A STRUCTURE-ACTIVITY RELATIONSHIP FOR INDUCTION OF MENINGEAL INFLAMMATION BY MURAMYL PEPTIDES

被引:57
作者
BURROUGHS, M [1 ]
ROZDZINSKI, E [1 ]
GEELEN, S [1 ]
TUOMANEN, E [1 ]
机构
[1] ROCKEFELLER UNIV,MOLEC INFECT DIS LAB,1230 YORK AVE,NEW YORK,NY 10021
关键词
MENINGITIS; PEPTIDOGLYCAN; CENTRAL NERVOUS SYSTEM INFLAMMATION; BLOOD BRAIN BARRIER PERMEABILITY; CELL WALL;
D O I
10.1172/JCI116565
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Components of bacterial peptidoglycans have potent biological activities, including adjuvant effects, cytotoxicity, and induction of sleep. Mixtures of peptidoglycan components also induce inflammation in the lung, subarachnoid space, and joint, but the structural requirements for activity are unknown. Using a rabbit model for meningitis, we determined the biological activities of 14 individual muramyl peptides constituting > 90% of the peptidoglycan of the gram-negative pediatric pathogen Haemophilus influenzae. Upon intracisternal inoculation, most of the muropeptides induced leukocytosis in cerebrospinal fluid (CSF), influx of protein into CSF, or brain edema, alone or in combination. The disaccharide-tetrapeptide, the major component of all gram-negative peptidoglycans, induced CSF leukocytosis and protein influx at doses as low as 0.4 mug (0.42 nM). Modification of the N-acetyl muramic acid or substitution of the alanine at position four in the peptide side chain decreased leukocytosis but enhanced brain edema. As the size of the muropeptide increased, the inflammatory activity decreased. Muropeptides carrying the diaminopimelyl-diaminopimelic acid cross-link specifically induced cytotoxic brain edema. These findings significantly expand the spectrum of biological activities of natural muramyl peptides and provide the basis for a structure-activity relationship for the inflammatory properties of bacterial muropeptides.
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页码:297 / 302
页数:6
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