Cryo-EM structures of Trypanosoma brucei gambiense ISG65 with human complement C3 and C3b and their roles in alternative pathway restriction

Hagen Sülzen, Jakub Began, Arun Dhillon, Sami Kereïche, Petr Pompach, Jitka Votrubova, Farnaz Zahedifard, Adriana Šubrtova, Marie Šafner, Martin Hubalek, Maaike Thompson, Martin Zoltner and Sebastian Zoll ()
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Hagen Sülzen: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Jakub Began: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Arun Dhillon: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Sami Kereïche: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Petr Pompach: Institute of Biotechnology of the Czech Academy of Sciences
Jitka Votrubova: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Farnaz Zahedifard: Charles University Prague, Biocev
Adriana Šubrtova: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Marie Šafner: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Martin Hubalek: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Maaike Thompson: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Martin Zoltner: Charles University Prague, Biocev
Sebastian Zoll: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37988-7

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