Transcriptomic Approaches in the Zebrafish Model for Tuberculosis-Insights Into Host- and Pathogen-specific Determinants of the Innate Immune Response.

Abstract

Mycobacterium marinum infection in zebrafish has become a well-established model of tuberculosis. Both embryonic and adult zebrafish infection studies have contributed to our knowledge of the development and function of tuberculous granulomas, which are typical of mycobacterial pathogenesis. In this review we discuss how transcriptome profiling studies have helped to characterize this infection process. We illustrate this using new RNA sequencing (RNA-Seq) data that reveals three main phases in the host response to M. marinum during the early stages of granuloma development in zebrafish embryos and larvae. The early phase shows induction of complement and transcription factors, followed by a relatively minor induction of pro-inflammatory cytokines within hours following phagocytosis of M. marinum. A minimal response is observed in the mid-phase, between 6 hours and 1day post infection, when the tissue dissemination of M. marinum begins. During subsequent larval development the granulomas expand and a late-phase response is apparent, which is characterized by progressively increasing induction of complement, transcription factors, pro-inflammatory cytokines, matrix metalloproteinases, and other defense and inflammation-related gene groups. This late-phase response shares common components with the strong and acute host transcriptome response that has previously been reported for Salmonella typhimurium infection in zebrafish embryos. In contrast, the early/mid-phase response to M. marinum infection, characterized by suppressed pro-inflammatory signaling, is strikingly different from the acute response to S. typhimurium infection. Furthermore, M. marinum infection shows a collective and strongly fluctuating regulation of lipoproteins, while S. typhimurium infection has pronounced effects on amino acid metabolism and glycolysis.