Invasive infection of Nesseria meningitidis can have fatal consequences for the victims, typically healthy young children. The project outlined here aims to enhance the current understanding of N. meningitidis infection by studying the pathogen in a relevant in vivo environment. Study of N. meningitidis has previously been hindered by a lack of appropriate in vivo models. This shortfall is related to the difficulties in emulating N. meningitidis’ infectious niche, the human blood stream. Here we aim to overcome the current limitations through a combination of innovative, multi-disciplinary techniques. The project will use a model in which human skin is grafted onto severe combined immunodeficient (SCID) mice. The human microvessels remain intact after grafting and anastomosis. Advanced intravital imaging techniques will then be used to study, with high spatial and temporal resolution, the progression of N. meningitidis infection in these microvessels. This will provide a unique opportunity to characterize the first stages of N. meningitidis interaction with living human blood vessels. Work will focus on the bacterial aspects of adhesion and invasion as well as physiological responses such as endothelial damage, vascular leakage and the initiation of the immune response. This project will push the boundaries of current N. meningitidis research by giving us a unique insight into the full pathophysiology of in vivo infection in a human vessel. While this project represents a significant advance in the study and understanding of N. meningitidis the results will also be of wide interest to infection biologists, particularly those studying human specific or vascular pathogens. This proposal will provide the fellow with the opportunity to acquire a broad range of skills, both technical and complementary, which are designed to support her career development towards becoming an independent research leader in the field of Infection Biology.
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