# ADAM10 polymorphism in susceptibility to S. aureus disease

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2024 · $194,375

## Abstract

PROJECT SUMMARY
Staphylococcus aureus infection in otherwise healthy adults and children is a significant cause of morbidity,
mortality, and economic loss. Recurrence of infection is common, highlighting the fact that S. aureus subverts
the development of protective immunity. The development of a vaccine to prevent S. aureus infection has been
a premier goal in the field for over two decades, yet multiple human vaccine candidates have failed in clinical
trials. Understanding the pathogen and host-specific factors that modulate susceptibility to S. aureus infection is
expected to provide insight to advance vaccine design and implementation, but also affords an opportunity to
develop specific bedside-accessible tools for objectively assessing individual patient risk. Such tools are required
to advance the field toward the goals of personalized and precision medicine. Extensive research, including our
own studies, supports the targeting of S. aureus α-toxin (Hla) as a virulence factor to protect against infection.
The interaction of Hla with its eukaryotic receptor ADAM10 provides an additional window of opportunity to
evaluate whether host-specific factors that modify ADAM10 expression or cellular activity impact susceptibility
to S. aureus disease. We have successfully leveraged human clinical studies of S. aureus-infected children and
experimental perturbation of ADAM10 in a mouse model system to examine whether a single nucleotide
polymorphism (SNP) in the ADAM10 promoter (rs653765) alters susceptibility to S. aureus infection. Two
complementary lines of data provide initial insight that this SNP is of functional relevance: 1) children with the
rs653765 GG genotype display a significant reduction in odds ratio of invasive S. aureus infection; 2) engineered
SNP variants of ADAM10 in novel mouse lines reflect the initial clinical findings observed in humans harboring
the rs653765 GG genotype, and suggest that the SNP type influences susceptibility to skin and soft tissue
infection. In this project, we propose to leverage existing human genomic DNA biospecimens from an ongoing
study of pediatric immunity to S. aureus infection to fully characterize the impact of ADAM10 rs653765 SNP
variation in susceptibility to S. aureus infection. We will pair this analysis with hypothesis-driven studies to define
the molecular and cellular mechanisms by which the rs653765 SNP alters host susceptibility to disease. These
studies which sit at the intersection of human genetic epidemiology and mechanistic research afford a rare
opportunity to define a focused biomarker that can inform an understanding of risk for S. aureus disease. The
successful completion of these studies would provide an unparalleled opportunity to utilize SNP typing to
advance personalized care in the context of infectious disease.

## Key facts

- **NIH application ID:** 10796998
- **Project number:** 5R21AI176063-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Juliane Bubeck Wardenburg
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2023-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10796998

## Citation

> US National Institutes of Health, RePORTER application 10796998, ADAM10 polymorphism in susceptibility to S. aureus disease (5R21AI176063-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10796998. Licensed CC0.

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