African Trypanosomes have developed elaborate mechanisms to escape the adaptive immune response, but little is known about complement evasion particularly at the early stage of infection. Here we show that ISG65 of the human-infective parasite Trypanosoma brucei gambiense is a receptor for human complement factor C3 and its activation fragments and that it takes over a role in selective inhibition of the alternative pathway C5 convertase and thus abrogation of the terminal pathway. No deposition of C4b, as part of the classical and lectin pathway convertases, was detected on trypanosomes. We present the cryo-electron microscopy (EM) structures of native C3 and C3b in complex with ISG65 which reveal a set of modes of complement interaction. Based on these findings, we propose a model for receptor-ligand interactions as they occur at the plasma membrane of blood-stage trypanosomes and may facilitate innate immune escape of the parasite.

1st Faculty of Medicine Charles University Albertov 4 12800 Prague Czech Republic

Agidens Industrial Machinery Manufacturing Zwijndrecht Antwerp Belgium

Department of Immunobiology University of Lausanne Chemin des Boveresses 155 1066 Epalinges Switzerland

Department of Parasitology Faculty of Science Charles University Prague Biocev 25250 Vestec Czech Republic

Faculty of Science Charles University Albertov 6 12800 Prague 2 Czech Republic

Institute of Biotechnology of the Czech Academy of Sciences 25250 Vestec Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo namesti 542 2 16000 Prague Czech Republic

University of Antwerp Antwerp Belgium

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Beyond the VSG layer: Exploring the role of intrinsic disorder in the invariant surface glycoproteins of African trypanosomes