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Infection and Immunity, August 2003, p. 4642-4646, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4642-4646.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Delineation of the Molecular Mechanisms of Francisella tularensis-Induced Apoptosis in Murine Macrophages

Xin-He Lai* and Anders Sjöstedt*

Department of Clinical Microbiology and Clinical Bacteriology, Umeå University, SE-901 85 Umeå, Sweden

Received 13 February 2003/ Returned for modification 15 April 2003/ Accepted 14 May 2003

Francisella tularensis is a facultative intracellular bacterium capable of inducing apoptosis in murine macrophages. Here we analyzed the pathway leading to apoptosis in the murine macrophage-like cell line J774A.1 after infection with F. tularensis strain LVS (named LVS for live vaccine strain). We obtained evidence that the infection affected the mitochondria of the macrophages, since it induced release of the mitochondrial molecule cytochrome c into the cytosol and changed the potential over the mitochondrial membrane. Moreover, activation of caspase 9 and the executioner caspase 3 was also observed in the LVS-infected J774A.1 macrophages. The activated caspase 3 degraded poly(ADP-ribose) polymerase (PARP). All of these events were observed within 9 to 12 h after the initiation of infection, and maximum degradation of a synthetic caspase 3 substrate occurred at 18 h. The internucleosomal fragmentation and PARP degradation resulting from activation of this apoptotic pathway was prevented by the caspase 3 inhibitor Z-DEVD-fmk. No involvement of caspase 1, caspase 8, Bcl-2, or Bid was observed. Thus, the F. tularensis infection induces macrophage apoptosis through a pathway partly resembling the intrinsic apoptotic pathway.

* Corresponding authors. Mailing address: Department of Clinical Microbiology and Clinical Bacteriology, Umeå University, SE-901 85 Umeå, Sweden. Phone: (46) 90 785 1120. Fax: (46) 90 785 2225. E-mail for A. Sjöstedt: anders.sjostedt{at}climi.umu.se. E-mail for X.-H. Lai: xin-he.lai{at}climi.umu.se.

Editor: B. B. Finlay

Infection and Immunity, August 2003, p. 4642-4646, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4642-4646.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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