Leishmania Disease Development Depends on the Presence of Apoptotic Promastigotes in the Virulent Inoculum

The obligate intracellular pathogen Leishmania major survives and multiplies in professional phagocytes. The evasion strategy to circumvent killing by host phagocytes and establish a productive infection is poorly understood. Here we report that the virulent inoculum of Leishmania promastigotes cont...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 103; no. 37; pp. 13837 - 13842
Main Authors van Zandbergen, Ger, Bollinger, Annalena, Wenzel, Alexander, Kamhawi, Shaden, Voll, Reinhard, Klinger, Matthias, Müller, Antje, Hölscher, Christoph, Herrmann, Martin, Sacks, David, Solbach, Werner, Laskay, Tamás
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 12.09.2006
National Acad Sciences
Subjects
Animals
Annexin A5 - analysis
Annexin A5 - metabolism
Apoptosis
Biological Sciences
Cells
Cytokines
Cytometry
Down-Regulation
Female
Infections
Intracellular parasitism
Leishmania major
Leishmania major - cytology
Leishmania major - metabolism
Leishmania major - pathogenicity
Leishmaniasis - immunology
Mice
Mice, Inbred BALB C
Neutrophils
Parasites
Parasitic diseases
Parasitic protozoa
Phagocytes
Phagocytes - parasitology
Promastigotes
Transforming Growth Factor alpha - metabolism
Transforming Growth Factor beta - metabolism
Up-Regulation
Virulence
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Summary:The obligate intracellular pathogen Leishmania major survives and multiplies in professional phagocytes. The evasion strategy to circumvent killing by host phagocytes and establish a productive infection is poorly understood. Here we report that the virulent inoculum of Leishmania promastigotes contains a high ratio of annexin A5-binding apoptotic parasites. This subpopulation of parasites is characterized by a round body shape, a swollen kinetoplast, nuclear condensation, and a lack of multiplication and represents dying or already dead parasites. After depleting the apoptotic parasites from a virulent population, Leishmania do not survive in phagocytes in vitro and lose their disease-inducing ability in vivo. TGF-β induced by apoptotic parasites is likely to mediate the silencing of phagocytes and lead to survival of infectious Leishmania populations. The data demonstrate that apoptotic promastigotes, in an altruistic way, enable the intracellular survival of the viable parasites.
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G.v.Z. and A.B. contributed equally to this work.
Edited by E. Peter Greenberg, University of Washington School of Medicine, Seattle, WA, and approved July 10, 2006
Author contributions: G.v.Z. designed research; G.v.Z., A.B., A.W., and S.K. performed research; G.v.Z., S.K., R.V., M.K., A.M., C.H., M.H., and D.S. contributed new reagents/analytic tools; G.v.Z., A.B., A.W., A.M., C.H., D.S., and T.L. analyzed data; and G.v.Z., W.S., and T.L. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0600843103