# Outer Membrane Vesicle (OMV) Production by Salmonella PhoPQ and Inflammasome Activation

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2020 · $201,250

## Abstract

Project Summary
Salmonella enterica remains the major laboratory-confirmed pathogen of foodborne disease in the US and is
responsible for typhoid fever in developing countries. As such, S. enterica infections incur substantial morbidity
and mortality in both humans and animals worldwide. To identify new strategies that could reduce the virulence
of S. enterica and support the development of alternative antimicrobials, our lab is focused on bacterial outer
membrane vesicles (OMVs) that efficiently deliver inflammatory LPS to host cells with which they interact. OMVs
from bacterial pathogens can modulate host cell signaling pathways that regulate innate immune responses and
most recently have emerged as critical activators of the caspase-11-dependent non-canonical inflammasome
response. Salmonella invade cells and immediately adapt to the lowered pH and magnesium levels of their
intracellular vacuolar compartment by activating their two-component master regulator PhoPQ. In vitro growth
conditions that recapitulate this environmental shift increase OMV production and modulate the repertoire of
outer membrane proteins (OMPs) as OMVs bud from bacteria. We hypothesize that PhoPQ-dependent
induction of distinct OMPs and/or LPS modifying enzymes will differentially regulate OMV number, size and OMP
repertoire, thereby dictating host immune responses. In support, our preliminary data indicate that isolated
OMVs from Salmonella grown under phoPQ-activating conditions induce a caspase 11-killing
mechanism in BMDM. In this high risk/high impact exploratory R21, we will specifically focus on OMPs that
may participate in OMV binding to host receptors to promote endocytosis (pagC, pagN, pgtE), lipidA-modifying
enzymes (pagP, pagL, lpxO) and the activator of LPS-core decorating enzymes (pmrAB). Exciting new
preliminary data identify both hyper- and hypo-vesiculating mutants in which the extent of OMV
production directly correlates with the degree of caspase-11 activation and BMDM death. We shall
continue to dissect the role of PhoPQ-regulated gene products in OMV phenotypes and determine how OMVs
and their producing strains impact host cell death and/or inflammasome activation. Identifying Salmonella
PhoPQ-regulated proteins that contribute to OMV biogenesis and OMV-dependent effects on cell death and
innate immune responses will better define the pathogenesis of Salmonella and support the discovery of new
targets for antimicrobial therapeutics. As OMV vaccines for other bacterial infections are already approved and
on the market, and OMVs have also been proposed for use in targeted drug delivery, our findings will highlight
OMV growth conditions and strain constructs that maximize immunogenicity while minimizing undesired side
effects.

## Key facts

- **NIH application ID:** 9861219
- **Project number:** 5R21AI139982-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Dieter M. Schifferli
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $201,250
- **Award type:** 5
- **Project period:** 2019-02-05 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861219

## Citation

> US National Institutes of Health, RePORTER application 9861219, Outer Membrane Vesicle (OMV) Production by Salmonella PhoPQ and Inflammasome Activation (5R21AI139982-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9861219. Licensed CC0.

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