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The influence of environmental factors on antimicrobial activity of human intestinal defensins

Objective

Human epithelia are permanently challenged by microorganisms. In the gut, the fraction of strict anaerobic bacteria increases from proximal to distal, reaching 99% of bacterial species in the colon. Moreover, microbial metabolism causes a reduction of the environment to a low redox potential of only –200 mV to –300 mV. Defensins, characterised by three intramolecular disulfide-bridges, are key effector molecules of innate immunity that protect the host from infectious microbes. Human β-defensin 1 (hBD-1) is one of the most prominent peptides of its class but comparison with other defensins suggested only minor antibiotic killing activity. We could recently show that hBD-1 becomes a potent antimicrobial peptide against C. albicans and anaerobic, Gram-positive commensals of the human normal flora in a reducing environment (Nature 2011). The effect was attributable to the linear, reduced hBD-1 peptide.
Here we aim to investigate the antimicrobial activity of reduced hBD-1 in more detail. We will study the mechanism of its reduction by cell-culture experiments and in vitro reduction assays. The molecular details of its antibiotic action will be investigated by using bacterial mutants and further in vitro assays. Additionally we aim to characterise the antibiotic spectrum of reduced hBD-1 by using different antimicrobial assays. Also, we plan to systematically test human defensins under reducing conditions and different pH values that occur in the gut
Besides we will screen extracts of human intestinal tissue and stool samples for antimicrobial substances by using the conditions described above. Extracts will be purified by HPLC and antimicrobially active fractions will be examined by MALDI-TOF peptide mass fingerprint technique. We hope to identify novel peptides which have been overlooked due to standardized testing methods. Resembling the natural conditions as close as possible will help to better understand antibiotic mucosal host defense in the intestinal tract.

Field of science

  • /natural sciences/biological sciences/microbiology/bacteriology

Call for proposal

ERC-2012-StG_20111109
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

EBERHARD KARLS UNIVERSITAET TUEBINGEN
Address
Geschwister-scholl-platz
72074 Tuebingen
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 133 480,69
Principal investigator
Jan Wehkamp (Dr.)
Administrative Contact
Susanne Stoppel (Ms.)

Beneficiaries (2)

EBERHARD KARLS UNIVERSITAET TUEBINGEN
Germany
EU contribution
€ 1 133 480,69
Address
Geschwister-scholl-platz
72074 Tuebingen
Activity type
Higher or Secondary Education Establishments
Principal investigator
Jan Wehkamp (Dr.)
Administrative Contact
Susanne Stoppel (Ms.)
ROBERT BOSCH GESELLSCHAFT FUR MEDIZINISCHE FORSCHUNG MBH

Participation ended

Germany
EU contribution
€ 366 519,31
Address
Auerbachstrasse 112
70376 Stuttgart
Activity type
Research Organisations
Administrative Contact
Christiane Schmiedl (Ms.)