# The Impact of Vancomycin-Resistant Entercoccus on Clostridium difficile Infection

> **NIH NIH K22** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $107,545

## Abstract

PROJECT SUMMARY
Clostridium difficile is the most commonly reported nosocomial pathogen in the United States and an urgent
public health threat worldwide. Over the past decade, incidence, severity, and costs associated with C. difficile
infection (CDI) have increased dramatically; however, the factors that govern this broad spectrum of disease
remain unclear. The primary risk factor for CDI is antibiotic use, which reduces colonization resistance to C.
difficile by altering the resident gut microbiota. Interestingly, the major nosocomial pathogen vancomycin-
resistant Enterococcus (VRE) shares numerous risk factors with C. difficile and these pathogens are commonly
found together in the gastrointestinal tract. Moreover, colonization with VRE is associated with more severe C.
difficile-associated disease and in subsets of patients, CDI increases the risk of bacteremia due to VRE.
Despite these strong associations, little work has been done to explore the molecular interactions between
Enteroccoci and C. difficile during infection and it is unclear what impact co-occurrence of these pathogens has
on C. difficile-associated disease. Interspecies interactions can be attributed to the development of numerous
polymicrobial infections, including CDI, and cross talk between bacteria is associated with exacerbation of
several diseases. Enterococcus is associated with increased susceptibility to CDI and the gut microbiota of
patients with CDI is highly enriched with Enterococci. Following excess Zn supplementation, commensal
Enterococci are highly enriched in the microbiota, which leads to increased susceptibility to CDI, exacerbation
of C. difficile-associated disease, and high levels of Enterococcus translocation to the liver. Preliminary data
suggests that in culture, Enterococcus and C. difficile directly interact and this cross-talk alters virulence and
behavior of these two pathogens. In this application, we propose to elucidate the interactions between
Enterococcus and C. difficile and define the impact that these interactions have on susceptibility and severity of
CDI. We hypothesize that (i) Enterococcus increases susceptibility to CDI by altering the landscape of the gut
to enhance C. difficile colonization and (ii) co-occurrence of Enterococcus and C. difficile in the gastrointestinal
tract facilitates cross-talk between these two important pathogens that increases persistence and exacerbates
disease during CDI. We plan to test these three hypotheses through a series of integrated Specific Aims. First,
we will dissect the relationship between Enterococcus abundance and susceptibility to C. difficile and
determine the contribution of Enterococcus to C. difficile virulence in mice (Aim 1). We will then define how
these pathogens interact during infection and examine the impact of bacterial cross-talk on disease (Aim 2).
These experiments will elucidate the impact of VRE on susceptibility, severity, and recurrence of CDI and will
substantially incr...

## Key facts

- **NIH application ID:** 9868253
- **Project number:** 5K22AI137220-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Joseph Paul Zackular
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $107,545
- **Award type:** 5
- **Project period:** 2019-02-08 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868253

## Citation

> US National Institutes of Health, RePORTER application 9868253, The Impact of Vancomycin-Resistant Entercoccus on Clostridium difficile Infection (5K22AI137220-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868253. Licensed CC0.

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