# How Regulated Proteolysis Controls Bacterial Virulence

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $530,849

## Abstract

PROJECT SUMMARY
All pathogens require proteins to cause disease. Protein abundance reflects a delicate balance
between synthesis and degradation critical for pathogenesis and antibiotic tolerance. Protein
degradation must be tightly controlled because its effects are irreversible. We aim to determine
how related bacterial species, including the human gastroenteritis- and murine typhoid-causing
Salmonella enterica serovar Typhimurium, deploy proteolysis as an essential virulence strategy.
We will investigate how the master virulence regulator PhoP controls the abundance, activity, or
specificity of all five ATP-dependent proteases: Lon, HslUV, ClpAP, ClpXP, and FtsH. We will
examine how the PhoP antagonist EIIANtr is proteolyzed in a phoP- and lon-dependent manner
and identify the role that proteolysis of PhoP and EIIANtr plays in the expression kinetics of
virulence genes when bacteria are inside macrophages. We will uncover proteins and behaviors
controlled by the poorly understood virulence-promoting protease HslUV; critically test the role
that proteolysis of gene silencer H-NS plays in expression of foreign genes; and solve the
mechanism(s) by which protease adaptors prevent protein degradation during infection. We will
identify the signals governing expression of virulence proteins CspI and IraP via their 5' leader
mRNAs and define the domain(s) of the virulence protein MgtB mediating growth in very low
Mg2+ and survival in Slc11a1+/+ macrophages. The proposed research program takes a
comprehensive approach, including technical and conceptual innovations, to reveal significant,
broadly applicable principles in bacterial physiology and pathogenesis and new therapeutic
interventions that overcome antibiotic resistance.

## Key facts

- **NIH application ID:** 10591582
- **Project number:** 5R01AI049561-31
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Eduardo Groisman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $530,849
- **Award type:** 5
- **Project period:** 1992-02-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10591582

## Citation

> US National Institutes of Health, RePORTER application 10591582, How Regulated Proteolysis Controls Bacterial Virulence (5R01AI049561-31). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10591582. Licensed CC0.

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