Dissecting the invasiveness of meningococcal infections

Highly invasive meningococcal infections with serogroup W of clonal type cc11 are rapidly increasing and have a high (16-25%) mortality rate. The aim of this project was to investigate why recent isolates are invasive and how different antibodies can protect. The special focus was on the protection of epithelial cells of the wall of the respiratory tract as prevention of infection may be key to protecting the public against MenW cc11 disease. The project started in 2019 and ran until 2021.

Results

Clinical isolates of different clinical invasiveness were subjected to pangenetic analyses to identify virulence factors. The ability of these isolates to infect epithelial cells was evaluated to compare virulence factors with functional invasiveness. Meningococcal-specific antibody levels in serum and saliva in different age groups with increased carriage and/or risk of meningococcal invasive disease were analysed. The antibodies were evaluated for their ability to protect against infection in two different functional assays: prevention of infection of respiratory epithelial cells and the gold standard serum bactericidal assay that predicts the ability to clear invaded meningococci. Finally, epithelial responses to meningococci and modulation of these responses were investigated. These studies analysed cytokine and chemokine production and the production of antibodies by B cells in epithelial-B cell co-cultures.

Clinical (n=56) and carriage (n=20) meningococcal isolates were investigated for their resistance to killing by antibodies via complement activation and their ability to infect the upper airways of humans. Clinical isolates originated from patients of all ages and with varying clinical symptoms and disease outcomes. 

Clinical isolates were resistant to killing by antibodies from serum from non-vaccinated individuals. Meningococcal isolates from carriage of healthy persons were killed by antibodies from non-vaccinated individuals. When serum antibodies of vaccinated adults were used, all severe clinical isolates were also killed, showing that the menACWY vaccine protects against invasive meningococcal isolates. 

Several isolates were also investigated for their ability to infect the epithelial cells that form the wall of the respiratory tract. Meningococcal bacteria caused stress to the epithelial cells that resulted in a partial loss of the mechanical barrier against infection. The different bacteria varied in their ability to bind to the epithelial cells, a model for the ability of the bacteria to infect humans. This ability to bind to epithelial cells also depended on the human donor the cells were derived from. Epithelial cells recognised the presence of the bacteria and started producing signals (cytokines and chemokines) to activate the immune system. This recognition was similar for all meningococcal isolates investigated.

RIVM colleagues Gerco den Hartog and Guy Berbers were involved in the project.

Funding

This project received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 835433.