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Infection and Immunity, December 2001, p. 7820-7831, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7820-7831.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Dynamic Nature of Host-Pathogen Interactions in Mycobacterium marinum Granulomas

Donna M. Bouley,1 Nafisa Ghori,2,3 K. Lynne Mercer,4,dagger Stanley Falkow,2 and Lalita Ramakrishnan2,*

Department of Comparative Medicine,1 Department of Microbiology and Immunology,2 and the Center for Electron Microscopy,3 Stanford University School of Medicine, Stanford, California 94305, and 5371 Castleford Court, Newark, California 945604

Received 25 June 2001/Returned for modification 27 August 2001/Accepted 16 September 2001

Mycobacterium marinum causes long-term subclinical granulomatous infection in immunocompetent leopard frogs (Rana pipiens). These granulomas, organized collections of activated macrophages, share many morphological features with persistent human tuberculous infection. We examined organs of frogs with chronic M. marinum infection using transmission electron microscopy in conjunction with immunohistochemistry and acid phosphatase cytochemistry to better define the bacterium-host interplay during persistent infection. Bacteria were always found within macrophage phagosomes. These phagosomes were often fused to lysosomes, in sharp contrast to those formed during in vitro infection of J774 macrophage-like cells by M. marinum. The infected macrophages in frog granulomas showed various levels of activation, as evidenced by morphological changes, including epithelioid transformation, recent phagocytic events, phagolysosomal fusion, and disintegration of bacteria. Our results demonstrate that even long-term granulomas are dynamic environments with regard to the level of host cell activation and bacterial turnover and suggest a continuum between constantly replicating bacteria and phagocytic killing that maintains relatively constant bacterial numbers despite an established immune response. Infection with a mutant bacterial strain with a reduced capacity for intracellular replication shifted the balance, leading to a greatly reduced bacterial burden and inflammatory foci that differed from typical granulomas.

* Corresponding author. Present address: Departments of Microbiology and Medicine, University of Washington, Box 357242, Health Sciences Building, 1959 NE Pacific St., Seattle, WA 98195-7242. Phone: (206) 616-4286. Fax: (206) 616-1575. E-mail: lalitar{at}u.washington.edu.

dagger Retired from the Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305.

Infection and Immunity, December 2001, p. 7820-7831, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7820-7831.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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