# Mechanisms Regulating Innate Immune Responses

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $418,750

## Abstract

Project Summary/Abstract
The interplay between host:microbial interactions is critical at mucosal surfaces. Dysregulation in
these interactions can lead to intestinal inflammatory diseases, such as inflammatory bowel disease
(IBD). The recognition and response to microbes is initially mediated by pattern recognition receptors
(PRR). PRR responses lead to secretion of cytokines and cellular activation, as well as microbial
clearance. The balance between these outcomes influences susceptibility between inflammatory
diseases and infectious diseases. Our long-term goal is to understand the mechanisms mediating IBD
pathogenesis, thereby ultimately improving the management and therapy of human IBD.
Polymorphisms in the IRF5 region are associated with a wide-range of immune-mediated diseases,
included IBD. We found that IRF5 is the single most important genetic determinant of the inter-
individual variation in PRR-initiated signaling and cytokines from myeloid-derived cells across the
population; carriers of the IRF5 disease risk polymorphisms secrete high levels of cytokines in
response to a range of PRR stimuli. Despite the importance of IRF5 in regulating inter-individual
variation in human myeloid-derived PRR-induced cytokines, how IRF5 contributes to IBD
pathogenesis in vivo has not been examined (SA IC&IIC). Key to IBD pathogenesis is the ability of
myeloid cells to clear microbes; however, how IRF5 regulates clearance of both resident and
pathogenic intestinal microbes is not known (SA III). Multiple cell subsets can contribute to intestinal
immune dysregulation, and limited in vivo studies in IRF5-/- mice have also demonstrated a role for
IRF5 in T cell outcomes, with decreased Th1 differentiation in lupus model systems. However,
whether IRF5 regulates T cell outcomes in a T cell-intrinsic (SA I) or T cell-extrinsic (SA II) manner is
not known, including in intestinal tissues. We hypothesize that IRF5 will contribute to multiple
immune cell functions essential in intestinal immune homeostasis in vivo through its role in both
myeloid and T cell subsets, and that although it may contribute to inflammatory outcomes in colitis, it
is essential for regulating intestinal pathogens. We further hypothesize that IRF5 IBD-associated
polymorphisms will modulate the identified roles for IRF5 in these pertinent immune outcomes. We
will integrate studies in primary human cells with in vivo mouse studies to dissect IRF5 contributions
to IBD pathogenesis

## Key facts

- **NIH application ID:** 9969312
- **Project number:** 5R01AI120369-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** CLARA ABRAHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969312

## Citation

> US National Institutes of Health, RePORTER application 9969312, Mechanisms Regulating Innate Immune Responses (5R01AI120369-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9969312. Licensed CC0.

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