# The Pathogenesis of Enteric Fever

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $512,109

## Abstract

PROJECT SUMMARY/ABSTRACT
Enteric fever, caused by the Salmonella serovars S. Typhi and S. Paratyphi, accounts for nearly 15 million
infections and 136,000 deaths each year. We have developed a novel lethal small animal model for enteric
fever using humanized mice engrafted with a functional human hematopoietic system. The ability of S. Typhi
and S. Paratyphi A to cause lethal infections in humanized mice engrafted with human hematopoietic cells
suggests that human macrophages are required for the pathogenesis of enteric fever and may provide a
reservoir for persistent infection. A genome-wide analysis of S. Typhi in humanized mice confirms some
suspected essential virulence determinants but also reveals unexpected differences between S. Typhi and
non-typhoidal Salmonella serovars. Moreover, we have discovered that S. Typhi persists in cultured human
macrophages by preventing apoptotic cell death, due to the absence of multiple SPI-2 type III secretion system
effectors that play a central role in non-typhoidal Salmonella pathogenesis. NF-κB inhibition selectively kill S.
Typhi-infected macrophages, suggesting a novel strategy for the treatment of chronic enteric fever. Recently
we have also found significant differences in the responses of enteric fever and non-typhoidal Salmonella to
iron deprivation, observed that the gut microbiota antagonizes S. Typhi intestinal colonization, and
demonstrated important parallels between S. Paratyphi A and S. Typhi in their interactions with human
macrophages and humanized mice.
Our central hypothesis is that the virulence of enteric fever Salmonella serovars depends on the
evasion of innate immunity and persistence in macrophages. The research plan will examine three
specific aims:
1. Avoidance of Macrophage Cell Death by Enteric Fever Salmonella Serovars. Genetic and biochemical
approaches will elucidate the molecular mechanisms by which S. Typhi promotes macrophage survival and
assess the relevance of macrophage survival to S. Typhi virulence in humanized mice.
2. Interactions of Salmonella Typhi with the Gut Microbiota. The contributions of extracytoplasmic stress
responses, microbiota antagonism and avoidance of macrophage cytotoxicity to the ability of S. Typhi to
persistently colonize the intestinal tract will be investigated.
3. Salmonella Paratyphi A Virulence. A systematic analysis of S. Paratyphi A virulence determinants and its
mechanisms of serum resistance, iron acquisition and macrophage persistence will be performed.
The proposed studies will advance our understanding of enteric fever pathogenesis and lead to novel
strategies for its prevention and treatment.

## Key facts

- **NIH application ID:** 10208146
- **Project number:** 1R01AI160130-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Ferric C Fang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $512,109
- **Award type:** 1
- **Project period:** 2021-02-24 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208146

## Citation

> US National Institutes of Health, RePORTER application 10208146, The Pathogenesis of Enteric Fever (1R01AI160130-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10208146. Licensed CC0.

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