Abstract
Neisseria meningitidis (the meningococcus) remains a major cause of bacterial meningitis and fatal sepsis. This commensal bacterium of the human nasopharynx can cause invasive diseases when it leaves its niche and reaches the bloodstream. Blood-borne meningococci have the ability to adhere to human endothelial cells and rapidly colonize microvessels. This crucial step enables dissemination into tissues and promotes deregulated inflammation and coagulation, leading to extensive necrotic purpura in the most severe cases. Adhesion to blood vessels relies on type IV pili (TFP). These long filamentous structures are highly dynamic as they can rapidly elongate and retract by the antagonistic action of two ATPases, PilF and PilT. However, the consequences of TFP dynamics on the pathophysiology and the outcome of meningococcal sepsis in vivo have been poorly studied. Here, we show that human graft microvessels are replicative niches for meningococci, that seed the bloodstream and promote sustained bacteremia and lethality in a humanized mouse model. Intriguingly, although pilus-retraction deficient N. meningitidis strain (ΔpilT) efficiently colonizes human graft tissue, this mutant did not promote sustained bacteremia nor induce mouse lethality. This effect was not due to a decreased inflammatory response, nor defects in bacterial clearance by the innate immune system. Rather, TFP-retraction was necessary to promote the release of TFP-dependent contacts between bacteria and, in turn, the detachment from colonized microvessels. The resulting sustained bacteremia was directly correlated with lethality. Altogether, these results demonstrate that pilus retraction plays a key role in the occurrence and outcome of meningococcal sepsis by supporting sustained bacteremia. These findings open new perspectives on the role of circulating bacteria in the pathological alterations leading to lethal sepsis.
Highlights
IntroductionNeisseria meningitidis (the meningococcus) is a Gram-negative extracellular bacterium whose ecological niche is the human nasopharynx [1]
Neisseria meningitidis is a Gram-negative extracellular bacterium whose ecological niche is the human nasopharynx [1]
We show that human skin graft microvessels are replicative niches for N. meningitidis that promote sustained bacteremia and subsequent lethality
Summary
Neisseria meningitidis (the meningococcus) is a Gram-negative extracellular bacterium whose ecological niche is the human nasopharynx [1]. N. meningitidis is responsible for invasive meningococcal diseases (IMD). A central step in the pathophysiology of meningococcal infections is the extensive adhesion of meningococci to the endothelium in a process referred to as vascular colonization [4,5,6,7]. This colonization induces thrombotic events, deregulated inflammation and a leakage syndrome [6,8,9] leading to the development of purpura fulminans in the most severe forms [10]. Vascular colonization is still present in the rare forms of chronic meningococcemia [17,18]
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