# Regulation and function of mucosal IgA immune responses to mycobiota in the gut.

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $584,882

## Abstract

Abstract
Immunoglobulin A (IgA) is prominently secreted at mucosal surfaces and coats a fraction of the intestinal
bacterial microbiota. In health and disease, secretory IgA (sIgA) binding influences intestinal immunity and
homeostasis by crosslinking microbiota in the lumen to prevent encroachment on the intestinal epithelium,
shuttling bound microbes to secondary lymphoid tissues, and directly modulating microbial metabolic activity.
Aside from the “natural” polyreactive IgA detectable in germ-free mice, sIgA is predominantly gut colonization
dependent. The identification of immunogenic commensal bacteria and their specific IgA epitopes have further
elucidated our understanding of the mechanisms governing gastrointestinal balance and how dysbiosis can drive
intestinal pathologies. Meanwhile, the potential involvement of the fungal component of the gut microbiota
(mycobiota) in these processes is largely unknown. Only recently have intestinal fungi been recognized as a
factor contributing to events associated with inflammatory disease or response to therapy prompting multiple
questions regarding the development of antifungal mucosal antibody responses, their specificity, and
mechanisms of induction in the gut. In recent work, we have shown that polymorphisms in the Dectin-1 gene
(CLEC7A) or the fractalkine receptor gene CX3CR1 are associated with defects in antifungal immunity in
Inflammatory Bowel Disease (IBD) patients, and notably the latter leading to gut fungal overgrowth and
substantial decrease of antifungal antibodies. In preliminary studies we unexpectedly identified a broad range of
fungal organisms that were targeted by sIgA antibodies. Hyphal formation is a primary mechanism used by many
dimorphic fungi to invade and survive within their hosts. Notably we found that mycobiota aggravated intestinal
damage and inflammation is dependent upon hyphae-produced virulence factors that are targets of sIgA. These
preliminary data support the overall hypothesis that antifungal sIgA antibody responses are naturally induced by
specific gut mycobiota species and act against fungi-produced factors to play a key role in mucosal immunity by
averting direct contact of fungi with the intestinal epithelium to prevent intestinal barrier damage and related gut
inflammation. We will investigate this hypothesis both in vitro and in in vivo models, aided by deep sequencing
and computational platforms, and genetically modified fungal strains. We will determine IgA-reactive gut
mycobiota and fungal morphotypes involved in the induction of antifungal sIgA antibodies and will make use of
several model systems to define the functional role of antifungal sIgA in gut.

## Key facts

- **NIH application ID:** 10844593
- **Project number:** 5R01AI163007-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** ILIYAN Dimitrov ILIEV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $584,882
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844593

## Citation

> US National Institutes of Health, RePORTER application 10844593, Regulation and function of mucosal IgA immune responses to mycobiota in the gut. (5R01AI163007-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10844593. Licensed CC0.

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