PCV - Programme interdiciplinaire en physique et chimie du vivant

Infections de la circulation sanguine : nouveaux modèles expérimentaux intégrant leur environnement mécanique spécifique – BUGS-IN-FLOW

Submission summary

Infectious diseases leading to colonization of the blood by the infectious agent are a major burden to society. Such infections lead to a wide array of devastating clinical manifestations including septic chocks, hemorrhagic syndromes and infection of the brain (meningitis). Pathogens triggering such diseases are diverse and include viruses, bacteria, parasites and fungi. The common characteristic of these pathogens is their incursion in the bloodstream at a given point of the infection process. This is a determining event, which marks a break out in the disease development. Advances in our understanding of these diseases and the development of innovative treatment crucially requires to improve existing knowledge of this particular stage of infection. Yet, up to now progresses in this question has been hampered by the lack of relevant model enabling investigations in the dynamic conditions of the blood stream. This is partly due to the fact that host pathogen interactions are often species specific preventing the use of animal models. Our analysis is that new technical and methodological approaches are now needed to create relevant in vitro experimental models to investigate infectious development in the human blood stream. The specific technical challenges raised here will not be met without a multidisciplinary approach at physics and biology interfaces. We thus propose to gather skills and technologies developed in vascular biology, colloid science and microfluidics to to provide a panel of innovative tools to study the interaction of pathogens with blood vessels in conditions mimicking those found in the context of the disease. The Gram-negative bacterium Neisseria meningitidis will be used here as a paradigm of a pathogen causing septic chock and meningitis. The short-term goal is to take advantage of these new tools to gain insight into the disease process but creating experimental models closely mimicking key steps of the disease process will also provide the means to directly test different strategies to block disease progression. From the experimental point of view, the presence of the bacteria in the blood has several implications and challenges. First, a complex array of interactions takes place with immune cells in the blood and also with endothelial cells lining the vessel lumen. Another important implication is that such pathogens are exposed to the mechanical forces exerted by the blood flow, which follows a complex pattern throughout the different types of vessels. This specific environment implies an adaptation of the pathogens, which determines disease development. The importance of shear force encountered in the blood is illustrated by several examples both in normal processes and in the context of infection. A third implication is the particular geometry of the vascular beds, which display diameters as low as 5 µm. The global experimental strategy of this project is to mimic the infection process in the context of blood vessels by progressively introducing biological complexity going from in vitro cell culture to in vivo infection. (i) The first step is to define the effect of blood flow on bacteria and bacterial aggregates in the absence of cells; (ii) second, bacterial infection will be studied in the context of flow chambers mimicking the geometry and particular blood flow conditions found in capillaries; (iii) third, introduce blood vessels as tissue in study and; (iv) fourth, to take advantage of a skin graft model to study the infection in the context of an animal model. A multidisciplinary approach is unavoidable to carry out this project.

Project coordination

Guillaume DUMENIL (Organisme de recherche)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSTITUT CURIE - SECTION DE RECHERCHE

Help of the ANR 320,000 euros
Beginning and duration of the scientific project: - 36 Months

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