# Detection of intestinal pathogens through host surveillance of bacterial toxins

> **NIH NIH F30** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $50,487

## Abstract

PROJECT SUMMARY/ABSTRACT
Although commensal and pathogenic bacteria can be recognized by host pattern recognition receptors,
intestinal epithelial cells target protective inflammatory responses towards pathogenic organisms through
mechanisms that are incompletely understood. Additional mechanisms of pathogen sensing must exist that
allow intestinal cells to target inflammatory defenses towards bona fide pathogens during an infection, and not
harmless commensal bacteria. Pathogenic bacteria can express virulence determinants. Phenazine toxins are
a family of redox active virulence determinants that are produced by a variety of human pathogens, including P.
aeruginosa. P. aeruginosa can colonize the intestines of immunocompromised patients and cause fulminant
septicemia and subsequent death. The mechanism by which intestinal epithelial cells detect P. aeruginosa, and
whether this involves the surveillance of phenazine toxins, is not known. Nuclear hormone receptors (NHR) are
transcription factors that program adaptive host responses following recognition of specific exogenous or
endogenous ligands. In particular, HNF4⍺ is an NHR expressed in the intestine. In the model organism C.
elegans, the HNF4⍺ homolog NHR-86 is required for the transcriptional activation of innate immune effector
genes that protect against P. aeruginosa infection. The central hypothesis of this proposal is that intestinal
epithelial cells detect infection through the surveillance of pathogen-derived phenazine toxins by NHR-86/
HNF4⍺, which directly activates protective anti-pathogen defenses in the intestinal epithelium. The following
key preliminary findings support this central hypothesis: i) P. aeruginosa mutants that cannot make phenazine
toxins do not activate C. elegans innate immune defenses; ii) synthetic phenazine toxins can activate immune
genes; and iii) induction of immune genes by phenazine toxins is dependent on the expression of NHR-86/
HNF4⍺. In this proposal, Aim 1 will characterize the C. elegans immune response towards bacterial phenazine
toxins, and Aim 2 will define the role of intestinal NHR-86/HNF4⍺ in detecting P. aeruginosa infection in C.
elegans. The research proposed here will define a new concept of immune activation in intestinal epithelial
cells and will also attribute a novel role for NHRs in pathogen sensing in the intestine. Insights from these
findings may identify unexplored approaches for the development of anti-inflammatory and anti-infective
therapies.

## Key facts

- **NIH application ID:** 10771996
- **Project number:** 5F30DK127690-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Samantha Tse
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $50,487
- **Award type:** 5
- **Project period:** 2021-02-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771996

## Citation

> US National Institutes of Health, RePORTER application 10771996, Detection of intestinal pathogens through host surveillance of bacterial toxins (5F30DK127690-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10771996. Licensed CC0.

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