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Infection and Immunity, November 2006, p. 6108-6117, Vol. 74, No. 11
0019-9567/06/$08.00+0     doi:10.1128/IAI.00887-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mycobacterium marinum Infection of Adult Zebrafish Causes Caseating Granulomatous Tuberculosis and Is Moderated by Adaptive Immunity

Laura E. Swaim,^1, Lynn E. Connolly,^2,* Hannah E. Volkman,³ Olivier Humbert,^1, Donald E. Born,⁴ and Lalita Ramakrishnan^1,2,5

Departments of Microbiology,¹ Medicine,² Immunology,⁵ Pathology,⁴ Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington 98195³

Received 5 June 2006/ Returned for modification 6 July 2006/ Accepted 31 July 2006

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 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 RD1 mutants are attenuated in adult zebrafish and extend this finding to show that RD1 predominantly produces nonnecrotizing, loose macrophage aggregates. This observation suggests that the macrophage aggregation defect associated with RD1 attenuation in zebrafish embryos is ongoing during adult infection.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: J. L. Flynn

L.E.S. and L.E.C. contributed equally to this work.

Present address: Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195.

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