# Targeting MT1-MMP to inhibit pathologic inflammation in TB

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $182,464

## Abstract

Tuberculosis remains the leading single cause of death from infection around the world; new treatments are
needed to change the shape of the epidemic. One proposed approach to expanding the available arsenal of
anti-TB drugs is targeting host factors to either enhance bacterial sterilization or modulate inflammation that
drives tissue damage. Tissue damage in the context of infection is typically conceptualized on a linear
spectrum, with “too much” driving host-mediated tissue destruction and “too little” resulting in progression of
bacterial infection. However, this linear model fails to capture the complexity of inflammation in TB; in fact,
some individual components of inflammation, including tissue remodeling enzymes such as matrix
metalloproteases (MMPs), likely contribute to destruction without promoting sterilization. Inhibiting such
enzymes could improve outcomes without compromising bacterial killing. We propose to take a systematic
approach to identifying and targeting the matrix enzymes that contribute to tissue destruction in TB infection
with two overarching goals: detailing the role of individual enzymes in TB pathogenesis and developing and
testing highly specific inhibitors of those enzymes as adjunct host-directed therapies in TB treatment. In
preliminary work using a murine model of cavitary TB, we performed serial transcriptional profiling of infected
lungs to identify the destructive matrix enzymes upregulated during infection. MT1-MMP stood out as
upregulated in an early and sustained pattern; this enzyme has previously been associated with human TB.
Using a highly specific MT1-MMP inhibitor developed by the Sagi laboratory, we performed a pilot experiment
to determine tolerability of low-level dosing over the first 8 weeks post-infection in the murine cavitary model of
TB. Mice tolerated the inhibitor well, and although the inhibitor was not dosed for maximum efficacy,
histopathologic analysis demonstrated a trend toward decreased lesion size and fewer dense inflammatory cell
infiltrates. In this proposed work, we will build upon those results to test both a role for MT1-MMP in
pathogenesis in this model and the effect of inhibition on molecular, cellular, and histologic outcomes of
disease. In aim 1, we will optimize dosing to maximize inhibition without inducing side-effects; we will then test
the effect of MT1-MMP inhibition on bacterial growth and lung histopathology. In aim 2, we will use single-cell
transcriptional profiling to both identify cellular drivers of MT1-MMP production and test the impact of MT1-
MMP inhibition on inflammatory cell recruitment to the infected lung. We will then test the impact of MT1-MMP
inhibition on the inflammatory milieu using multiplexed cytokine profiling and high resolution microscopy. Upon
achieving these aims, we anticipate having characterized the role of MT1-MMP in the pathologic progression of
TB in a murine model of disease. We anticipate these results will inform targeted studi...

## Key facts

- **NIH application ID:** 9990682
- **Project number:** 5R21AI146813-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Amy K Barczak
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $182,464
- **Award type:** 5
- **Project period:** 2019-08-07 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990682

## Citation

> US National Institutes of Health, RePORTER application 9990682, Targeting MT1-MMP to inhibit pathologic inflammation in TB (5R21AI146813-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9990682. Licensed CC0.

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