# Regulation of Legionella pneumophila pathogenesis by the central eukaryotic metabolic checkpoint kinase Mechanistic Target of Rapamycin (MTOR)

> **NIH NIH R01** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2022 · $365,000

## Abstract

The work proposed here seeks to investigate the mechanism by which mammalian
macrophages suppress the metabolic checkpoint kinase Mechanistic target of rapamycin
(MTOR) to promote immune defenses and counteract anabolic reprogramming by the vacuolar
pathogen Legionella pneumophila. MTOR is a universally conserved master switch regulating
catabolism to anabolism transition in eukaryotic cells. Vacuolar pathogens rely on host
metabolites not only for bacterial replication but also for maintenance of their intracellular
niches. The human respiratory pathogen Legionella pneumophila is a prototypical vacuolar
pathogen that infects and replicates within mammalian macrophages. We uncovered that
Legionella stimulates host membrane biosynthesis to expand its niche by subverting MTOR.
However, a host suppression pathway counteracts L. pneumophila-induced MTOR activation by
targeting MTOR for ubiquitin-dependent proteolysis. In macrophages, MTOR suppression
promotes cell intrinsic (autophagy) and cell extrinsic (inflammation) host defenses. Specifically,
pathogenic L. pneumophila expressing the type IVb secretion system (T4bSS) but not the
avirulent mutants lacking a functional T4bSS elicited the host MTOR suppression response.
Thus, we hypothesize that in mammalian macrophages MTOR functions downstream of
homeostatic mechanisms that sense the pathogenic potential of invading microbes to potentiate
host defenses. Such mechanisms operate by detecting virulence adaptations encoded by
bacterial pathogens (such as specialized secretion systems and secreted toxins), which
frequently produce pathogen-specific signatures. In the first aim we will determine the
mechanism by which Legionella subverts MTOR function, when the host suppression pathway is
inactivated. In the second aim we are going to use biochemical and genetic approaches to
determine how the Legionella intracellular niche is controlled by host metabolic regulators. Our
third aim is to elucidate how the pathogen signature that elicits MTOR suppression is
generated. To this end, we will perform a systematic analysis of the Legionella intracellular niche
using a variety of imaging approaches to define the early events that trigger MTOR
suppression.

## Key facts

- **NIH application ID:** 10329977
- **Project number:** 5R01AI143839-04
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Stanimir Stefanov Ivanov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $365,000
- **Award type:** 5
- **Project period:** 2019-02-11 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329977

## Citation

> US National Institutes of Health, RePORTER application 10329977, Regulation of Legionella pneumophila pathogenesis by the central eukaryotic metabolic checkpoint kinase Mechanistic Target of Rapamycin (MTOR) (5R01AI143839-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10329977. Licensed CC0.

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