Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood-brain barrier

doi:10.1084/jem.20060482

Published online 24 July 2006 doi:10.1084/jem.20060482
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 8, 1939-1950

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Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood–brain barrier

Emilie Mairey¹^,3, Auguste Genovesio⁴^,5, Emmanuel Donnadieu⁶^,7, Christine Bernard¹^,3, Francis Jaubert², Elisabeth Pinard⁸^,9, Jacques Seylaz⁸^,9, Jean-Christophe Olivo-Marin⁴^,5, Xavier Nassif¹^,2^,3, and Guillaume Duménil¹^,3

¹ Institut National de la Santé et de la Recherche Médicale (INSERM), U570 and ² AP-HP, Hôpital Necker-Enfants Malades, Paris, F-75015 France
³ Université Paris Descartes, Faculté de Médecine René Descartes, UMR-S570, Paris, F-75006 France
⁴ Centre National de la Recherche Scientifique, URA2582 and ⁵ Institut Pasteur, Quantitative Image Analysis Unit, Paris, F-75724 France
⁶ INSERM, U567 and ⁷ Institut Cochin, Département de biologie cellulaire, Paris, F-75014 France
⁸ INSERM, U689 and ⁹ Université Denis Diderot, Faculté de médecine Lariboisière-St. Louis, Paris, F-75010 France

CORRESPONDENCE Guillaume Duménil: dumenil{at}necker.fr

Neisseria meningitidis is a commensal bacterium of the humannasopharynx. Occasionally, this bacterium reaches the bloodstreamand causes meningitis after crossing the blood–brain barrierby an unknown mechanism. An immunohistological study of a meningococcalsepsis case revealed that neisserial adhesion was restrictedto capillaries located in low blood flow regions in the infectedorgans. This study led to the hypothesis that drag forces encounteredby the meningococcus in the bloodstream determine its attachmentsite in vessels. We therefore investigated the ability of N.meningitidis to bind to endothelial cells in the presence ofliquid flow mimicking the bloodstream with a laminar flow chamber.Strikingly, average blood flows reported for various organsstrongly inhibited initial adhesion. As cerebral microcirculationis known to be highly heterogeneous, cerebral blood velocitywas investigated at the level of individual vessels using intravitalimaging of rat brain. In agreement with the histological study,shear stress levels compatible with meningococcal adhesion wereonly observed in capillaries, which exhibited transient reductionsin flow. The flow chamber assay revealed that, after initialattachment, bacteria resisted high blood velocities and evenmultiplied, forming microcolonies resembling those observedin the septicemia case. These results argue that the combinedmechanical properties of neisserial adhesion and blood microcirculationtarget meningococci to transiently underperfused cerebral capillariesand thus determine disease development.

Abbreviations used: BBB, blood–brain barrier; DIC, disseminatedintravascular coagulation; FMS, fulminant meningococcal sepsis;HUVEC, human umbilical vein endothelial cell; Tfp, type IV pili.

A. Genovesio's present address is Institut Pasteur Korea, Seongbuk-gu,136-791 Seoul, South Korea.

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