# Investigating the role of interferon lambda in protection against severe Clostridioides difficile infection

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $48,974

## Abstract

Project Summary/Abstract
 Clostridioides difficile is the leading cause of hospital-acquired gastrointestinal infections in the United
States. Pathogenesis is mediated by secreted toxins that cause the death of intestinal epithelial cells (IECs) and
breakdown of the intestinal barrier. C. difficile infection is primarily treated with antibiotics; however, the high rate
of recurrent infections necessitates alternative treatment options. Our lab has found that orally administering a
toll-like receptor 7 (TLR7) agonist, R848, protects mice against severe disease following lethal C. difficile
challenge. R848 treatment induces the expression of inflammatory cytokines including interferons. Interestingly,
while protection was not dependent on type I or type II interferon signaling, we found that mice deficient for type
III interferon (IFN-λ) signaling are not protected following R848 treatment. While IFN-λ is best known for its role
in antiviral immunity, recent works by others has shown that IFN-λ stimulates intestinal stem cell proliferation to
reduce the severity of experimental colitis. This proposal seeks to determine the mechanism by which IFN-λ
contributes to R848-mediated protection against C. difficile infection. The overarching hypothesis for this
project is that IFN-λ directly acts on IECs to stimulate stem cell proliferation and thereby repairing the
damage to the intestinal barrier from C. difficile toxin. Aim 1 will identify the critical cell type that responds
to IFN-λ for R848-mediated protection against C. difficile infection using bone marrow chimeric mice and cell-
lineage specific knockout mice. Aim 2 will test the hypothesis that IFN-λ promotes intestinal stem cell function
and stimulates proliferation by utilizing Lgr5EGFP reporter mice and intestinal organoid culture models. This project
will elucidate the mechanism behind a novel role for IFN-λ in the immune response against C. difficile and may
inform future development of therapeutics against this major public health threat.

## Key facts

- **NIH application ID:** 10820861
- **Project number:** 1F31DK138546-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kevin Stanton Mears
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-05-15 → 2027-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820861

## Citation

> US National Institutes of Health, RePORTER application 10820861, Investigating the role of interferon lambda in protection against severe Clostridioides difficile infection (1F31DK138546-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10820861. Licensed CC0.

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