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Infection and Immunity, March 2002, p. 1501-1506, Vol. 70, No. 3
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.3.1501-1506.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Survival of Tropheryma whipplei, the Agent of Whipple's Disease, Requires Phagosome Acidification

Eric Ghigo,1 Christian Capo,1 Marianne Aurouze,1 Ching-Hsuan Tung,2 Jean-Pierre Gorvel,3 Didier Raoult,1 and Jean-Louis Mege1*

Unité des Rickettsies, CNRS UMR 6020, Université de la Méditerranée, Faculté de Médecine, 13385 Marseille Cedex 5,1 Centre d'Immunologie de Marseille-Luminy, Case 906, 13288 Marseille Cedex 9, France,3 Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts2

Received 31 May 2001/ Returned for modification 15 August 2001/ Accepted 1 November 2001

Tropheryma whipplei was established as the agent of Whipple's disease in 2000, but the mechanisms by which it survives within host cells are still unknown. We show here that T. whipplei survives within HeLa cells by controlling the biogenesis of its phagosome. Indeed, T. whipplei colocalized with lysosome-associated membrane protein 1, a membrane marker of late endosomal and lysosomal compartments, but not with cathepsin D, a lysosomal hydrolase. This defect in phagosome maturation is specific to live organisms, since heat-killed bacilli colocalized with cathepsin D. In addition, T. whipplei survived within HeLa cells by adapting to acidic pH. The vacuoles containing T. whipplei were acidic (pH 4.7 ± 0.3) and acquired vacuolar ATPase, responsible for the acidic pH of late phagosomes. The treatment of HeLa cells with pH-neutralizing reagents, such as ammonium chloride, N-ethylmaleimide, bafilomycin A1, and chloroquine, increased the intravacuolar pH and promoted the killing of T. whipplei. The ability of T. whipplei to survive in an acidic environment and to interfere with phagosome-lysosome fusion is likely critical for its prolonged persistence in host cells during the course of Whipple's disease. Our results suggest that manipulating the intravacuolar pH may provide a new approach for the treatment of Whipple's disease.

* Corresponding author. Mailing address: Unité des Rickettsies, CNRS UMR 6020, Faculté de Médecine, 27 Bd. Jean Moulin, 13385 Marseille Cedex 5, France. Phone: (33) 4 91 32 43 75. Fax: (33) 4 91 38 77 72. E-mail: Jean-Louis.Mege{at}medecine.univ-mrs.fr.

Infection and Immunity, March 2002, p. 1501-1506, Vol. 70, No. 3
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.3.1501-1506.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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