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Key innate immune components controlling intracellular infection

Promotor: H.P. Spaink, Co-Promotor: A.H. Meijer

E.L. Benard
25 september 2014
Thesis in Leiden Repository

This thesis is focused on the innate immune defence mechanisms responsible for controlling mycobacterial growth after infection. To provide a detailed description of the host’s innate immune response to M. marinum infection, zebrafish gene expression levels were analysed by RNA sequencing at various time points during infection and correlated with imaging data of the process of pathogenesis. We demonstrate that the scavenger receptor Marco (macrophage receptor with collagenous structure) is a key player in the rapid phagocytosis of M. marinum and we use gene expression analysis in combination with gene knockdown studies to show that it is also essential in the establishment of an initial transient pro-inflammatory response to M. marinum infection. Once phagocytosed, M. marinum is capable of avoiding killing mechanisms of the host cell and can continue to grow within macrophages. This is the period when Membrane Attack Complex/Perforin proteins are involved in killing intracellular bacteria by their pore-forming activities. We reveal the regulatory mechanisms and function of two macrophage specific genes, mpeg1 and mpeg1.2 (macrophage expressed gene 1.2). The results from this thesis complement knowledge obtained from other model organisms by providing new insights into both counteracting and supporting mechanisms underlying the innate immune response.

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