# Host-directed therapy of tuberculosis: Rescuing macrophages and enhancing their activation

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $747,665

## Abstract

Mycobacterium tuberculosis (Mtb) is a bacterium that causes tuberculosis (TB), the single leading cause of
death in the world from infectious disease today. The macrophage is the host cell most commonly infected by
Mtb and ultimately responsible for determining whether the outcome of exposure to Mtb is no infection, latent
infection or active disease. We are testing two ways to improve the host's control of TB, both of which involve
inhibiting targets in the macrophage, rather than in the bacterium, with the expectation that such host-directed
therapies (HDT) can be combined with conventional anti-mycobacterial therapy (AMT) to shorten the course of
curative treatment. We will test the following hypotheses. (1) Host control of Mtb will be favored by blocking
Mtb-induced death of macrophages. Our preliminary evidence supports the specific hypothesis that Mtb-
induced death of macrophages is exacerbated by the autocrine action of type I interferon. (2) Host control of
Mtb will also be favored by enhancing macrophage activation over the level achieved with interferon- (IFN)
alone. Our preliminary evidence supports the specific hypothesis that such enhancement is favored by a novel,
drug-like chemical compound we have identified whose action leads to inhibition of mechanistic target of
rapamycin (mTOR), resulting in the activation of certain transcription factors, including TFEB, that promote
lysosomal biogenesis and autophagy. (3) The combination of enhanced survival of macrophages and their
enhanced activation will be additive or synergistic in improving the control of Mtb and will not exacerbate
immunopathology if the resulting reduction in bacterial burden and antigenic load is great enough. Accordingly,
we will test the two HDTs alone and together in Mtb-infected mice, with and without AMT. Finally, we
hypothesize that host-directed therapy (HDT) combined with anti-mycobacterial therapy (AMT) will allow
treatment-shortening for relapse-free cure of Mtb-infected mice. The focus of Aim 1 is to prolong the survival of
Mtb-infected macrophages in a healthy state and to define the mechanisms by which blockade of type I IFN
signaling does so. The focus of Aim 2 is to enhance the activation of surviving macrophages and to define the
role of mTOR and TFEB family transcription factors in doing so. The role of Aim 3 is to test these two
interventions in combination with each other and with AMT.

## Key facts

- **NIH application ID:** 9991728
- **Project number:** 5R01AI138940-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** CARL Francis NATHAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $747,665
- **Award type:** 5
- **Project period:** 2018-09-24 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991728

## Citation

> US National Institutes of Health, RePORTER application 9991728, Host-directed therapy of tuberculosis: Rescuing macrophages and enhancing their activation (5R01AI138940-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9991728. Licensed CC0.

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