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

Ehmann, D., Wendler, J., Koeninger, L., Larsen, I., Klag, T., Berger, J., et al. (2019). 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, 116(9), 3746-3751. doi:10.1073/pnas.1817376116.

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 Creators:
Ehmann, D, Author
Wendler, J, Author
Koeninger, L, Author
Larsen, IS, Author
Klag, T, Author
Berger, J1, Author           
Marette, A, Author
Schaller, M, Author
Stange, EF, Author
Malek, NP, Author
Jensen, BAH, Author
Wehkamp, J, Author
Affiliations:
1Electron Microscopy, Max Planck Institute for Developmental Biology, Max Planck Society, ou_3375794              

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 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.

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 Dates: 2019-02
 Publication Status: Issued
 Pages: -
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 Rev. Type: -
 Identifiers: DOI: 10.1073/pnas.1817376116
PMID: 30808760
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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : PNAS
  Other : Proceedings of the National Academy of Sciences of the USA
  Abbreviation : Proc. Natl. Acad. Sci. U. S. A.
Source Genre: Journal
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Publ. Info: Washington, D.C. : National Academy of Sciences
Pages: - Volume / Issue: 116 (9) Sequence Number: - Start / End Page: 3746 - 3751 Identifier: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230