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Infection and Immunity, July 2002, p. 3727-3735, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3727-3735.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Nitric Oxide-Mediated Proteasome-Dependent Oligonucleosomal DNA Fragmentation in Leishmania amazonensis Amastigotes

Philippe Holzmuller,1 Denis Sereno,1 Mireille Cavaleyra,1 Isabelle Mangot,1 Sylvie Daulouede,2 Philippe Vincendeau,2 and Jean-Loup Lemesre1*

UR 008 Pathogénie des Trypanosomatidés, Institut de Recherche pour le Développement, 34032 Montpellier Cedex 1,1 Laboratoire de Parasitologie, Université Victor Segalen Bordeaux II, 33076 Bordeaux Cedex, France2

Received 4 September 2001/ Returned for modification 15 November 2001/ Accepted 21 March 2002

Resistance to leishmanial infections depends on intracellular parasite killing by activated host macrophages through the L-arginine-nitric oxide (NO) metabolic pathway. Here we investigate the cell death process induced by NO for the intracellular protozoan Leishmania amazonensis. Exposure of amastigotes to moderate concentrations of NO-donating compounds (acidified sodium nitrite NaNO2 or nitrosylated albumin) or to endogenous NO produced by lipopolysaccharide or gamma interferon treatment of infected macrophages resulted in a dramatic time-dependent cell death. The combined use of several standard DNA status analysis techniques (including electrophoresis ladder banding patterns, YOPRO-1 staining in flow cytofluorometry, and in situ recognition of DNA strand breaks by TUNEL [terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling] assay) revealed a rapid and extensive fragmentation of nuclear DNA in both axenic and intracellular NO-treated amastigotes of L. amazonensis. Despite some similarities to apoptosis, the nuclease activation responsible for characteristic DNA degradation was not under the control of caspase activity as indicated by the lack of involvement of cell-permeable inhibitors of caspases and cysteine proteases. In contrast, exposure of NO-treated amastigotes with specific proteasome inhibitors, such as lactacystin or calpain inhibitor I, markedly reduced the induction of the NO-mediated apoptosis-like process. These data strongly suggest that NO-induced oligonucleosomal DNA fragmentation in Leishmania amastigotes is, at least in part, regulated by noncaspase proteases of the proteasome. The determination of biochemical pathways leading up to cell death might ultimately allow the identification of new therapeutic targets.

* Corresponding author. Mailing address: UR 008 Pathogénie des Trypanosomatidés, IRD (Institut de Recherche pour le Développement), 911 Ave. Agropolis, BP 5045, 34032 Montpellier Cedex 1, France. Fax: 33(0)4-67-41-63-30. Phone: 33(0)4-67-41-62-20. E-mail: lemesre{at}melusine.mpl.ird.fr.

Editor: B. B. Finlay

Infection and Immunity, July 2002, p. 3727-3735, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3727-3735.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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