# The physiological activation and consequences of Toxin-Antitoxin systems in Salmonella

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2022 · $508,309

## Abstract

PROJECT SUMMARY/ABSTRACT
Bacteria control their growth in response to environmental challenges and sometimes enter a growth arrested
state. Growth-arrested bacteria often show remarkable abilities to survive exposure to antibiotics and are known
as antibiotic persisters. These bacterial persisters are thought to contribute to the relapse of many infections and
to the worrying burden of antimicrobial resistance. Understanding how bacteria establish this growth arrested
state can help to develop better antibiotics. Toxin-Antitoxin (TA) modules are widespread pairs of genes
involved in bacterial growth control. They are stress responsive systems that enable bacteria to adapt their
growth in response to insults such as attack by phage or host immune defense cells. TA systems encode a non-
secreted toxin which inhibits an essential cellular function thereby controlling growth, and an antitoxin that
neutralizes the toxin. The antitoxin exerts control over the toxin at two levels, through repression of expression
and direct neutralization. It is thought that upon stress, the antitoxin is degraded, on one hand de-repressing
expression of the operon, and on the other hand liberating the toxin. However, despite numerous studies on
toxin functions, very little information is available on how stresses lead to activation of TA systems, from “de-
repression” of the TA operon and liberation of the toxin to actual consequences of the activity of the toxin on the
bacteria; and the role of these ubiquitous elements remains disputed. The foundation of the work is our prior
demonstration that uptake of Salmonella Typhimurium by macrophages is a natural trigger of expression and
activity of each of the TA modules encoded by the bacteria. Using a combination of genetic, biochemical,
structural and imaging approaches, we will take advantage of this powerful trigger to study how TA systems of
the TacAT group are activated (de-repression in aim 1 and liberation of the toxin in aim 2) and the physiological
consequences of the activity of Tac toxins in response to attacks inflicted on bacteria by their environment
(intoxication in aim 3 and effects of intoxication in aim 4). The knowledge generated will undoubtedly provide
insight on other TA systems beyond the Tac family. In addition, it has the potential to transform our
understanding of bacterial growth heterogeneity and the associated phenomenon of antibiotic persistence and
serve as a springboard to develop better antibiotics.

## Key facts

- **NIH application ID:** 10418802
- **Project number:** 5R01AI155552-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Sophie Helaine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $508,309
- **Award type:** 5
- **Project period:** 2021-06-07 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418802

## Citation

> US National Institutes of Health, RePORTER application 10418802, The physiological activation and consequences of Toxin-Antitoxin systems in Salmonella (5R01AI155552-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10418802. Licensed CC0.

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