This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Wickstrum, J. R.
Right arrow Articles by Parmely, M. J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wickstrum, J. R.
Right arrow Articles by Parmely, M. J.

 Previous Article  |  Next Article 

Infection and Immunity, November 2009, p. 4827-4836, Vol. 77, No. 11
0019-9567/09/$08.00+0     doi:10.1128/IAI.00246-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Francisella tularensis Induces Extensive Caspase-3 Activation and Apoptotic Cell Death in the Tissues of Infected Mice{triangledown}

Jason R. Wickstrum,1,{dagger} Sirosh M. Bokhari,1,{dagger} Jeffrey L. Fischer,1,{dagger} David M. Pinson,2 Hung-Wen Yeh,3 Rebecca T. Horvat,2 and Michael J. Parmely1*

Department of Microbiology, Molecular Genetics, and Immunology,1 Department of Pathology and Laboratory Medicine,2 Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas 661603

Received 3 March 2009/ Returned for modification 15 April 2009/ Accepted 17 August 2009

Although Francisella tularensis subsp. tularensis is known to cause extensive tissue necrosis, the pathogenesis of tissue injury has not been elucidated. To characterize cell death in tularemia, C57BL/6 mice were challenged by the intranasal route with type A F. tularensis, and the pathological changes in infected tissues were characterized over the next 4 days. At 3 days postinfection, well-organized inflammatory infiltrates developed in the spleen and liver following the spread of infection from the lungs. By the next day, extensive cell death, characterized by the presence of pyknotic cells containing double-strand DNA breaks, was apparent throughout these inflammatory foci. Cell death was not mediated by activated caspase-1, as has been reported for cells infected with other Francisella subspecies. Mouse macrophages and dendritic cells that had been stimulated with type A F. tularensis did not release interleukin-18 in vitro, a response that requires the activation of procaspase-1. Dying cells within type A F. tularensis-infected tissues expressed activated caspase-3 but very little activated caspase-1. When caspase-1-deficient mice were challenged with type A F. tularensis, pathological changes, including extensive cell death, were similar to those seen in infected wild-type mice. In contrast, type A F. tularensis-infected caspase-3-deficient mice showed much less death among their F4/80+ spleen cells than did infected wild-type mice, and they retained the ability to express tumor necrosis factor alpha and inducible NO synthase. These findings suggest that type A F. tularensis induces caspase-3-dependent macrophage apoptosis, resulting in the loss of potentially important innate immune responses to the pathogen.

* Corresponding author. Mailing address: Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160. Phone: (913) 588-7053. Fax: (913) 588-7295. E-mail: mparmely{at}kumc.edu

{triangledown} Published ahead of print on 24 August 2009.

Editor: W. A. Petri, Jr.

{dagger} J.R.W., S.M.B., and J.L.F. contributed equally to this study.

Infection and Immunity, November 2009, p. 4827-4836, Vol. 77, No. 11
0019-9567/09/$08.00+0     doi:10.1128/IAI.00246-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»