# Toxin secretion and trafficking by Mycobacterium tuberculosis

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $754,637

## Abstract

Project Summary - Toxin secretion and trafficking by Mycobacterium tuberculosis
The ability to control the timing and mode of host cell death plays a pivotal role in microbial infections. Most
pathogenic bacteria use toxins to evade and/or subvert immune responses, to survive and replicate in the host.
CpnT is an outer membrane protein with an N-terminal channel domain and a C-terminal toxin domain (TNT),
which causes necrotic cell death in host cells. Up-to-date TNT is the only known exotoxin of Mycobacterium
tuberculosis. We showed that TNT is secreted into the cytosol of macrophages infected with M. tuberculosis
where it hydrolyzes NAD+. NAD+ depletion by TNT activates necroptosis, a programmed cell death pathway.
Importantly, necroptosis-deficient mice are more resistent to infection with M. tuberculosis, underlining the
importance of this pathway for tuberculosis pathogenesis. Permeabilization of the phagosomal membrane is a
critical step in the pathogenesis of M. tuberculosis, not only because it required for M. tuberculosis proteins
such as the toxin TNT to reach the cytosol of infected cells, but it also enables M. tuberculosis to escape from
the phagosome resulting in bacterial dissemination. Thus, TNT secretion and trafficking are an important
components of the intracellular survival strategy of M. tuberculosis and for tuberculosis pathogenesis. This
research project will reveal novel molecular mechanisms of toxin secretion and trafficking by M. tuberculosis
and the role of these mechanisms in virulence and pathogenesis of M. tuberculosis.

## Key facts

- **NIH application ID:** 10889031
- **Project number:** 5R01AI175106-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** MICHAEL NIEDERWEIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $754,637
- **Award type:** 5
- **Project period:** 2023-07-17 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889031

## Citation

> US National Institutes of Health, RePORTER application 10889031, Toxin secretion and trafficking by Mycobacterium tuberculosis (5R01AI175106-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10889031. Licensed CC0.

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