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Mycobacterium marinum infection of adult zebrafish causes caseating granulomatous tuberculosis and is moderated by adaptive immunity.

ABSTRACT: The zebrafish, a genetically tractable model vertebrate, is naturally susceptible to tuberculosis caused by Mycobacterium marinum, a close genetic relative of the causative agent of human tuberculosis, Mycobacterium tuberculosis. We previously developed a zebrafish embryo-M. marinum infection model to study host-pathogen interactions in the context of innate immunity. Here, we have constructed a flowthrough fish facility for the large-scale longitudinal study of M. marinum-induced tuberculosis in adult zebrafish where both innate and adaptive immunity are operant. We find that zebrafish are exquisitely susceptible to M. marinum strain M. Intraperitoneal injection of five organisms produces persistent granulomatous tuberculosis, while the injection of approximately 9,000 organisms leads to acute, fulminant disease. Bacterial burden, extent of disease, pathology, and host mortality progress in a time- and dose-dependent fashion. Zebrafish tuberculous granulomas undergo caseous necrosis, similar to human tuberculous granulomas. In contrast to mammalian tuberculous granulomas, zebrafish lesions contain few lymphocytes, calling into question the role of adaptive immunity in fish tuberculosis. However, like rag1 mutant mice infected with M. tuberculosis, we find that rag1 mutant zebrafish are hypersusceptible to M. marinum infection, demonstrating that the control of fish tuberculosis is dependent on adaptive immunity. We confirm the previous finding that M. marinum DeltaRD1 mutants are attenuated in adult zebrafish and extend this finding to show that DeltaRD1 predominantly produces nonnecrotizing, loose macrophage aggregates. This observation suggests that the macrophage aggregation defect associated with DeltaRD1 attenuation in zebrafish embryos is ongoing during adult infection.

SUBMITTER: Swaim LE

PROVIDER: S-EPMC1695491 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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Mycobacterium marinum infection of adult zebrafish causes caseating granulomatous tuberculosis and is moderated by adaptive immunity.

Swaim Laura E LE Connolly Lynn E LE Volkman Hannah E HE Humbert Olivier O Born Donald E DE Ramakrishnan Lalita L

Infection and immunity 20061101 11

The zebrafish, a genetically tractable model vertebrate, is naturally susceptible to tuberculosis caused by Mycobacterium marinum, a close genetic relative of the causative agent of human tuberculosis, Mycobacterium tuberculosis. We previously developed a zebrafish embryo-M. marinum infection model to study host-pathogen interactions in the context of innate immunity. Here, we have constructed a flowthrough fish facility for the large-scale longitudinal study of M. marinum-induced tuberculosis i ...[more]

PMID: 17057088

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Project description:Novel high-throughput deep sequencing technology has dramatically changed the way that the functional complexity of transcriptomes can be studied. Here we report on the first use of this technology to gain insight into the wide range of transcriptional alterations that are associated with an infectious disease process. Using Solexa/IlluminaM-bM-^@M-^Ys digital gene expression (DGE) system, a tag-based transcriptome sequencing method, we investigated mycobacterium-induced transcriptome changes in a model vertebrate species, the zebrafish. Our DGE data substantiate recent RNA-seq results from other models indicating a much larger extent of genome transcription than previously thought, and demonstrate that the host response to bacterial infection adds a further degree of complexity to the transcriptome. We obtained a sequencing depth of over 5 million tags per sample with strong correlation between replicates. Tag mapping indicated that mycobacterium-infected adult zebrafish express over 70% of all genes represented in transcript databases. Comparison of our DGE data with a previous multiplatform microarray analysis showed that both types of technologies identified regulation of similar functional groups of genes, more specifically the up-regulation of different classes of immune response genes concomitant with a broad down-regulation of metabolic genes. However, the unbiased nature of DGE analysis provided insights that microarray analysis could not have achieved. As demonstrated here, DGE data are useful for the verification of predicted gene models and allowed us to detect mycobacterium-regulated switching between different transcript isoforms. Moreover, genomic mapping of infection-induced DGE tags revealed novel transcript forms for which any previous EST-based evidence of expression was lacking. Adult male zebrafish were infected by intraperitoneal inoculation with approximately 1x 10-3 M. marinum bacteria. All four infected fish were sacrificed when they showed overt signs of fish tuberculosis, including lethargy, skin ulcers and extensive granuloma formation in organs such as liver and kidney. Histological examination of fish from the same experiments confirmed that the pathology of infected fish corresponded to fish tuberculosis and that no characteristics of the disease were present in the control fish. For DGE analysis RNA samples from the four control adult zebrafish (c1,c2,c3,c4) were pooled, and RNA samples from the four M.marinum-infected adult zebrafish (i1,i2,i3,i4) were pooled. Before pooling the individual RNA samples had been checked by microarray analysis for correlation between biological replicates.

Dataset Information

Mycobacterium marinum infection of adult zebrafish causes caseating granulomatous tuberculosis and is moderated by adaptive immunity.

Publications

Mycobacterium marinum infection of adult zebrafish causes caseating granulomatous tuberculosis and is moderated by adaptive immunity.

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