# Quorum Sensing Dependent Interactions with Biofilms and Innate Immunity Defense

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2024 · —

## 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 active-duty military and veterans, and skin colonization is a known precursor of
infection. How this pathogen colonizes the skin is unknown. In recent microscopy studies, S. aureus developed
biofilm communities during skin colonization and the quorum-sensing pathway was found to be activated. To
investigate this further, we developed a new mouse skin colonization model and determined the MRSA global
transcriptional response. Based on these RNAseq studies, our central hypothesis is that MRSA has a unique
expression program that supports adherence and survival in the skin environment. We will address the
innovative idea that MRSA specifically induces a select group of virulence factors to survive in the harsh skin
environment and evade innate defenses. In Specific Aim 1, we will investigate the MRSA skin adherence and
regulatory profile. We hypothesize that MRSA adapts to the skin environment by expressing a specific
subset of adhesins, toxins and exo-enzymes. We will evaluate the contributions of specific virulence factors
using in vitro adherence to human keratinocytes, skin explant colonization, wound healing assays and mouse
models of skin colonization. In Specific Aim 2, we will determine the contribution of quorum-sensing and skin
upregulated factors to MRSA immune evasion. We hypothesize that MRSA evades skin immunity using
quorum-sensing regulated factors. Toward this end, we will define the role of urease in pH homeostasis and
biofilm development, and the function of SasF surface protein in skin fatty acid resistance. We will use our
developed human skin-like media to aid functional and regulatory studies on MRSA immune evasion factors. We
will also determine the contribution of quorum-sensing factors in resistance mechanisms to antimicrobial
peptides and skin fatty acids. In Specific Aim 3, we will assess the function of surface proteins in MRSA
dissemination from colonization. In preliminary studies, we discovered an important role for SasF in skin infection
and immune evasion. We hypothesize that MRSA strains with SasF have enhanced capacity to cause
systemic disease. We will determine the function of SasF in response to neutrophil challenge, and we will
evaluate the contribution of this protein to systemic dissemination in mouse models. Finally we will characterize
civilian and military MRSA strain collections for presence and function of SasF to determine whether this protein
is a biomarker of invasive disease. An improved understanding of how MRSA colonizes the skin and transitions
to infection could open avenues to developing therapeutic strategies for minimizing the skin in...

## Key facts

- **NIH application ID:** 10925441
- **Project number:** 2I01BX002711-09A2
- **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:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2015-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10925441

## Citation

> US National Institutes of Health, RePORTER application 10925441, Quorum Sensing Dependent Interactions with Biofilms and Innate Immunity Defense (2I01BX002711-09A2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10925441. Licensed CC0.

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