help explain how HCMV induces metabolic changes that promote
disease. This knowledge can point to therapeutic targets for restoring metabolic health and for treating HCMV-
linked pathologies. This research will take place in the Molecular Biology Department of Princeton University, a
program known for its multidisciplinary research and supportive environment for graduate student training and
career development.

## Key facts

- **NIH application ID:** 10381483
- **Project number:** 5F31AI154796-02
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Cora Nicole Betsinger
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10381483

## Citation

> US National Institutes of Health, RePORTER application 10381483, Defining the regulation of mitochondrial bioenergetics during virus infection (5F31AI154796-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10381483. Licensed CC0.

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