Role of Proapoptotic BAX in Propagation of Chlamydia muridarum (the Mouse Pneumonitis Strain of Chlamydia trachomatis) and the Host Inflammatory Response

doi:10.1074/jbc.M211275200

Role of Proapoptotic BAX in Propagation of Chlamydia muridarum (the Mouse Pneumonitis Strain of Chlamydia trachomatis) and the Host Inflammatory Response*

From the ^‡Université Paris 7, Institut Pasteur, Unité de Biologie Moléculaire du Gène, INSERM U277, Paris, France, ^**Sacred Heart Medical Center, Department of Laboratory Medicine, Spokane, Washington 99220,^‡Howard Hughes Medical Institute, Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and the ^§§Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Abstract

The BCL-2 family member BAX plays a critical role in regulating apoptosis. Surprisingly, bax-deficient mice display limited phenotypic abnormalities. Here we investigate the effect of BAX on infection by the sexually transmitted pathogen,Chlamydia muridarum (the mouse pneumonitis strain ofChlamydia trachomatis). Bax ^−/−cells are relatively resistant to Chlamydia-induced apoptosis, and fewer bacteria are recovered after two infection cycles from Bax ^−/− cells than from wild-type cells. These results suggest that BAX-dependent apoptosis may be used to initiate a new round of infection, most likely by releasingChlamydia-containing apoptotic bodies from infected cells that could be internalized by neighboring uninfected cells. Nonetheless, infected Bax ^−/− cells die through necrosis, which is normally associated with inflammation, more often than infected wild-type cells. These studies were confirmed in mice infected intravaginally with C. muridarum; since the infection disappears more quickly from Bax ^−/−mice than from wild-type mice, secretion of proinflammatory cytokines is increased in Bax ^−/− mice, and large granulomas are present in the genital tract ofBax ^−/− mice. Taken together, these data suggest that chlamydia-induced apoptosis via BAX contributes to bacterial propagation and decreases inflammation. Baxdeficiency results in lower infection and an increased inflammatory cytokine response associated with more severe pathology.

Footnotes

↵* This work was supported by the Institut Pasteur (PTR 60), INSERM, Université Paris 7, National Institutes of Health Grant AI054624, and the Bates-Wheeler Foundations, Arkansas Children's Hospital Research Institute.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵§ Supported by a fellowship from the Fondation pour la Recherche Médicale.
↵¶ These two authors share senior authorship.
↵‖ To whom correspondence should be addressed: Institut Jacques Monod, Universite Paris 7, 2 place Jussieu, Tour 43, 75251 Paris cedex 05, France. Fax: 33-1-44275265; E-mail: ojcius@noos.fr.
Published, JBC Papers in Press, December 31, 2002, DOI 10.1074/jbc.M211275200
Abbreviations:

MoPn

C. trachomatis mouse pneumonitis strain

EB

elementary body

IL

interleukin

TNF

tumor necrosis factor

PS

phosphatidylserine

PI

propidium iodide

PMN

polymorphonuclear neutrophils

IFN

interferon
- Received November 4, 2002.
- Revision received December 31, 2002.
The American Society for Biochemistry and Molecular Biology, Inc.