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Science 337 (6093): 477-481

Copyright © 2012 by the American Association for the Advancement of Science

Human α-Defensin 6 Promotes Mucosal Innate Immunity Through Self-Assembled Peptide Nanonets

Hiutung Chu,1 Marzena Pazgier,2 Grace Jung,3 Sean-Paul Nuccio,1 Patricia A. Castillo,1 Maarten F. de Jong,1 Maria G. Winter,1 Sebastian E. Winter,1 Jan Wehkamp,1,* Bo Shen,4 Nita H. Salzman,5 Mark A. Underwood,6 Renee M. Tsolis,1 Glenn M. Young,7 Wuyuan Lu,2,{dagger} Robert I. Lehrer,3,{dagger} Andreas J. Bäumler,1,{dagger} Charles L. Bevins1,{dagger},{ddagger}

Abstract: Defensins are antimicrobial peptides that contribute broadly to innate immunity, including protection of mucosal tissues. Human α-defensin (HD) 6 is highly expressed by secretory Paneth cells of the small intestine. However, in contrast to the other defensins, it lacks appreciable bactericidal activity. Nevertheless, we report here that HD6 affords protection against invasion by enteric bacterial pathogens in vitro and in vivo. After stochastic binding to bacterial surface proteins, HD6 undergoes ordered self-assembly to form fibrils and nanonets that surround and entangle bacteria. This self-assembly mechanism occurs in vivo, requires histidine-27, and is consistent with x-ray crystallography data. These findings support a key role for HD6 in protecting the small intestine against invasion by diverse enteric pathogens and may explain the conservation of HD6 throughout Hominidae evolution.

1 Department of Microbiology and Immunology, School of Medicine, University of California, Davis, CA 95616, USA.
2 Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
3 Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
4 Department of Gastroenterology and Hepatology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
5 Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
6 Department of Pediatrics, School of Medicine, University of California, Davis, CA 95616, USA.
7 Department of Food Science and Technology, University of California, Davis, CA 95616, USA.

* Present address: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: clbevins{at}ucdavis.edu


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