Human epithelia are permanently challenged by bacteria and fungi, including commensal and pathogenic microbiota1,2. In the gut, the fraction of strict anaerobes increases from proximal to distal, reaching 99% of bacterial species in the colon3. At colonic mucosa, oxygen partial pressure is below 25% of airborne oxygen content, moreover microbial metabolism causes reduction to a low redox potential of −200 mV to –300 mV in the colon4. Defensins, characterized by three intramolecular disulphide-bridges, are key effector molecules of innate immunity that protect the host from infectious microbes and shape the composition of microbiota at mucosal surfaces5,6,7,8. Human β-defensin 1 (hBD-1) is one of the most prominent peptides of its class but despite ubiquitous expression by all human epithelia, comparison with other defensins suggested only minor antibiotic killing activity9,10. Whereas much is known about the activity of antimicrobial peptides in aerobic environments, data about reducing environments are limited. Herein we show that after reduction of disulphide-bridges hBD-1 becomes a potent antimicrobial peptide against the opportunistic pathogenic fungus Candida albicans and against anaerobic, Gram-positive commensals of Bifidobacterium and Lactobacillus species. Reduced hBD-1 differs structurally from oxidized hBD-1 and free cysteines in the carboxy terminus seem important for the bactericidal effect. In vitro, the thioredoxin (TRX) system11 is able to reduce hBD-1 and TRX co-localizes with reduced hBD-1 in human epithelia. Hence our study indicates that reduced hBD-1 shields the healthy epithelium against colonisation by commensal bacteria and opportunistic fungi. Accordingly, an intimate interplay between redox-regulation and innate immune defence seems crucial for an effective barrier protecting human epithelia.
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We thank M. Katajew, H. Löffler, C. Martensen-Kerl, C. Mehrens, J. Quitzau and A. Rose for technical assistance, B. Fehrenbacher for performing electron microscopy and H.-P. Kreichgauer, C. Schäfer, O. Müller, K. R. Herrlinger and M. Escher for collecting biopsies. Furthermore we thank M. Schwab for discussions and support, C. L. Bevins and J.-M. Schröder for discussions and reading of the manuscript and Ardeypharm GmbH for providing anaerobic bacterial strains and L. Zabel for providing C. albicans strains. This work was supported by Deutsche Forschungsgemeinschaft (WE 436/1-1, SCH 897/1-3 and SFB685) and the Robert-Bosch Foundation (Stuttgart, Germany). J.W. is an Emmy Noether Scholar of Deutsche Forschungsgemeinschaft.
B.O.S., S.N., E.F.S. and J.W. filed a patent application on the subject of this manuscript.
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Schroeder, B., Wu, Z., Nuding, S. et al. Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1. Nature 469, 419–423 (2011). https://doi.org/10.1038/nature09674
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