# Typhoid Pathogenesis and Immunity

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2020 · $574,409

## 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. Our laboratory has developed a 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 mononuclear phagocytes are
required for the pathogenesis of enteric fever. A genome-wide analysis of S. Typhi virulence
determinants in humanized mice has confirmed some suspected essential virulence determinants
but has also revealed unexpected differences between S. Typhi and non-typhoidal Salmonella
serovars. Furthermore, we have discovered that S. Typhi persists in cultured human macrophages
by preventing 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. We have recently 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 shown 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 mononuclear phagocytes. 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 virulence determinants
and its mechanisms of iron acquisition and macrophage persistence will be performed.
The proposed studies will advance our understanding of enteric fever pathogenesis and can lead
to novel strategies for its prevention and treatment.

## Key facts

- **NIH application ID:** 10237011
- **Project number:** 2R56AI112640-06
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Ferric C Fang
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $574,409
- **Award type:** 2
- **Project period:** 2015-08-06 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237011

## Citation

> US National Institutes of Health, RePORTER application 10237011, Typhoid Pathogenesis and Immunity (2R56AI112640-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10237011. Licensed CC0.

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