# Development of a mouse model of tuberculosis that generates human-like pathology

> **NIH NIH R21** · TRUDEAU INSTITUTE, INC. · 2022 · $297,000

## Abstract

ABSTRACT Though very few new tuberculosis (TB) drugs have been introduced over the past forty
years, the pivotal questions relevant to TB therapeutic development are well articulated across the field and
are being pursued with great vigor in the biomedical community. Can we find a way to shorten treatment for
from the current six months? Which novel mechanisms of action will support complete sterilization when
combined with existing standard of care treatment? Are persister populations completely eliminated through a
specific treatment regimen?
In order to succeed in the clinic, first we must address these questions preclinically through the use of
predictive animal models. Evaluation of the efficacy of experimental tuberculosis therapeutics is commonly
performed using mouse models, due to the relatively small size and low cost of mice. However, many mouse
models fail to reproducibly develop human-like pathology, specifically hypoxic necrotic granulomas, and
thereby may have limited predictive value for certain compounds. Mouse models which do develop human-like
pathology may suffer from substantial heterogeneity or complex protocols required to limit significant morbidity.
Our recent work has overcome these significant limitations, and here we propose to refine, validate and
characterize an innovative mouse model of TB that is more predictive of outcomes in patients.
We have completed a series of studies in mice that strengthen our ability to advance a more predictive model
of TB, one that consistently produces human-like pathology in the form of hypoxic necrotic granulomas. This
new model builds on work that demonstrated the development of hypoxic granulomas in Nos2-/-mice, but adds
significant value by simplifying the protocol and utilizing the natural aerosol route to infect mice with the
partially attenuated Mycobacterium tuberculosis (Mtb) strain R1Rv. We have paired this novel model with
fluorescent reporter strains that specifically mark drug and immune tolerant Mtb cells. When deployed together
to support pharmacological evaluation of potential TB drug regimens, these two tools can provide unique
insights into why some therapeutic approaches may work well to shorten chemotherapy in patients, while
others will not do so. In this proposal, we seek to establish the predictive value of the model to determine drug
efficacy responses, and to reveal new insights into the biology of drug-tolerant Mtb.
In the first two Specific Aims we seek to optimize the novel mouse model and validate it as a more rigorous
measure of in vivo anti-tubercular drug efficacy, and in the third Aim we employ the model to identify the niche
occupied by drug tolerant cells, to better understand their potential vulnerabilities. Completion of the three
Aims of this proposal will deliver a more predictive and well-characterized mouse model of Mtb
infection that will have the potential to become a new standard for small animal testing of TB drugs.

## Key facts

- **NIH application ID:** 10453288
- **Project number:** 1R21AI159731-01A1
- **Recipient organization:** TRUDEAU INSTITUTE, INC.
- **Principal Investigator:** Brian Weinrick
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $297,000
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453288

## Citation

> US National Institutes of Health, RePORTER application 10453288, Development of a mouse model of tuberculosis that generates human-like pathology (1R21AI159731-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10453288. Licensed CC0.

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