Peripheral blood vessels are a niche for blood-borne meningococci

Abstract

Neisseria meningitidis is the causative agent of cerebrospinal meningitis and that of a rapidly progressing fatal septic shock known as purpura fulminans. Meningococcemia is characterized by bacterial adhesion to human endothelial cells of the microvessels. Host specificity has hampered studies on the role of blood vessels colonization in N. meningitidis associated pathogenesis. In this work, using a humanized model of SCID mice allowing the study of bacterial adhesion to human cells in an in vivo context we demonstrate that meningococcal colonization of human blood vessels is a prerequisite to the establishment of sepsis and lethality. To identify the molecular pathways involved in bacterial virulence, we performed transposon insertion site sequencing (Tn-seq) in vivo. Our results demonstrate that 36% of the genes that are important for growth in the blood of mice are dispensable when bacteria colonize human blood vessels, suggesting that human endothelial cells lining the blood vessels are feeding niches for N. meningitidis in vivo. Altogether, our work proposes a new paradigm for meningococcal virulence in which colonization of blood vessels is associated with metabolic adaptation and sustained bacteremia responsible for sepsis and subsequent lethality.

Molecular interactions betweenNeisseria meningitidisand its human host

“…In this model, where vessels of human origin from the graft anastomose to the mice vessels, blood-borne N. meningitidis readily adhere to human endothelial cells. Bacterial-induced vascular damages are very similar to those described in patients, including perivascular infiltrates, thrombosis, and vascular leakage associated with massively infected vessels (Harrison et al, 2002) that ultimately lead to the death of infected grafted animals (Capel et al, 2017). In addition, vascular damages are localised only in vessels colonised by meningococci.…”

“…They reduce colonisation of the human vessels by circulating meningococci and prevent subsequent vascular dysfunctions, intravascular coagulation, and overwhelming inflammation, the hallmarks of invasive meningococcal infections. Finally, in consistence with the role of the vascular niche in promoting sustained bacteraemia leading to mice lethality (Capel et al, ), these compounds reduce bacteraemia and increase mice survival. In association with antibiotics, they reduce vascular inflammatory and thrombotic responses that were shown to be highly detrimental and correlated with the severity of the disease in patients (Girardin, Grau, Dayer, Roux‐Lombard, & Lambert, ; van Deuren et al, ; Waage, Brandtzaeg, Halstensen, Kierulf, & Espevik, ).…”

“…Capel et al showed that adhesion to human skin vessels is a prerequisite for virulence of N . meningitidis and the maintenance of a sustained bacteremia because bacteria unable to adhere to microvessels are rapidly cleared from the bloodstream (Capel et al, ). Altogether, this points out the essential role of microvascular colonisation in meningococcal pathogenesis (Figure b).…”

“…meningitidis may invade the bloodstream where it becomes one of the most harmful extracellular bacterial pathogen. In some cases, meningococcemia will rapidly progress toward a septic shock leading in the worst cases to a purpura fulminans , an acute systemic inflammatory response associated with an intravascular coagulation and tissue necrosis (Bonazzi et al, ; Brandtzaeg & van Deuren, ; Capel et al, ; Lecuyer et al, ; Lecuyer, Borgel, Nassif, & Coureuil, ). Alternatively, N .…”

Meningococcal disease: A paradigm of type‐IV pilus dependent pathogenesis

“…Of most interest, this model also revealed that, in the absence of vascular colonisation, bacteraemia rapidly drops and mice survive to infection, whereas Tfp‐mediated colonisation is associated with sustained bacteraemia and mice lethality. Thus, Tfp‐mediated interaction with vascular wall provides a niche for bacterial replication and constitutes a decisive step in disease progression (Capel et al, ; Denis et al, ). Overall, these studies demonstrated the essential role of Tfp in meningococcal pathogenesis.…”