# Mycobacterium LDs sequester proteins leading to NRP

> **NIH NIH R21** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $192,500

## Abstract

Project Summary
 Mycobacterium tuberculosis is a human-specific pathogen and the etiological agent of the respiratory
disease tuberculosis (TB). This bacterium is responsible for significant morbidity and mortality worldwide,
producing more than 10 million new cases of active TB disease, and killing more than 1.7 million individuals each
year. A key aspect of the M. tuberculosis lifecycle is the ability to produce intracytoplasmic lipid droplets (LDs)
and enter into an altered physiological state of non-replicating persistence (NRP). These processes are critical
for long-term survival of M. tuberculosis during latency. LDs are quasi-organelles comprised of a neutral fatty
acid core surrounded by a phospholipid monolayer and proteins. It is thought that the primary role for LDs in
Mycobacterium is to store the neutral fatty acid triacylglycerol (TAG) for use in energy-generating pathways
during latency. However, preliminary data described in this application indicates that Mycobacterium LDs may
carry out additional functions. In particular, we have demonstrated that Mycobacterium LDs contain an unusually
large number of proteins that participate in active cellular processes at the plasma membrane or in the
cytoplasmic compartment including ATP production, transcription and translation, and DNA replication.
Furthermore, Mycobacterium LDs harbor numerous DNA-binding proteins, including HupB, which is an HU-like
DNA-binding protein capable of compacting genomic DNA into condensed DNA nucleoids. In this application, a
novel LD culture model and a surrogate Mycobacterium smegmatis host will be used to test the hypothesis that
LDs directly regulate the transition of Mycobacterium into NRP. This hypothesis will be tested by
determining if Mycobacterium LDs: (i) sequester proteins that normally function in key cellular processes
occurring in the cytoplasm or at the plasma membrane (Aim 1), and (ii) bind and compact genomic DNA into
condensed DNA nucleoids that are inaccessible for DNA replication (Aim 2). If one or both of these activities are
validated, this information is expected to be paradigm changing and will greatly enhance our understanding of
M. tuberculosis physiology during NRP within the host.

## Key facts

- **NIH application ID:** 9880392
- **Project number:** 5R21AI144225-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** THOMAS C. ZAHRT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880392

## Citation

> US National Institutes of Health, RePORTER application 9880392, Mycobacterium LDs sequester proteins leading to NRP (5R21AI144225-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9880392. Licensed CC0.

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