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

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 environmentally dependent increase of antimicrobial defense by clustering in active peptide fragments. This complex clustering mechanism dramatically increases the host's ability to control pathogens and commensals. These findings broaden our understanding of host modulation of the microbiome as well as the complexity of human mucosal defense mechanisms, thus providing promising avenues to explore for drug development.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Ehmann D,Wendler J,Koeninger L,Larsen IS,Klag T,Berger J,Marette A,Schaller M,Stange EF,Malek NP,Jensen BAH,Wehkamp J

doi

10.1073/pnas.1817376116

subject

Has Abstract

pub_date

2019-02-26 00:00:00

pages

3746-3751

issue

eissn

0027-8424

issn

1091-6490

pii

1817376116

journal_volume

116

pub_type

杂志文章

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