# Novel Defensins in Human Epithelial Tissues

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $396,231

## Abstract

Abstract:
The immune system of mucosal tissues must effectively protect the host from pathogen
invasion, while facilitating homeostatic interactions with a diverse colonizing microbiota.
A clear understanding of the key molecules and mechanisms that achieve this delicate
balance remains incomplete, leaving a gap in critical knowledge. This investigation,
AI32438, has focused on D-defensins HD5 (DEFA5) and HD6 (DEFA6) as key effector
molecules of innate immunity. These D-defensins are the most abundant antimicrobial
peptides of human Paneth cells and compelling evidence shows that dysrupted Paneth
cell function increases susceptibility to enteric pathogens, as well as to chronic
inflammatory bowel disease. Published studies previously funded by this grant have
established significant knowledge about the structure, microbicidal activities, and
biological functions of HD5. In contrast, comparatively little is known about its Paneth
cell partner, HD6 - an abundant D-defensin that is exceptionally well-conserved among
primates. We discovered that HD6 has a novel mechanism of protective action. Unlike
HD5 and other defensin peptides that protect the host through microbicidal activity, HD6
does not kill microbes but rather protects the intestinal mucosa by blocking microbial
invasion. Our recently published data support a mechanism that involves trypsin-
mediated processing of inactive stored proHD6 that generates a mature peptide capable
of binding to surface proteins of microbes, followed by self-assembly of additional HD6
peptide molecules to form microbe-entangling nanofibrils and nanonets, which prevent
penetration into host cells. The objectives for this proposal are to define the molecular
details of this process, including pinpointing the target on microbial surface proteins that
initiates initial binding of HD6 peptides, elucidating the structural features of HD6 that
promote self-assembly, determining how HD6 impairs fagellar-driven microbial
propulsion to mediate protection, and illuimate the consequences of HD6 binding to
microbial antigens in shaping mucosal immune respones. We propose a combination of
complementary approaches to accomplish these goals. By determining the fundamental
features of HD6 function, these experiments will characterize a novel mechanism of
protection and mucosal homeostasis afforded by the innate immune system. Successful
completion of these studies will have broad impact on our mechanistic understanding of
mucosal innate immunity will fill a void in knowledge on a conserved, highly abundant
human defensin, as identification of the target for HD6 binding may reveal a new
pathogen-associated molecular pattern (PAMP), and the structure-function analyses of
HD6 will yield fundamental knowledge on mechanisms of peptide self-assembly.

## Key facts

- **NIH application ID:** 9799168
- **Project number:** 4R37AI032738-21
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Charles L Bevins
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,231
- **Award type:** 4C
- **Project period:** 1993-07-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9799168

## Citation

> US National Institutes of Health, RePORTER application 9799168, Novel Defensins in Human Epithelial Tissues (4R37AI032738-21). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9799168. Licensed CC0.

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