# Determinants of polymicrobial diabetic wound infections

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2024 · $194,375

## Abstract

PROJECT SUMMARY
Group B Streptococcus (GBS), is an opportunistic pathogen that asymptomatically colonizes the urogenital and
female reproductive tract of approximately 25-30% of individuals. However, GBS can cause serious infections
in immunocompromised individuals including those with diabetes. Diabetic wound infections are a major public
health burden, with approximately 25% of diabetic individuals developing a wound in their lifetime, 25% of these
wounds not healing and 28% requiring surgical amputation. Poor infection outcomes are correlated with the
presence of numerous bacterial pathogens, and GBS, along with Staphylococcus aureus, is one of the most
common bacteria found in these wounds. Despite its prevalence, no prior work has been done on GBS
pathogenesis in the diabetic wound environment. Recently, we developed a Type 2 diabetic murine model of
GBS diabetic wound infection in leprdb mice, and demonstrated that GBS forms a robust wound and persists in
this environment. Further observations found that GBS colonies recovered from diabetic wound tissue were
hyper-pigmented/hemolytic, suggesting selection of more virulent GBS mutants during diabetic infection.
These phenotypes mimic those of a covR mutant, as CovR is a major repressor of GBS virulence factors such
as the GBS hemolysin/pigment, nuclease (NucA), and surface adhesin plasminogen binding protein PbsP. Dual
RNA-sequencing of GBS and the murine wound revealed that these same CovR regulated genes were highly
upregulated in the diabetic wound. In addition, GBS infection triggered the recruitment of neutrophils, neutrophil
activation and NET formation at the site of infection. Finally, we have shown in our murine model that the
presence of S. aureus promotes GBS persistence in the diabetic wound. With these preliminary data, we have
formulated hypotheses which address multiple mechanisms by which GBS may survive and persist in the
diabetic wound environment. These hypotheses will be addressed in the following specific aims: Aim 1:
Determine how CovR regulation contributes to diabetic wound infection, Aim 2: Characterize the
contribution of PbsP to GBS diabetic wound formation, persistence, and dissemination, Aim 3: Examine
the contribution of nuclease activity in promoting GBS immune evasion and wound persistence. These
studies will increase our understanding of the pathogenesis of GBS diabetic wound infection and will provide a
platform for additional studies.

## Key facts

- **NIH application ID:** 10876341
- **Project number:** 5R21AI171853-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Kelly S Doran
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876341

## Citation

> US National Institutes of Health, RePORTER application 10876341, Determinants of polymicrobial diabetic wound infections (5R21AI171853-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10876341. Licensed CC0.

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