# HUMAN GENETIC VARIATION REGULATING SALMONELLA HOST-PATHOGEN INTERACTIONS AND DISEASE SUSCEPTIBILITY

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $453,579

## Abstract

Salmonellae cause an estimated 150 million cases of gastroenteritis and 25 million cases of invasive disease
(enteric fever and non-typhoidal bacteremia), leading to 300,000 deaths per year. Findings based on inbred
mouse strains and rare human mutations indicate that the clinical presentations and outcomes of salmonellosis
are influenced by the host’s genetic makeup. However, we do not understand the impact of common, naturally
occurring human genetic differences on Salmonella infections. Our long-term goal is to leverage high-
throughput cellular phenotyping of infection and natural genetic diversity to define molecular parameters of
susceptibility to human infectious diseases. While genome-wide association studies (GWAS) of enteric fever and
bacteremia identified genetic differences regulating susceptibility, such studies are limited by high variability in
patient exposure, pathogen genetic diversity, and a limited understanding of the pathophysiology of identified
variants. We developed a complementary cellular GWAS approach (Hi-HOST: High-throughput Human in vitrO
Susceptibility Testing; http://h2p2.oit.duke.edu) to perform high resolution analysis of human genetic differences
that impact host-pathogen traits while enabling experimental dissection of these traits. In the previous funding
period, we focused on human genetic variants that regulate Salmonella invasion of host cells. We identified a
regulatory variant in VAC14 that modulates levels of plasma membrane cholesterol and thus limits the docking
of the Salmonella SPI-1 type III secretion system to host cells. Humans with the high-invasion allele of VAC14
have increased risk of typhoid fever and bacteremia. The objectives of this application are to define and
characterize human genetic differences that alter the full spectrum of Salmonella host-pathogen
interactions and assess their impact on disease.
Building from our unique resource of Hi-HOST cellular GWAS of Salmonella invasion, replication, and host
cytokine levels, we have identified SNPs mediating susceptibility to infection phenotypes that will undergo
experimental validation and mechanistic studies. We will determine how regulatory SNPs affecting ARHGEF26
and MCOLN2 expression impact Salmonella invasion and replication and the role these genes play during
infection in mice. For ARHGEF26, a Rho GEF that stimulates Salmonella-induced membrane ruffling, our
association data and experimental evidence indicate SNPs regulate ARHGEF26 expression to increase invasion
dependent on the Salmonella effector sopB. For MCOLN2, we hypothesize that this divalent cation channel is a
novel factor that regulates intracellular replication by modulating nutrient access, metal toxicity, and/or immune
cell polarization. Using Arhgef26 and Mcoln2 mice, we will elucidate how altered expression of these genes
regulates bacterial burden and immune response during infection. Finally, we will test whether SNPs identified
by Hi-HOST are associated with ent...

## Key facts

- **NIH application ID:** 10840360
- **Project number:** 5R01AI118903-10
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Dennis Chun-Yone Ko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,579
- **Award type:** 5
- **Project period:** 2015-08-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840360

## Citation

> US National Institutes of Health, RePORTER application 10840360, HUMAN GENETIC VARIATION REGULATING SALMONELLA HOST-PATHOGEN INTERACTIONS AND DISEASE SUSCEPTIBILITY (5R01AI118903-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10840360. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*