# Quorum Sensing Dependent Interactions with Biofilms and Innate Immunity Defenses

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2022 · —

## Abstract

Staphylococcus aureus is an opportunistic pathogen that causes a broad spectrum of acute and chronic
infections. Antibiotic resistance is a growing challenge and methicillin-resistant S. aureus (MRSA) infections are
more difficult to treat, resulting in increased burden for both patients and healthcare systems. S. aureus causes
the majority of skin infections in civilians and the military, but how this pathogen colonizes the skin is unknown.
In recent microscopy studies on skin explants, S. aureus developed biofilm communities during skin colonization,
and these biofilms were found to produce virulence factors under control of the agr quorum-sensing system. In
our preliminary studies, we found that MRSA strains lacking agr show striking defects in skin explant colonization,
and in rodent skin colonization models. Our central hypothesis is that MRSA quorum-sensing is essential
for skin colonization and evasion of host defenses. Additionally, we believe quorum-sensing plays a critical
role in the transition from skin to systemic infection. In Specific Aim 1, we will determine the role of quorum-
sensing during MRSA skin colonization. We hypothesize that MRSA strains use agr-regulated factors to
colonize the skin. To address this hypothesis, we will compare MRSA WT and ∆agr mutant strains using in
vitro models of adherence and compare them in a mouse skin colonization model. We will also identify agr-
regulated factors required for colonization and determine whether known biofilm factors are important. Lastly,
we will perform RNAseq to obtain a broader assessment of MRSA regulated functions on skin. In Specific Aim
2, we will determine the contribution of quorum-sensing to MRSA immune evasion on the skin. We hypothesize
that MRSA evades skin immunity using agr-regulated factors. Toward this end, we will determine the role
of quorum-sensing in the induction and resistance to antimicrobial peptides and assess the quorum-sensing
response to skin unsaturated fatty acids. We will also determine whether MRSA urease and other agr-regulated
factors contribute to pH homeostasis, and we will evaluate the host skin response by single-cell RNAseq. In
Specific Aim 3, we will assess the function of quorum-sensing in dissemination from colonization. We
hypothesize that the MRSA quorum-sensing is required for systemic dissemination from the skin. To
further investigate this mechanism, we will determine the requirement for MRSA quorum-sensing function and
agr-regulated factors in skin dissemination to distal sites. We will also perform real-time imaging of infections
and determine the quorum-sensing contribution to evasion of host immunity. An improved understanding of how
MRSA colonizes the skin and transitions to infection could open avenues to developing therapeutic strategies
for minimizing the skin infection burden.

## Key facts

- **NIH application ID:** 10412904
- **Project number:** 5I01BX002711-07
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** ALEXANDER R HORSWILL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2015-07-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412904

## Citation

> US National Institutes of Health, RePORTER application 10412904, Quorum Sensing Dependent Interactions with Biofilms and Innate Immunity Defenses (5I01BX002711-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10412904. Licensed CC0.

---

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