Science：布氏锥虫腺苷环化酶调节宿主固有免疫防御

6月14日，Science杂志在线报道腺苷环化酶在布氏锥虫感染宿主的免疫反应中的发挥重要作用。寄生虫布氏锥虫（Trypanosoma brucei）有一大家族跨膜受体样腺苷环化酶。激活这些酶需要催化结构域的二聚化。这常常发生于应激条件下。

利用显性抑制策略，研究者发现，降低腺苷环化酶活力50%可允许睡病虫生长，但降低了它控制宿主早期固有免疫防御的能力。特别是，肝脏骨髓样细胞吞噬活化睡病虫后引发的该寄生虫腺苷环化酶激活，可通过激活这些细胞的蛋白激酶A来抑制睡病虫控制的肿瘤坏死因子-α。因此，裂解的睡病虫产生的腺苷环化酶促进活寄生虫在宿主体内的早期繁殖。

腺苷环化酶在宿主-寄生虫之间相互作用中的重要作用解释了该基因家族的扩增和多态性。该研究，为人类理解和治疗锥虫病带来新的启示。

doi:10.1016/j.cell.2011.10.017
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Adenylate Cyclases of Trypanosoma brucei Inhibit the Innate Immune Response of the Host

Didier Salmon1,2,*,?, Gilles Vanwalleghem1,?, Yannick Morias3,4, Julie Denoeud5, Carsten Krumbholz6, Frédéric Lhommé7, Sabine Bachmaier6, Markus Kador6, Jasmin Gossmann6, Fernando Braga Stehling Dias1,2, Géraldine De Muylder1, Pierrick Uzureau1, Stefan Magez4,8, Muriel Moser5, Patrick De Baetselier3,4, Jan Van Den Abbeele9, Alain Beschin3,4, Michael Boshart6,*, Etienne Pays1,10,*

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 ~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.