# Fungal-bacterial dynamics driving dysregulated host responses and lethal synergism

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2024 · $822,646

## Abstract

Polymicrobial infections involving fungal and bacterial pathogens are increasingly common among hospitalized
patients. However, there is a paucity of research focused on studying polymicrobial infections. The fungal
pathogen Candida albicans is the most common cause of invasive fungal infection and the third most common
cause of nosocomial bloodstream infections in the US. Invasive fungal infections with C. albicans have
devastatingly high mortality rates compared with bacterial infections. Bloodstream fungal infections, which are
mostly monomicrobial, result in a 40% mortality rate. In contrast, intra-abdominal fungal infections (IAI), which
are often polymicrobial involving both fungal and bacterial species, result in a 50-75% mortality rate, which far
exceeds bacterial mono- or polymicrobial IAI mortality rates (20%). Fungal involvement also leads to increased
rates of relapse and more severe disease scores. The mechanisms associated with this exacerbated mortality
are currently unknown. The objective of this proposal is to delineate host and microbial mechanisms contributing
to synergistic lethality during polymicrobial fungal-bacterial IAI. Our central hypothesis is that polymicrobial
fungal–bacterial IAIs promote synergistic effects on mortality induced by microbe-microbe interactions that
increase bacterial toxin production, leading to upregulation of immune signaling pathways, dysregulation of
hemostasis and coagulation, and altered bone marrow remodeling. This hypothesis will be tested by modeling
polymicrobial interactions with C. albicans and the Gram-positive bacterium Staphylococcus aureus, which is
the most commonly co-isolated bacterial pathogen from fungal-bacterial co-infections. The first specific aim of
this project is to interrogate the mechanisms by which Candida induces of S. aureus toxin production during
polymicrobial IAI. The second specific aim will define bacterial mechanisms and virulence regulators that drive
dysregulated hemostasis and coagulation that contribute to lethality during polymicrobial IAI. The third specific
aim will functionally characterize the consequences of Candida-induced S. aureus toxin production on bone
marrow homeostasis and trained innate immunity. Completion of this project will identify both new mechanisms
that underlie exacerbated pathogenicity of polymicrobial infections and therapeutic approaches to improve
outcomes of IAI.

## Key facts

- **NIH application ID:** 10981752
- **Project number:** 1R01AI177615-01A1
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** JAMES E CASSAT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $822,646
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981752

## Citation

> US National Institutes of Health, RePORTER application 10981752, Fungal-bacterial dynamics driving dysregulated host responses and lethal synergism (1R01AI177615-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10981752. Licensed CC0.

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