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Abstract
Neisseria meningitidis (meningococcus) is an invasive bacterial pathogen that colonizes human vessels, causing thrombotic lesions and meningitis. Establishment of tight interactions with endothelial cells is crucial for meningococci to resist haemodynamic forces. Two endothelial receptors, CD147 and the β2-adrenergic receptor (β2AR), are sequentially engaged by meningococci to adhere and promote signalling events leading to vascular colonization, but their spatiotemporal coordination is unknown. Here we report that CD147 and β2AR form constitutive hetero-oligomeric complexes. The scaffolding protein α-actinin-4 directly binds to the cytosolic tail of CD147 and governs the assembly of CD147–β2AR complexes in highly ordered clusters at bacterial adhesion sites. This multimolecular assembly process increases the binding strength of meningococci to endothelial cells under shear stress, and creates molecular platforms for the elongation of membrane protrusions surrounding adherent bacteria. Thus, the specific organization of cellular receptors has major impacts on host–pathogen interaction.
Highlights
Neisseria meningitidis is an invasive bacterial pathogen that colonizes human vessels, causing thrombotic lesions and meningitis
Because CD147-dependent adhesion and b2-adrenergic receptor (b2AR) activation occur consecutively and in a short time frame, we investigated whether these receptors might be associated in a complex independently of meningococcal infection
The relative cellular distribution of endogenous CD147 and b2AR fused to the yellow fluorescent protein (b2AR-YFP) was analysed in human bone marrow endothelial cells (HBMECs)[17]
Summary
Neisseria meningitidis (meningococcus) is an invasive bacterial pathogen that colonizes human vessels, causing thrombotic lesions and meningitis. The scaffolding protein a-actinin-4 directly binds to the cytosolic tail of CD147 and governs the assembly of CD147–b2AR complexes in highly ordered clusters at bacterial adhesion sites This multimolecular assembly process increases the binding strength of meningococci to endothelial cells under shear stress, and creates molecular platforms for the elongation of membrane protrusions surrounding adherent bacteria. Meningococcal dissemination through the blood stream relies on the capacity of these bacteria to interact with microvessels and proliferate on the endothelial cell surface to form bacterial aggregates[4] This vascular colonization precedes dissemination into tissues, including meninges, and promotes deregulated inflammation and coagulation, leading to extensive necrotic purpura in the most severe cases. The intimate interaction of meningococcus with endothelial cells, which is essential for vascular colonization, is a pre-requisite for vascular dysfunction[16]
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