# Candida mediated protection against polymicrobial sepsis

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2021 · $575,832

## Abstract

Project Description
The fungal pathogen Candida albicans is the most common cause of invasive fungal infection
often originating from outgrowth and invasion from the GI tract. Invasion initially causes intra-
abdominal infections (IAI), which are often polymicrobial, and can lead to bloodstream infection
and fatal sepsis. When fungal species are involved, mortality rates increase dramatically to 50-
75% depending on patient risk factors. We recently developed an animal model of polymicrobial
fungal/bacterial intra-abdominal infection (IAI) with C. albicans (Ca) and Staphylococcus aureus
(Sa) that mimics clinical invasive disease (dissemination/sepsis) resulting in 80-100% mortality
within 96 h post-inoculation. In contrast, co-infection with the closely related C. dubliniensis (Cd)
resulted in <10% mortality. Of particular interest, survivors of Cd/Sa or Cd alone re-challenged
with a lethal co-infection (Ca/Sa) resulted in >90% survival. The protective response is sustained
long term (up to at least 60 days prior to re-challenge) and is broad-spectrum providing protection
against similarly lethal C. tropicalis/Sa and C. krusei/Sa IAI. Surprisingly, the Cd-induced
protection against lethal IAI is NOT mediated by adaptive immunity, but instead appears to be
through a mechanism of trained innate immunity (non-specific memory mediated by innate cells).
Preliminary data indicate that the trained innate response by Cd is mediated by Gr-1+ myeloid
derived suppressor cells (MDSC) that have been reported in human sepsis. The concept of
trained innate immunity mediated by MDSCs is novel for infectious disease. Accordingly, our
central hypothesis is that exposure to low virulence Candida species induce sustained broad
spectrum trained innate immune protection against lethal polymicrobial fungal-bacterial sepsis.
Mechanistically, we hypothesize that the protective response is mediated by epigenetically re-
programed MDSCs during trained innate immunity. The objective of this proposal is to define
host and microbial requirements for induction of protective trained innate immunity during
polymicrobial sepsis and investigate mechanisms involved in induction, training and effector
functions.

## Key facts

- **NIH application ID:** 10134233
- **Project number:** 5R01AI145096-03
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Mairi C Noverr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $575,832
- **Award type:** 5
- **Project period:** 2019-04-22 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134233

## Citation

> US National Institutes of Health, RePORTER application 10134233, Candida mediated protection against polymicrobial sepsis (5R01AI145096-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134233. Licensed CC0.

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