# Sirtuins and Host Metabolism in TB Pathogenesis and Treatment

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $608,967

## Abstract

PROJECT SUMMARY
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death due to infection
and many TB survivors are left with permanent lung impairment due to immune-mediated cavitation and fibrotic
healing. Sirtuins (SIRTs) are a family of energy-sensing NAD+-dependent deacetylases that modify histones,
transcription factors, metabolic enzymes, and other targets to defend starvation, restore homeostasis during
stress, support mitochondrial integrity, and promote the resolution of inflammation. In published and unpublished
preliminary studies, we found that levels of SIRT1 (the major cytosolic SIRT) and SIRT3 (the major mitochondrial
SIRT) are downregulated in macrophages (MΦ) infected with Mycobacterium tuberculosis (Mtb). Preliminary
data support a model in which SIRT1/3 axis suppression by Mtb in MΦ alters the expression levels of genes in
the tricarboxylic acid cycle, electron transport chain, and glycolytic pathway. This causes a shift from oxidative
phosphorylation to glycolysis, increases production of mitochondrial reactive oxygen species (ROS), and impairs
ROS scavenging. The result is increased mitochondrial stress and MΦ cell death. The glycolytic shift (Warburg
effect) rapidly enhances MΦ antimicrobial performance but at the expense of perturbing multiple SIRT1/3
regulated processes that lead to increased inflammation and TB disease severity with chronic infection. Studies
in Aim 1 build on and fill gaps in our preliminary data, with in vitro experiments investigating the mechanism of
SIRT1/3 downregulation by Mtb and the downstream effects on metabolic and epigenetic reprogramming. Aim
2 uses existing strains of SIRT1 and SIRT3 null mice, and other strains in development, for aerosol TB studies
that will relate in vitro data from Aim1 to host defense at the systemic level in vivo. The project culminates with
testing of several SIRT agonists for host-directed therapy of TB. We predict that these agents will restore
mitochondrial homeostasis, hasten lesion sterilization, and reduce pulmonary TB immune pathology. The effects
of these agents on immunometabolic pathways in vivo will be interpreted in the context of in vitro data produced
in Aim 1. Our project addresses an important gap in understanding the upstream triggers and downstream
consequences of the Warburg effect in TB while at the same time producing new knowledge about potential
adjunctive treatments to improve TB treatment outcomes and reduce the burden of pulmonary impairment in TB
survivors.

## Key facts

- **NIH application ID:** 10816617
- **Project number:** 5R01HL153162-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Hardy Kornfeld
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $608,967
- **Award type:** 5
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816617

## Citation

> US National Institutes of Health, RePORTER application 10816617, Sirtuins and Host Metabolism in TB Pathogenesis and Treatment (5R01HL153162-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10816617. Licensed CC0.

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