Journal article
Human α-Defensins Inhibit Hemolysis Mediated by Cholesterol-Dependent Cytolysins
Infection and immunity, v 77(9), pp 4028-4040
Sep 2009
PMID: 19581399
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Many pathogenic gram-positive bacteria release exotoxins that belong to the family of cholesterol-dependent cytolysins. Here, we report that human α-defensins HNP-1 to HNP-3 acted in a concentration-dependent manner to protect human red blood cells from the lytic effects of three of these exotoxins: anthrolysin O (ALO), listeriolysin O, and pneumolysin. HD-5 was very effective against listeriolysin O but less effective against the other toxins. Human α-defensins HNP-4 and HD-6 and human β-defensin-1, -2, and -3 lacked protective ability. HNP-1 required intact disulfide bonds to prevent toxin-mediated hemolysis. A fully linearized analog, in which all six cysteines were replaced by aminobutyric acid (Abu) residues, showed greatly reduced binding and protection. A partially unfolded HNP-1 analog, in which only cysteines 9 and 29 were replaced by Abu residues, showed intact ALO binding but was 10-fold less potent in preventing hemolysis. Surface plasmon resonance assays revealed that HNP-1 to HNP-3 bound all three toxins at multiple sites and also that solution-phase HNP molecules could bind immobilized HNP molecules. Defensin concentrations that inhibited hemolysis by ALO and listeriolysin did not prevent these toxins from binding either to red blood cells or to cholesterol. Others have shown that HNP-1 to HNP-3 inhibit lethal toxin of
B
acillus anthracis
, toxin B of
Clostridium difficile
, diphtheria toxin, and exotoxin A of
Pseudomonas aeruginosa
; however, this is the first time these defensins have been shown to inhibit pore-forming toxins. An “ABCDE mechanism” that can account for the ability of HNP-1 to HNP-3 to inhibit so many different exotoxins is proposed.
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Details
- Title
- Human α-Defensins Inhibit Hemolysis Mediated by Cholesterol-Dependent Cytolysins
- Creators
- Robert I Lehrer - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095Grace Jung - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095Piotr Ruchala - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095Wei Wang - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095Ewa D Micewicz - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095Alan J Waring - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095Eugene J Gillespie - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095Kenneth A Bradley - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095Adam J Ratner - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095Richard F Rest - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095Wuyuan Lu - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
- Publication Details
- Infection and immunity, v 77(9), pp 4028-4040
- Publisher
- American Society for Microbiology (ASM)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- [Retired Faculty]
- Web of Science ID
- WOS:000269947200054
- Scopus ID
- 2-s2.0-69049119234
- Other Identifier
- 991014877878804721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Immunology
- Infectious Diseases