The Human Pathogen Mycobacterium tuberculosis and the Fish Pathogen Mycobacterium marinum Trigger a Core Set of Late Innate Immune Response Genes in Zebrafish Larvae

Zebrafish is a natural host of various <i>Mycobacterium</i> species and a surrogate model organism for tuberculosis research. <i>Mycobacterium marinum</i> is evolutionarily one of the closest non-tuberculous species related to <i>M. tuberculosis</i> and shares the majority of virulence genes. Although zebrafish is not a natural host of the human pathogen, we have previously demonstrated successful robotic infection of zebrafish embryos with <i>M. tuberculosis</i> and performed drug treatment of the infected larvae. In the present study, we examined for how long <i>M. tuberculosis</i> can be propagated in zebrafish larvae and tested a time series of infected larvae to study the transcriptional response via Illumina RNA deep sequencing (RNAseq). Bacterial aggregates carrying fluorescently labeled <i>M. tuberculosis</i> could be detected up to 9 days post-infection. The infected larvae showed a clear and specific transcriptional immune response with a high similarity to the inflammatory response of zebrafish larvae infected with the surrogate species <i>M. marinum</i>. We conclude that <i>M. tuberculosis</i> can be propagated in zebrafish larvae for at least one week after infection and provide further evidence that <i>M. marinum</i> is a good surrogate model for <i>M. tuberculosis</i>. The generated extensive transcriptome data sets will be of great use to add translational value to zebrafish as a model for infection of tuberculosis using the <i>M. marinum</i> infection system. In addition, we identify new marker genes such as <i>dusp8</i> and CD180 that are induced by <i>M. tuberculosis</i> infection in zebrafish and in human macrophages at later stages of infection that can be further investigated.