# Salmonella Interactions with Macrophages

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $761,850

## Abstract

Project Summary
Typhoidal Salmonella serovars, including Salmonella enterica serovars Typhi (STy) and Paratyphi A (SPTyA),
are the culprits behind devastating human-exclusive infections known as enteric fever, causing immense global
morbidity and mortality. These pathogenic microbes adeptly outmaneuver the immune system by thriving in
macrophages (MΦs), a critical aspect of Salmonella’s virulence. However, our understanding of how these
typhoidal Salmonella strains interact with MΦs remains limited, with most research focused on non-typhoidal S.
Typhimurium (STm). This gap in knowledge spurred our investigation. To bridge this gap in knowledge, we’ve
employed unbiased methodologies, including random barcode transposon-site sequencing (RB-TnSeq) library
screens under infection relevant conditions, genomic comparisons across different Salmonella serovars, and
transcriptional profiling of MΦs infected by STy. These approaches have allowed us to identify typhoidal-specific
fitness traits and factors. Our preliminary findings suggest that essential genes governing metal homeostasis
contribute to typhoidal Salmonella’s fitness in MΦs due to pseudogenization of genes functioning in similar
pathways. We have designed experiments to test these hypotheses (Aim 1). Furthermore, our bioinformatics
analyses have led us to a putative typhoidal-specific virulence factor, which is translocated into MΦs via a type
3 secretion system (T3SS) and is vital for intracellular replication. We will take molecular and biochemical
approaches to characterize this unique virulence factor within human MΦs (Aim 2). Finally, our comparative
transcriptional profiling of MΦs containing replicating vs. non-replicating STy has unveiled a distinctive phenotype
for MΦs containing replicating bacteria – anti-inflammatory, M2-like MΦs marked by phosphorylated STAT3
(pSTAT3). Elevated pSTAT3 levels in STy-infected MΦs are T3SS-dependent, suggesting that STy effectors
manipulate the metabolic and immune landscape of human MΦs. We are determined to uncover specific
virulence factors employed by STy to shape MΦ phenotypes (Aim 3). In essence, our research delves into the
intricate strategies employed by typhoidal Salmonella to manipulate the host and inform new strategies for
combating this formidable pathogen effectively.

## Key facts

- **NIH application ID:** 10980412
- **Project number:** 1R01AI179893-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Denise M Monack
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $761,850
- **Award type:** 1
- **Project period:** 2024-07-03 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980412

## Citation

> US National Institutes of Health, RePORTER application 10980412, Salmonella Interactions with Macrophages (1R01AI179893-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10980412. Licensed CC0.

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