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Destabilizing vascular colonization to stop meningitis

Project description

Mechanistic insight into bacterial meningitis

Bacterial meningitis is a serious infection that causes inflammation of the protective membranes covering the brain and spinal cord. It is caused by bacteria such as Neisseria meningitidis and exhibits high mortality rates despite antibiotic treatment. Funded by the European Research Council, the DESTOP project is working under the hypothesis that vascular colonisation by bacteria leads to antibiotic resistance. Researchers will decipher meningitis pathogenesis mechanisms by investigating the processes of bacterial adhesion and membrane deformation, and intravascular coagulation caused by bacteria. Apart from fundamental insight, the work has the potential to lead to novel strategies implicating vascular colonisation for enhancing meningitis treatment.

Objective

Before the antibiotic era chances of survival to bacterial meningitis were minimal. Nevertheless, nearly 100 years later, surprisingly little progress has been made and mortality rates currently remain unacceptably high (10-25%). Supported by clinical and experimental data, the central concept of the Destop project is that bacteria rapidly become insensitive to antibiotics during infection, which leads to treatment failure. We hypothesize that the emergence of such antibiotic insensitivity results from vascular colonization by Neisseria meningitidis i.e. when the bacteria adhere to the surface of the endothelium, proliferate and progressively occlude the vessel lumen. We propose to explore the mechanisms underlying four steps of vascular colonization that potentially alter bacterial sensitivity to antibiotics: (i) bacterial adhesion to the endothelium and auto-aggregation; (ii) colonization dependent changes in bacterial physiology, (iii) bacteria-induced plasma membrane deformation shielding adhering bacteria, and (iv) bacteria-triggered intravascular coagulation. For this, we will develop a multidisciplinary approach that involves: an in vivo humanized mouse model and innovative microfluidic devices - vessel-on-a-chip model and a bacterial confinement chamber. The Destop project will not only provide novel mechanistic insights in the meningitis pathogenesis process and allow to develop novel strategies to combat bacterial meningitis but also have broader impact by providing a better understanding of how tissues, as a context for infections, reduce the efficiency of treatment of numerous other bacterial pathogens.

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Topic(s)

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2022-ADG

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Host institution

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 507 250,00
Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 2 477 250,00

Beneficiaries (2)

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