Exploring how meningitis-associated hyper-virulent CC17 group B Streptococcus infects the brain – strepB2brain

Meningitis may be caused by infection with microorganisms such as bacteria, viruses, fungi or parasites. Bacterial meningitis is the most common serious infection of the central nervous system and a major cause of death and disability worldwide, especially in children. Group B Streptococcus (GBS), an adult commensal bacterium, is a major pathogen of the neonate, being the main responsible for neonatal invasive diseases including meningitis. Although antibiotic therapy and improved critical care have changed the systematic fatal outcome of bacterial meningitis to an occasionally curable one, GBS meningitis is still an unresolved problem in medicine with mortality of 5 to 50% and permanent neurologic sequelae occurring in 20 to 50% of neonates. Alternative strategies are therefore urgently needed to prevent this deadly disease.
Neonates get contaminated from colonized mothers by ingestion or inhalation of vaginal secretions during birth. Epidemiological analyses have shown that the clonal complex 17 (CC17), designed hyper-virulent GBS clone, is the major clone responsible for neonatal meningitis cases (70 % to 95%) indicating that this clone has a striking meningeal tropism compared to non-CC17 GBS strains.
The brain is protected against microbial invasion by physiological barriers, such as the Blood-Brain Barrier (BBB) and the Blood-CerebroSpinal Fluid Barrier (BCSFB). GBS must cross these barriers by one or more mechanisms which remain to be specified. Our team has been pioneer in discovering CC17 specific surface proteins. We have characterized two CC17 proteins that act as adhesins, contribute to virulence and favor brain barrier crossing. Nevertheless, the pathogenesis of GBS meningitis remains incompletely understood. The site of entry and the mechanism to reach the brain have not yet been defined and no host cell receptors have yet been identified for these adhesins.
Mechanistic data on how the GBS CC17 clone accesses the central nervous system are still lacking and a holistic view of the pathophysiological process involved is still missed. The StrepB2brain project aims at deciphering, at the cellular and molecular levels how GBS CC17 penetrates the brain by investigating both routes of infection (BBB or BCSFB) and the three putative mechanisms of infection (paracellular, transcellular or Trojan horse mechanisms). To this aim we constituted a very powerful consortium that gathers a cellular microbiologist, a brain barrier specialist, an endothelial cell biologist, an in vivo model specialist and a prediction structure specialist. We will combine our expertise to decipher, in vitro and in vivo, the interactions between CC17-specific surface proteins and the host cell that enable GBS CC17 to cross these barriers. For this, we will use multidisciplinary and highly innovative approaches that are fully mastered by the partners, involving genetics, cell biology, live imaging, in silico structural prediction, and animal models (zebrafish and mouse) in order to identify host cell surface ligands that interact directly or indirectly with GBS CC17 specific components.
Neonatal meningitis is still fatal or causes serious neurological damages. The data from this project will provide a new paradigm for investigating the pathogenesis, prevention and therapy for GBS neonatal bacterial meningitis. The identification of eukaryotic ligands targeted by CC17 GBS involved in BBB/BCSFB crossing should pave the way to the development of new anti-infectious strategies, such as the use of antibodies or antagonists drug blocking cellular receptors, or the identification of biomarkers including specific receptor polymorphism that could be linked to CC17 GBS-meningitis.