# Mechanisms of macrophage death co-dependent on M. tuberculosis and IFN-a,b receptor

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $211,875

## Abstract

ABSTRACT
Mycobacterium tuberculosis (Mtb) was the world’s single leading cause of death from infection before COVID-
19. Direct-acting antimycobacterial regimens are long, often toxic and plagued by emergence of drug resistance.
Adjunctive therapies could potentially speed the cure of tuberculosis by targeting a process in the host that alters
the host-pathogen interaction to the advantage of the host. One potential form of host-directed therapy would be
to help macrophages better survive Mtb infection. In vitro, the death of Mtb-infected mouse macrophages is co-
dependent on a type I interferon (IFN), IFN-beta, that macrophages produce in response to Mtb, along with an
additional contribution by Mtb. This application seeks to identify specific molecular participants in Mtb-induced
macrophage death that are downstream of the type I IFN receptor. We have identified potential molecular
participants by two approaches—a CRISPR activation screen that restored Mtb-induced cell death to
macrophages lacking the type I IFN receptor, and an innovative biochemical pulldown approach using a probe
based on a small chemical compound that rescues Mtb-infected macrophages from Mtb-induced cell death
without impairing the growth of Mtb. This application aims to validate the candidates genetically, test the ability
of already existing inhibitors to recapitulate the effect of knocking them out, and then place the validated
candidates on a mechanistic path. That would set the stage for future studies, beyond the scope of this
application, to find, improve or develop drug-like inhibitors for tests in preclinical models of TB to see if they
mitigate pathology and hasten cure when used in combination with direct-acting antimycobacterial agents.

## Key facts

- **NIH application ID:** 10875431
- **Project number:** 5R21AI178133-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** CARL Francis NATHAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $211,875
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875431

## Citation

> US National Institutes of Health, RePORTER application 10875431, Mechanisms of macrophage death co-dependent on M. tuberculosis and IFN-a,b receptor (5R21AI178133-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10875431. Licensed CC0.

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