Paneth cell α-defensins HD-5 and HD-6 display differential degradation into active antimicrobial fragments.

Proceedings of the National Academy of Sciences of the United States of America
D EhmannJan Wehkamp

Abstract

Antimicrobial peptides, in particular α-defensins expressed by Paneth cells, control microbiota composition and play a key role in intestinal barrier function and homeostasis. Dynamic conditions in the local microenvironment, such as pH and redox potential, significantly affect the antimicrobial spectrum. In contrast to oxidized peptides, some reduced defensins exhibit increased vulnerability to proteolytic degradation. In this report, we investigated the susceptibility of Paneth-cell-specific human α-defensin 5 (HD-5) and -6 (HD-6) to intestinal proteases using natural human duodenal fluid. We systematically assessed proteolytic degradation using liquid chromatography-mass spectrometry and identified several active defensin fragments capable of impacting bacterial growth of both commensal and pathogenic origins. Of note, incubation of mucus with HD-5 resulted in 255-8,000 new antimicrobial combinations. In contrast, HD-6 remained stable with consistent preserved nanonet formation. In vivo studies demonstrated proof of concept that a HD-5 fragment shifted microbiota composition (e.g., increases of Akkermansia sp.) without decreasing diversity. Our data support the concept that secretion of host peptides results in an environmen...Continue Reading

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Citations

Mar 13, 2019·American Journal of Physiology. Endocrinology and Metabolism·Ida Søgaard LarsenBenjamin Anderschou Holbech Jensen
Oct 31, 2019·Clinical and Translational Gastroenterology·Inés Moret-TatayBelén Beltrán
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Jul 31, 2021·Frontiers in Cell and Developmental Biology·Gaelle NoelMarcela F Pasetti
Aug 4, 2021·Nature Microbiology·Pedro H PapottoBruno Silva-Santos

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Methods Mentioned

BETA
scanning electron microscopy
transmission electron microscopy
Assay

Software Mentioned

Adonis PERMANOVA

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