# Salmonella type III secretion: substrate targeting and injectisome assembly

> **NIH NIH R56** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $728,244

## Abstract

Project Summary
 In the face of increasing antimicrobial resistance, understanding the mechanism of virulence factor(s)
characteristics in bacteria is critical for developing new therapeutics. For many pathogens, large multi-protein
molecular machines called injectisomes (also known as type III secretion systems) are central to pathogenesis.
Injectisomes are central to virulence by many human pathogens including Salmonella (gastroenteritis and
typhoid fever), Shigella (dysentery), Vibrio (gastroenteritis) Pseudomonas (diverse systemic infections), Yersinia
(plague), and Chlamydia (sexually transmitted diseases), presenting significant health burdens. By
understanding the mechanisms of injectisome biogenesis, function and coupled gene regulatory mechanisms,
we poise ourselves to develop novel antimicrobial therapeutics. Although these pathogens are common, a barrier
to fighting infections by injectisome-utilizing organisms has been incomplete structural insights into core
mechanisms of secretion. Understanding these core mechanisms is crucial to developing novel anti-pathogen
strategies. We propose experiments that provide fundamental knowledge about injectisome mechanisms for use
in combating these significant pathogens. Understanding the molecular mechanisms controlling effector
secretion will provide crucial knowledge toward combating injectisome-deploying pathogens.
 Type III secretion (T3S) is arguably the most important route through which gram-negative plant and
animal pathogens translocate effector proteins into host cells and is a key component in bacterial symbiosis with
eukaryotic organisms. There are beautiful structures lacking mechanisms of assembly with superficial knowledge
of coupled gene regulatory systems that we will uncover. Our track-record on the related flagellar systems leaves
no doubt that we are most qualified to do this. For more than twenty years, the selectivity of substrates for specific
secretion by the injectisome-associated T3S systems from thousands of proteins produced in the cell has been
an unsolvable mystery until now. T3S is the only secretion system in Biology that undergoes a secretion-
specificity switch from one class of secretion-substrates to a completely different class. Using newly devised
genetic selections and screens we will determine how specific substrates are recognized and targeted for
secretion by the Salmonella Pathogenicity Island 1 (SPI1) T3S systems in coordination with SPI1 injectisome
assembly and the secretion-specificity switch.

## Key facts

- **NIH application ID:** 11131602
- **Project number:** 1R56AI184395-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** KELLY T HUGHES
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $728,244
- **Award type:** 1
- **Project period:** 2024-08-02 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11131602

## Citation

> US National Institutes of Health, RePORTER application 11131602, Salmonella type III secretion: substrate targeting and injectisome assembly (1R56AI184395-01). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/11131602. Licensed CC0.

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