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.
Highlights
Bacterial meningitis is one of the top ten causes of infectionrelated mortality worldwide [1]
We demonstrate that group B Streptococcus (GBS) expresses a specific protein on its surface that can bind to sugar molecules known as glycosaminoglycans (GAGs) on the surface of brain capillary cells, initiating infection of the blood-brain barrier (BBB)
Our results identify a role for bacterial-GAG interactions in the pathogenesis of newborn meningitis and highlight how the simpler yet genetically conserved fruit fly GAG biosynthetic pathways make the fruit fly a good model organism to screen candidate molecules that can interrupt pathogen-GAG interactions for future therapeutic applications
Summary
Bacterial meningitis is one of the top ten causes of infectionrelated mortality worldwide [1]. The most common agent of neonatal bacterial meningitis in the United States, Europe and Asia is group B Streptococcus (GBS). GBS has emerged as a cause of serious infections including meningitis in nonpregnant adult populations, with an invasive disease incidence approaching that reported for the neonate [6,7,8]. In gaining access to the central nervous system (CNS), GBS reveals an ability to cross the blood-brain barrier (BBB), a specialized layer of brain microvascular endothelial cells (BMECs) that regulates macromolecular traffic to maintain biochemical homeostasis in brain tissues. The fundamental mechanisms by which GBS establishes CNS infection remain incompletely understood [10]
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