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Science 337 (6093): 463-466

Copyright © 2012 by the American Association for the Advancement of Science

Adenylate Cyclases of Trypanosoma brucei Inhibit the Innate Immune Response of the Host

Didier Salmon,1,2,*,{dagger} Gilles Vanwalleghem,1,{dagger} Yannick Morias,3,4 Julie Denoeud,5 Carsten Krumbholz,6 Frédéric Lhommé,7 Sabine Bachmaier,6 Markus Kador,6 Jasmin Gossmann,6 Fernando Braga Stehling Dias,1,2 Géraldine De Muylder,1 Pierrick Uzureau,1 Stefan Magez,4,8 Muriel Moser,5 Patrick De Baetselier,3,4 Jan Van Den Abbeele,9 Alain Beschin,3,4 Michael Boshart,6,* Etienne Pays1,10,*

Abstract: The parasite Trypanosoma brucei possesses a large family of transmembrane receptor–like adenylate cyclases. Activation of these enzymes requires the dimerization of the catalytic domain and typically occurs under stress. Using a dominant-negative strategy, we found that reducing adenylate cyclase activity by about 50% allowed trypanosome growth but reduced the parasite’s ability to control the early innate immune defense of the host. Specifically, activation of trypanosome adenylate cyclase resulting from parasite phagocytosis by liver myeloid cells inhibited the synthesis of the trypanosome-controlling cytokine tumor necrosis factor–α through activation of protein kinase A in these cells. Thus, adenylate cyclase activity of lyzed trypanosomes favors early host colonization by live parasites. The role of adenylate cyclases at the host-parasite interface could explain the expansion and polymorphism of this gene family.

1 Laboratory of Molecular Parasitology, Institute for Molecular Biology and Medicine (IBMM), Université Libre de Bruxelles, 12, rue des Professeurs Jeener et Brachet, B6041 Gosselies, Belgium.
2 Institute of Medical Biochemistry, Centro de Ciências e da Saude, Federal University of Rio de Janeiro, Avenida General Trompowsky, Rio de Janeiro 21941-590, Brazil.
3 Myeloid Cell Immunology Laboratory, Vlaams Instituut voor Biotechnologie, Brussels, Belgium.
4 Cellular and Molecular Immunology Unit, Vrije Universiteit Brussel, Brussels, Belgium.
5 Laboratory of Immunobiology, IBMM, Université Libre de Bruxelles, Gosselies, Belgium.
6 Biocenter, Section Genetics, Ludwig-Maximilians-Universität München, Martinsried, Germany.
7 Center for Microscopy and Molecular Imaging, Gosselies, Belgium.
8 Department of Structural Biology, VIB, Brussels, Belgium.
9 Department of Biomedical Sciences, Unit of Veterinary Protozoology, Institute of Tropical Medicine Antwerp, Antwerp, Belgium.
10 Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wavre, Belgium.

{dagger} These authors contributed equally to this work.

* To whom correspondence should be addressed. E-mail: salmon{at}bioqmed.ufrj.br (D.S.); boshart{at}lmu.de (M.B.); epays{at}ulb.ac.be (E.P.)

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