Meningococcal Infections-on-Chip: Integration of the Tissue Architecture – MeningoChip

Dissemination of pathogenic microorganisms throughout the organism relies on their ability to cross biological barriers. Neisseria meningitidis (Nm) is a human-restricted bacterium responsible for sepsis and meningitis although the bacterium is commonly found as a commensal of the human nasopharynx in a large percentage of the human population. Occasionally, this bacterium engages in a multi-step pathogenic process allowing it to cross several cellular barriers: (i) the nasopharynx epithelium, (ii) the endothelium to reach the blood circulation, (iii) the endothelium constituting the blood-brain barrier to reach the cerebrospinal fluid. The progression of meningococcal diseases therefore relies on the ability of Neisseria meningitidis to sequentially encounter, breach and adapt to particular and specific tissue architectures and microenvironments. The global aim of the present project is thus to decipher the mechanisms that confer this bacterium the ability to undergo this pathogenic sequence by recapitulating both the structure and the function of Nm-target tissues in vitro, in order to investigate the course of meningococcal infections. Today, our understanding of the Nm-infection process relies on either over-simplified in vitro models (2D monolayers of endothelial cells or Transwell) or on a complex in vivo human skin xenograft mouse model because of Nm’s human-species specificity. The recent emergence of new technological approaches including microfluidics and organ-on-chip strategies has permitted the design of advanced in vitro assays such as perfusable 3D microvascular networks on-chip. Accordingly, we here propose to recapitulate both the structure and the function of Nm-target tissues in microfluidic platforms supporting the generation of a polarized epithelia (WP1), a perfusable 3D microvascular networks (WP2) and a functional blood-brain barrier (WP3). These devices will either be used separately or in combination (WP4) providing an integrated in vitro infection model. The two partners of this consortium who work in close proximity possess complementary skills and expertise and have been intensely collaborating for the past two years. This proposal will ultimately represent an important step forward in the understanding of meningococcal pathogenicity and provide a reliable platform for pharmaceutical drug screening. In addition, by developing a tunable integrated platform will allow the easy transfer of the technology to others pathogenic microorganisms, such as Listeria, Plasmodium or Trypanosome, studied in other laboratories.