title: Glycosaminoglycan binding facilitates entry of a bacterial pathogen into central nervous systems.
abstract: Certain microbes invade brain microvascular endothelial cells (BMECs) to breach the blood-brain barrier (BBB) and establish central nervous system (CNS) infection. Here we use the leading meningitis pathogen group B Streptococcus (GBS) together with insect and mammalian infection models to probe a potential role of glycosaminoglycan (GAG) interactions in the pathogenesis of CNS entry. Site-directed mutagenesis of a GAG-binding domain of the surface GBS alpha C protein impeded GBS penetration of the Drosophila BBB in vivo and diminished GBS adherence to and invasion of human BMECs in vitro. Conversely, genetic impairment of GAG expression in flies or mice reduced GBS dissemination into the brain. These complementary approaches identify a role for bacterial-GAG interactions in the pathogenesis of CNS infection. Our results also highlight how the simpler yet genetically conserved Drosophila GAG pathways can provide a model organism to screen candidate molecules that can interrupt pathogen-GAG interactions for future therapeutic applications.
authors: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, United States of America.
authors: Yung-Chi
authors: YC
authors: Chang
authors: Zhipeng
authors: Z
authors: Wang
authors: Lindsay A
authors: LA
authors: Flax
authors: Ding
authors: D
authors: Xu
authors: Jeffrey D
authors: JD
authors: Esko
authors: Victor
authors: V
authors: Nizet
authors: Miriam J
authors: MJ
authors: Baron
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001424:Bacterial Infections / Q000209:etiology / Q000473:pathology*; D001426:Bacterial Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000382:microbiology*; D001921:Brain / Q000382:microbiology; D002490:Central Nervous System / Q000382:microbiology*; D004330:Drosophila / Q000382:microbiology; D042783:Endothelial Cells / Q000382:microbiology; D004730:Endothelium, Vascular / Q000382:microbiology; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D013292:Streptococcus agalactiae / Q000472:pathogenicity*
chemical_list: D000954:Antigens, Surface; D001426:Bacterial Proteins; D006025:Glycosaminoglycans; C077961:alpha C protein, group B streptococci