Journal article

Targeting the Extrinsic Pathway of Hepatocyte Apoptosis Promotes Clearance of Plasmodium Liver Infection

Gregor Ebert, Sash Lopaticki, Matthew T O'Neill, Ryan WJ Steel, Marcel Doerflinger, Pravin Rajasekaran, Annie SP Yang, Sara Erickson, Lisa Ioannidis, Philip Arandjelovic, Liana Mackiewicz, Cody Allison, John Silke, Marc Pellegrini, Justin A Boddey

Cell Reports | CELL PRESS | Published : 2020

Abstract

Plasmodium sporozoites infect the liver and develop into exoerythrocytic merozoites that initiate blood-stage disease. The hepatocyte molecular pathways that permit or abrogate parasite replication and merozoite formation have not been thoroughly explored, and a deeper understanding may identify therapeutic strategies to mitigate malaria. Cellular inhibitor of apoptosis (cIAP) proteins regulate cell survival and are co-opted by intracellular pathogens to support development. Here, we show that cIAP1 levels are upregulated during Plasmodium liver infection and that genetic or pharmacological targeting of cIAPs using clinical-stage antagonists preferentially kills infected hepatocytes and prom..

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Grants

Awarded by Australian National Health and Medical Research Council


Awarded by National Health and Medical Research Council (NHMRC)


Awarded by Human Frontiers Science Program


Funding Acknowledgements

We thank the Australian Red Cross Blood Service for supplying buffy packs, Lachlan Whitehead and Charlie Jennison for valuable technical assistance, and Diana Hansen for helpful discussions. This work was supported by Australian National Health and Medical Research Council Project Grants 1049811, 1139153 (J.A.B.), 1006592, 1045549, and 1065626 (M.P.); National Health and Medical Research Council (NHMRC) Fellowships 1123727 (J.A.B.) and 1107149 (J.S.); The Sylvia & Charles Viertel Senior Medical Research Fellowship (M.P.); the Human Frontiers Science Program (Young Investigator Grant RGY0073 to J.A.B.); Australian Postgraduate Awards (P.R. and A.S.P.Y.); the Victorian State Government Operational Infrastructure Support; and the Independent Research Institutes Infrastructure Support Scheme of the Australian Government NHMRC.