The Blood brain barrier: from bacterial meningitis to drug delivery into the CNS – NEMBRAIN

The blood-brain barrier (BBB) is the specialized system of brain microvascular endothelial cells that shields the brain from toxic substances in the blood, supplies brain tissues with nutrients, and filters harmful compounds from the brain back to the bloodstream. The unique barrier properties of the cerebral microvessels rely on their complex organisation in interaction with other components of the neurovascular unit (NVU components: astrocytes, pericytes, neurons, and basement membrane), a pre-requisite to ensure proper function of the central nervous system (CNS). Transport across the BBB is strictly limited through both physical (tight junctions) and metabolic barriers (enzymes, diverse transport systems)1. As a result of restricted permeability, only 2% of small drugs and negligible amounts of larger therapeutic compounds in clinical use get access to the brain. Although advances in deciphering properties of the neurovascular unit components have been made in the past years, our limited knowledge of the functional interplay between these components and the lack of suitable models of human BBB clearly contribute to the major difficulties currently encountered in designing efficient drug-based treatments in brain diseases, including some with a paramount socio-economic impact (stroke, Alzheimer’s disease, epilepsy, multiple sclerosis).

Among the microorganisms that are pathogenic to humans and capable of invading the bloodstream, only a few have gained the ability to colonize human brain tissues after crossing the BBB. Among those Neisseria meningitidis (Nm or meningococcus) is the one that achieves this task most frequently and efficiently. This bacterium has selected efficient strategies to modulate and subvert fundamental properties of the BBB to colonize the brain with a minimal loss of BBB integrity. As such, this microorganism might represent a powerful tool to probe for complex pathways that are involved in the control of BBB homeostasis and to identify novel strategies for the delivery of therapeutic compounds to the brain.

Our goal here is therefore to conduct a comprehensive study of the mechanisms by which N. meningitidis modifies BBB properties to get access to the CNS. This project is based on recent developments that have allowed us to precise some of the key events of meningococcal interaction with brain endothelial cells and on the use of a novel in vitro model of human BBB and of an original in vivo model of humanized BBB into a mouse brain that we are currently engineering. Taking advantage of this knowledge, our ultimate objective is to design regulated, transient – and thus safe - strategies for drug delivery into the brain.

To achieve this objective, we will:

i) Elucidate the intricate network of interactions and associated signalling pathways selected by N. meningitidis to colonize brain vasculature and modify BBB permeability, with the objective to identify mimicking strategies for drug delivery across the BBB;
ii) Taking advantage of the newly developed in vitro and in vivo models of human BBB, demonstrate that a chimeric molecule encompassing meningococcal pilus components responsible for the opening of the BBB can constitute the basis of a cargo moiety for drug delivery across the BBB.


This collaborative project will be conducted by teams highly recognized for their complementary expertise in the physiology and pathophysiology of the cerebral vasculature and receptor pharmacology (Sandrine Bourdoulous & Stefano Marullo, Institut Cochin, Paris) and in microbiology (Xavier Nassif, Necker, Paris), providing a unique opportunity to combine their expertise to develop novel tools and approaches to address a major human healthcare issue.