# Salmonella chronic infection: Biofilm matrix factors and innate immune tolerance

> **NIH NIH R21** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2021 · $231,000

## Abstract

PROJECT SUMMARY
Salmonellae are Enterobacteriaceae that cause a spectrum of diseases in humans and animals, including enteric
(typhoid) fever and gastroenteritis. Typhoid fever, caused primarily by Salmonella enterica serovar Typhi (S.
Typhi), results in a life-threatening systemic disease that is annually responsible for significant morbidity and
mortality worldwide. Approximately 5% of individuals infected with S. Typhi become chronic carriers with the
gallbladder (GB) as the primary site of persistence. S. Typhi is a human-restricted pathogen, therefore
asymptomatic carriers represent a critical reservoir for further spread of disease. We have demonstrated that
gallstones (GSs) aid in the development and maintenance of GB carriage in a mouse model (utilizing S.
Typhimurium, which causes a typhoid fever-like disease in mice) and in humans, serving as a substrate to which
salmonellae attach and form a protective biofilm. Thus, biofilm formation is a key step in the establishment of
carriers. Salmonella in biofilms are known to be recalcitrant to antibiotics and host immunity, presenting a challenge
for traditional treatment methods. A hallmark of chronic S. Typhi infections is the production of extracellular polymeric
substances (EPSs) which are integral to biofilm development on GSs. How the bacteria subvert innate immunity
during early stages of biofilm development and establish chronic infections is not known. Immune escape likely
involves EPS, but a complete understanding of the EPSs responsible for this function is not known. We hypothesize
one or more EPS has a critical role in biofilm development and contributes to the chronic pathogenicity of S. Typhi
biofilms via innate immune evasion. Identification of the essential EPS(s) will allow us to determine the mechanism
of immune evasion, likely due to a combination of a physical barrier function and regulation of innate host responses.
To build on our prelinminary data, we will further investigate which EPSs are responsible for this perturbation and
conduct quantitative assays to evaluate innate phagocyte activity in response to WT and EPS mutant biofilms.
Assays for soluable factors (e.g. antimicrobial peptides, complement) and polymorphonuclear cell (neutrophil)
functions (chemotaxis, neutrophil extracellular trapping, and induction of respiratory burst) have been or will be
conducted. Confocal imaging of EPSs from in vitro and in vivo GSs will determine the structural contribution of each
EPS during chronic infection and will be correlated to functional assays of immune modulation. Overall, an improved
understanding of how biofilms develop in vivo and how EPSs skew innate immunity will be critical for development
of new treatment and prevention methods. Disruption of carrier state infections will have a significant impact on
endemic S. Typhi persistence and the spread of typhoid fever.

## Key facts

- **NIH application ID:** 10109468
- **Project number:** 1R21AI156328-01
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** JOHN S GUNN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $231,000
- **Award type:** 1
- **Project period:** 2020-12-17 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109468

## Citation

> US National Institutes of Health, RePORTER application 10109468, Salmonella chronic infection: Biofilm matrix factors and innate immune tolerance (1R21AI156328-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10109468. Licensed CC0.

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