Abstract

Neisseria meningitidis is a commensal bacterium of the human nasopharynx. However, when this bacterium reaches the bloodstream, it is responsible for severe infections (septicemia, meningitis, and purpura fulminans) associated with high morbidity and mortality rates despite the early initiation of antibiotic treatment. The core of meningococcal pathogenesis lies in its ability to adhere to the endothelium via filamentous structures known as type IV pili. This interaction is responsible for the endothelial dysfunction observed during infection, characterized by dysregulated inflammation, vascular leakage, and intravascular coagulation. Endothelial dysfunction can progress to organ failure and death. In addition to type IV pili, N. meningitidis is equipped with factors involved in its survival and virulence, including surface lipoproteins. Surface lipoproteins of N. meningitidis are of particular interest for the development of new vaccines, especially against serogroup B.

A hypothetical surface lipoprotein unique to the Neisseria genus had previously been characterized as a vaccine candidate, without its biological function being investigated. Therefore, characterizing the function of this protein during invasive meningococcal infections was the focus of this thesis.

We confirmed the conservation and uniqueness of this protein sequence within the Neisseria genus. We also confirmed that this protein possesses all the specific characteristics of surface lipoproteins. Unlike other surface lipoproteins characterized in N. meningitidis, this lipoprotein is not involved in bacterial growth and morphology, host colonization, or survival in the bloodstream. In contrast, using both in vitro and in vivo approaches, we demonstrated that deletion of this lipoprotein reduces endothelial dysfunction, including thrombosis, organ failure, and sepsis-associated mortality, without affecting bacteremia or systemic inflammation. Conversely, overexpression of this lipoprotein tended to increase endothelial dysfunction and accelerate mortality. We therefore named this surface lipoprotein “Vascular Dysfunction Potentiator” (VDP).

Using a proximity biotinylation approach, we investigated potential cellular receptors that might interact with VDP. This approach enabled us to identify three potential receptors (CRIM1, MCAM, and ITGB1), whose contribution to invasive meningococcal infections has never been characterized. Finally, our results suggest that VDP expression may be regulated in vivo by type IV pilus retraction.

This thesis work led to the characterization of VDP, a novel surface lipoprotein of N. meningitidis, and demonstrated its involvement in endothelial dysfunction independently of any role in bacterial survival or systemic inflammation. These findings pave the way for the identification of new therapeutic targets aimed at limiting the severity of meningococcal infections.

Keywords: Neisseria meningitidis, surface lipoprotein, endothelial dysfunction