# Molecular mechanisms of host cell escape by Mycobacterium tuberculosis

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2022 · $615,827

## Abstract

Abstract
Mycobacterium tuberculosis (Mtb) causes pulmonary tuberculosis (TB) in humans. In 2015 alone,10.4 million
new cases were reported, leading to approximately 1.4 million deaths. There are no effective vaccines for TB
and only sub-optimal chemotherapeutics exist. Mtb, after a period of intracellular replication and inhibition of host
cell apoptosis, leaves the phagosome and triggers cell lysis in order to exit the host cell. There is a gap in our
understanding of how Mtb exploits host cell signaling in order to mediate these events. We have discovered a
novel transcriptional repressor, Rv3167c, that is important for suppression of phagosomal escape, host cell
necrosis and of macroautophagy (autophagy) induction. This activity is mediated via suppression of gene
transcription of genes encoding for synthesis and transport of the outer cell membrane lipid phthiocerol
dimycocerosates (PDIM). In the current application we propose to utilize a unique set of Mtb mutants discovered
in our lab to elucidate the molecular mechanisms of Mtb-mediated host cell necrosis induction.
In AIM1 we will characterize the host cell necrosis and autophagy signaling pathways engaged after phagosomal
exit of Mtb. AIM1.1. will test how Mtb mediates the regulation of the host kinase AKT. The Aims 1.2 and 1.3 will
explore cell signaling events downstream of AKT leading to necrosis or autophagy induction, respectively. These
approaches will be used to identify central signaling hubs within the signaling network that will be most interesting
for host directed therapeutic approaches. In AIM2 we will characterize the relevance of host cell escape pathway
for virulence of Mtb and its potential as a target for therapeutic approaches. In Aim 2.1, knock-out or knock-in
mice will be used to corroborate the ex vivo findings of the importance of select host cell signaling proteins during
in vivo infection. In Aim 2.2 our discovery of host cell necrosis signaling components will be exploited to test their
relevance for Mtb virulence during aerosol infection of mice and thus determine their potential as novel
candidates for host-targeted therapeutics using the mouse model of tuberculosis.
We believe that our findings will have great translational potential since inhibition of Mtb-mediated necrosis
should reduce virulence of the bacteria and decrease host lung pathology.

## Key facts

- **NIH application ID:** 10322367
- **Project number:** 5R01AI139492-04
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** VOLKER BRIKEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $615,827
- **Award type:** 5
- **Project period:** 2019-01-10 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322367

## Citation

> US National Institutes of Health, RePORTER application 10322367, Molecular mechanisms of host cell escape by Mycobacterium tuberculosis (5R01AI139492-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10322367. Licensed CC0.

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