Survival of Tropheryma whipplei, the agent of Whipple's disease, requires phagosome acidification.
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.
Ghigo
Eric
E
Unité des Rickettsies, CNRS UMR 6020, Université de la Méditerranée, Faculté de Médecine, 13385 Marseille Cedex 5, France.
Capo
Christian
C
Aurouze
Marianne
M
Tung
Ching-Hsuan
CH
Gorvel
Jean-Pierre
JP
Raoult
Didier
D
Mege
Jean-Louis
JL
D000143:Acids; D039903:Actinobacteria / Q000254:growth & development*; D015703:Antigens, CD / Q000302:isolation & purification; D002402:Cathepsin D / Q000302:isolation & purification; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000378:metabolism; D008561:Membrane Fusion; D008562:Membrane Glycoproteins / Q000302:isolation & purification; D010588:Phagosomes / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism; D008061:Whipple Disease / Q000382:microbiology*
D000143:Acids; D015703:Antigens, CD; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D002402:Cathepsin D