Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor MprF is based on modification of membrane lipids with L-lysine

被引:612
作者
Peschel, A
Jack, RW
Otto, M
Collins, LV
Staubitz, P
Nicholson, G
Kalbacher, H
Nieuwenhuizen, WF
Jung, G
Tarkowski, A
van Kessel, KPM
van Strijp, JAG
机构
[1] Univ Tubingen, D-72076 Tubingen, Germany
[2] Univ Med Ctr Utrecht, Eijkman Winkler Inst, NL-3584 CX Utrecht, Netherlands
[3] EMC Microcollect, D-72070 Tubingen, Germany
[4] Gothenburg Univ, Dept Rheumatol, S-41346 Gothenburg, Sweden
[5] Univ Tubingen, Med & Nat Sci Res Ctr, D-72074 Tubingen, Germany
[6] TNO, NL-3700 AJ Zeist, Netherlands
关键词
host defense peptides; oxygen-independent killing; Staphylococcus aureus virulence; phospholipids; innate immunity;
D O I
10.1084/jem.193.9.1067
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Defensins, antimicrobial peptides of the innate immune system, protect human mucosal epithelia and skin against microbial infections and are produced in large amounts by neutrophils. The bacterial pathogen Staphylococcus aureus is insensitive to defensins by virtue of an unknown resistance mechanism. We describe a novel staphylococcal gene, mprF, which determines resistance to several host defense peptides such as defensins and protegrins. An mprF mutant strain was killed considerably faster by human neutrophils and exhibited attenuated virulence in mice, indicating a key role for defensin resistance in the pathogenicity of S. aureus. Analysis of membrane lipids demonstrated that the mprF mutant no longer modifies phosphatidylglycerol with L-lysine. As this unusual modification leads to a reduced negative charge of the membrane surface, MprF-mediated peptide resistance is most likely based on repulsion of the cationic peptides. Accordingly, inactivation of mprF led to increased binding of antimicrobial peptides by the bacteria. MprF has no similarity with genes of known function, but related genes were identified in the genomes of several pathogens including Mycobacterium tuberculosis, Pseudomonas aeruginosa, and Enterococcus faecalis. MprF thus constitutes a novel virulence factor, which may be of general relevance for bacterial pathogens and represents a new targe for attacking multidrug resistant bacteria.
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页码:1067 / 1076
页数:10
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