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    Pull the string, the latch will open…

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    Study directed by Stéfano Marullo, published in Nature Communications

    Pull the string, the latch will open…

    This sentence, taken from a famous tale (Little Red Riding Hood, by Charles Perrault), summarizes a recent discovery of a group of researchers from the University of Paris, working at the Institut Cochin (Marullo team) and the Institut Necker, interested in the molecular mechanisms used by meningococcus to interact with and activate receptors carried by the endothelial cells lining the vessels.

     

    Meningococcus is a Gram-negative bacterium that causes cerebrospinal meningitis, a serious infection of the brain envelope that can be associated with an often deadly septic shock known as "purpura fulminans". This pathogen is characterized by particular, filiform organelles, called pili, which allow it to interact with endothelial cells.


    After several years of research, it could be established that meningococcus was interacting successively with two receptors. The first, called CD147, is a receptor for the early adhesion of the bacterium to endothelial cells, the second is a receptor receptor for adrenalin, known as the β2-adrenergic receptor. Cellular signals following meningococcal binding to this receptor are required for the stabilization of bacterial colonies at the surface of endothelial cells and for subsequent tissue infection. The β2-adrenergic eceptor is a sensor for chemical molecules (adrenalin, in particular) that bind into a a special pocket inside the receptor triggering its activation. The current study shows that the meningococcus activates this same receptor by exerting traction forces on it. The receptor-activating force is generated by both a small molecular engine located at the base of the bacterial pili and by the force generated by blood flow that “pushes” the bacteria adhering to vessel walls. Interestingly, pili do not interact with the protein framework of the receptor, as it would have been expected, but with sugars branched to the N-terminal region of the receptor: two glycan chains placed at a particular distance and terminated by a sialic acid. TA receptor of the same family as the β2-adrenergic receptor, but which is not usually activated by the meningococcus becomes competent for activation upon insertion of these glycan chains in the receptor N-terminus by genetic engineering. The cherry on the cake, is that this discovery also explains the species specificity of meningococcus that only infects humans. Indeed, human sialic acid differs from that of other animals because of the evolutionary loss of an enzyme about 3 million years ago. This loss, probably selected because it ptovides some resistance to a parasite, has made the human species susceptible to meningococcus, which has adapted to it specifically. Fortunately, the relative rarity of meningococcal infection explains its low impact on the development of our species.

     

     Legend: The β2-adrenergic receptor (β2AR) is both a chemo-sensor and a mechano-sensor. It is stimulated by catecholamines that bind to a receptor pocket and trigger a conformational change that activates the Gs protein and then recruits the β-arrestins (β-arr). These two events induce distinct cellular signals. The pathogen (right) binds to the sugars of the receptor. It thus applies to the receptor a pulling force that induces another mode of activation of the receptor: recruiting the β-arrestins without activating the G protein. 

     

     

     

    This new information opens new therapeutic perspectives to fight meningococcal infection, and also avenues of research on mechanisms and physiological effects of the mechanical activation of this family of receptors.

     

    Reference

    Sialic acid mediated mechanical activation of β2 adrenergic receptors by bacterial pili. Virion Z, Doly S, Saha K, Lambert M, Guillonneau F, Bied C, Duke RM, Rudd PM, Robbe-Masselot C, Nassif X, Coureuil M, Marullo S.  Nat Commun. 2019, Oct 18;10(1):4752.

     

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