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.

Concepts and Mechanisms: Crossing Host Barriers

“…Similarly, fibronectin bridges N. meningitidis to a 5 b 1 integrin on BMEC surface enabling bacterial internalization (Unkmeir et al 2002). Glycan structures, specially glucosaminoglycans (GAG), that interact with integrin signaling machinery, have been shown to interact with bacterial proteins such as the GBS a C protein (Chang et al 2011). Given that many of these host cell factors preferentially localize to the basolateral surface of polarized endothelium, disruption of junctional protein complexes on infection may result in a nonpolarized distribution of proteins on the BBB plasma membrane and their luminal accessibility (see below).…”

Competence-induced protein Ccs4 facilitates pneumococcal invasion into brain tissue and virulence in meningitis

“…Streptococcus agalactiae penetrates the BBB via interactions between bacterial surface alpha C protein and host surface heparan sulfate chains [19]. It has been shown that heparan sulfate and heparin are defined by similar underlying backbones (GlcNAcα1-4GlcAβ1-4/IdoAα1-4) n , though heparin undergoes more extensive sulfation and uronic acid epimerization [20].…”

“…Bacterial association with and invasion into hBMECs or the human alveolar cell line A549 were quantified as previously described, with minor modifications [12,19,26,52]. hBMECs or A549 cells were seeded at 2 × 10 5 cells into 24-well plates 1 day prior to bacterial infection.…”

Heparan Sulfate Modulates Neutrophil and Endothelial Function in Antibacterial Innate Immunity

“…We showed previously that genetic impairment of HS expression in flies or mice reduced GBS dissemination into the brain (24). To examine how altering 2-O-sulfation might influence susceptibility to GBS meningitis, we measured GBS dissemination into brain after intravenous challenge (Fig.…”