Adenylate cyclases of Trypanosoma brucei inhibit the innate immune response of the host.
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.
Laboratory of Molecular Parasitology, Institute for Molecular Biology and Medicine, Université Libre de Bruxelles, 12, rue des Professeurs Jeener et Brachet, B6041 Gosselies, Belgium. salmon@bioqmed.ufrj.br
Didier
D
Salmon
Gilles
G
Vanwalleghem
Yannick
Y
Morias
Julie
J
Denoeud
Carsten
C
Krumbholz
Frédéric
F
Lhommé
Sabine
S
Bachmaier
Markus
M
Kador
Jasmin
J
Gossmann
Fernando Braga Stehling
FB
Dias
Géraldine
G
De Muylder
Pierrick
P
Uzureau
Stefan
S
Magez
Muriel
M
Moser
Patrick
P
De Baetselier
Jan
J
Van Den Abbeele
Alain
A
Beschin
Michael
M
Boshart
Etienne
E
Pays
D000262:Adenylyl Cyclases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D006790:Host-Parasite Interactions; D007113:Immunity, Innate; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D022423:Myeloid Cells / Q000276:immunology; D018512:Parasitemia; D010587:Phagocytosis; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000201:enzymology* / Q000254:growth & development / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood
D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases