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Common mechanisms of host membrane trafficking subversion by intracellular pathogens to rupture bacterial containing vacuoles

Objective

A common strategy of bacterial pathogens is active or passive uptake into host cells. There, they can localize within a bacterial containing vacuole (BCV) or access the host cytoplasm through BCV rupture. Hence, intracellular pathogens are often classified as vacuole-bound or cytoplasmic. Recently, this definition has been challenged by the discovery that many vacuole-bound pathogens, including Mycobacterium tuberculosis and Salmonella enterica, access the host cytoplasm, and by the insight that cytoplasmic bacteria, like Shigella flexneri or Listeria monocytogenes, do not always escape the BCV. Despite this increasing complexity, a precise understanding lacks for why and how a pathogen “chooses” between a BCV or the cytoplasm and yet this is very important: because of differential pathogen sensing in membrane-bound and cytoplasmic compartments, intracellular localization leads to induction of different host responses. Therefore, a comprehensive understanding of the processes controlling BCV integrity is not only essential, but can provide new therapeutic targets. Our previous research has implemented innovative fluorescence microscopy to track the invasion steps of pathogenic bacteria. We have further integrated a large-volume, correlative, light/electron microscopy (CLEM) workflow via focused ion beam scanning electron microscopy. This uncovered the subversion of host Rab cascades by Shigella to rupture its BCV. Starting with the Shigella model of epithelial cell invasion, we will delineate the precise molecular mechanisms controlling BCV integrity in different host cell types. We will analyze (i) the scaffolds of host pathways for membrane remodeling, (ii) their subversion by various pathogens, and (iii) their differential regulation depending on pathophysiological conditions. Together, this will allow development of novel, rational antimicrobial strategies and will yield fundamental insight into understudied cell biological mechanisms of membrane trafficking.

Fields of science (EuroSciVoc)

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Programme(s)

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Topic(s)

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Funding Scheme

Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.

ERC-COG - Consolidator Grant

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Call for proposal

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(opens in new window) ERC-2015-CoG

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Host institution

INSTITUT PASTEUR
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.

€ 2 000 000,00
Address
RUE DU DOCTEUR ROUX 25-28
75724 Paris
France

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Region
Ile-de-France Ile-de-France Hauts-de-Seine
Activity type
Research Organisations
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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.

€ 2 000 000,00

Beneficiaries (1)

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