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Infection and Immunity, August 2000, p. 4653-4657, Vol. 68, No. 8
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

L-Arginine Availability Modulates Local Nitric Oxide Production and Parasite Killing in Experimental Trypanosomiasis

Alain P. Gobert,1,2 Sylvie Daulouede,1 Michel Lepoivre,3 Jean Luc Boucher,4 Bernard Bouteille,5 Alain Buguet,6 Raymond Cespuglio,7 Bernard Veyret,2 and Philippe Vincendeau1,*

Laboratoire de Parasitologie, Université Bordeaux II, Bordeaux,1 Laboratoire PIOM, UMR 5501, CNRS, ENSCPB, Talence,2 UMR 8619, CNRS, Université Paris-Sud, Orsay,3 Laboratoire de Chimie et Biochimie Pharmacologiques, UMR 8601 CNRS, Université René Descartes, Paris,4 Institut d'Epidémiologie Neurologique et de Neurologie Tropicale, Faculté de Médecine, Limoges,5 Unité Physiologie de la Vigilance, CRSSA, La Tronche,6 and Département de Médecine Expérimentale, INSERM U52, Lyon,7 France

Received 14 February 2000/Returned for modification 24 March 2000/Accepted 19 May 2000

Nitric oxide (NO) is an important effector molecule of the immune system in eliminating numerous pathogens. Peritoneal macrophages from Trypanosoma brucei brucei-infected mice express type II NO synthase (NOS-II), produce NO, and kill parasites in the presence of L-arginine in vitro. Nevertheless, parasites proliferate in the vicinity of these macrophages in vivo. The present study shows that L-arginine availability modulates NO production. Trypanosomes use L-arginine for polyamine synthesis, required for DNA and trypanothione synthesis. Moreover, arginase activity is up-regulated in macrophages from infected mice from the first days of infection. Arginase competes with NOS-II for their common substrate, L-arginine. In vitro, arginase inhibitors decreased urea production, increased macrophage nitrite production, and restored trypanosome killing. In vivo, a dramatic decrease in L-arginine concentration was observed in plasma from infected mice. In situ restoration of NO production and trypanosome killing were observed when excess L-arginine, but not D-arginine or L-arginine plus Nomega -nitro-L-arginine (a NOS inhibitor), was injected into the peritoneum of infected mice. These data indicate the role of L-arginine depletion, induced by arginase and parasites, in modulating the L-arginine-NO pathway under pathophysiological conditions.

* Corresponding author. Mailing address: Laboratoire de Parasitologie, Université de Bordeaux II, Bât 1B, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France. Phone: 33-557-57-17-73. Fax: 33-556-84-66-29. E-mail: Philippe.Vincendeau{at}parasito.u-bordeaux2.fr.

Infection and Immunity, August 2000, p. 4653-4657, Vol. 68, No. 8
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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