Mycobacterium tuberculosis (Mtb) is still the most deadly bacterial pathogen worldwide. The World Health Organization estimates that one third of the world population is infected with tuberculosis (TB), mostly in a latent form, where mycobacteria can persist for many years inside macrophages that form specialized host structures called granulomas. The burden of TB is further exacerbated by the widespread emergence of multi-drug resistant and extensively drug-resistant strains. The main goal of the proposed project is to use the well-characterized zebrafish embryo model for tuberculosis to increase understanding of host genes involved in susceptibility and resistance to mycobacterial infection. The zebrafish embryo model has specific advantages for studying host-pathogen interaction during infection with Mycobacterium marinum (Mm), a natural pathogen of fish, which is the closest genetic relative of Mtb. Mm infection of zebrafish causes “fish tuberculosis”, a disease that manifests itself similarly to human TB, including the formation of granulomas. This project is based on the previous unique transcriptome data of the host lab giving insights into host macrophage expression profiles and knowledge of host gene expression alterations during bacterial infections in zebrafish. Harvesting from these data, candidate genes will be selected that are both macrophage-specific and transcriptionally induced or repressed during infection, and these genes will be used to perform a morpholino knockdown screen. The functional studies will take advantage of the possibility of high resolution imaging in the optically transparent zebrafish embryos to unravel which step of the host-pathogen interaction is affected by the gene knockdown. Due to the availability of the highly-specific and unique expression data for pre-selecting candidate genes, this reverse genetics screening approach has a high likelihood of hitting genes that play a role in mycobacterial pathogenesis.
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