Abstract

Neisseria meningitidis (meningococcus), is a nasopharyngeal commensal bacterium that sometimes reaches the blood flow, from where it can act as a pathogen causing sepsis, up to purpura fulminans, and/or meningitis, with high morbidity and mortality. Meningococci express type IV pili (T4P) which are essential attributes for the colonisation of human microvessels. This essential step of invasive meningococcal disease leads to endothelial dysfunction with vascular leakage, deregulated inflammation and intravascular coagulation that can lead to multiorgan failure and death. T4P are dynamic filamentous appendages that are also found in other pathogenic bacteria. Meningococcal T4P can retract due to the action of an ATPase, PilT. In a meningococcal infection model using SCID mice grafted with human skin, it was recently shown that retraction is associated with pejorative evolution and lethality. 

Using high throughput transcriptional analysis, we comparatively analysed intrinsic functional response in cerebral and peripheral endothelia during meningococcal infection. We identified angiopoietin-like 4 (ANGPTL4) as a major protective factor for endothelial cells in the course of infection, both in vitro and in murine models of invasive meningococcal infection and endotoxin-induced sepsis. 

With an in vivo transcriptomic approach (Dual-RNAseq) using a human skin-grafted mice infection model, and comparing infection caused by wild type meningococci and a retraction–deficient isogenic strain (∆pilT), we analysed the impact of retraction for both the host and the meningococcus. For the infected host, we show that forces associated with retraction trigger a mechanical stress in endothelial cells, the release of exosomes, cell death and endothelial dysfunction eventually leading to death. In the absence of retraction, infection triggers damage repair and infection tolerance responses in the host, with the release of mediators protective for endothelial cells, such as the PDGFs and ANGPTL4. For the first time, these data demonstrate how T4P-mediated retraction allows a pathogen to manipulate the host tolerance response to infection.

We also show the impact of T4P retraction in the meningococcus with the identification of novel virulence factors expressed under the control of retraction. More specifically, we characterised in vivo and in vitro a novel lipoprotein, NMV_1457, that appears specifically associated with vascular alterations.

Taken together, this work led to the identification of novel bacterial and endothelial factors that play key roles in the severity of meningococcal infections and that constitute new therapeutic approaches in the treatment of infections.