Journal
CELL REPORTS
Volume 30, Issue 13, Pages 4343-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.03.032
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Funding
- Australian National Health and Medical Research Council [1049811, 1139153, 1006592, 1045549, 1065626]
- National Health and Medical Research Council (NHMRC) [1123727, 1107149]
- Sylvia & Charles Viertel Senior Medical Research Fellowship
- Human Frontiers Science Program [RGY0073]
- Australian Postgraduate Awards
- Victorian State Government Operational Infrastructure Support
- Independent Research Institutes Infrastructure Support Scheme of the Australian Government NHMRC
- National Health and Medical Research Council of Australia [1139153, 1065626] Funding Source: NHMRC
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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 promotes immunity. Using gene-targeted mice, the mechanism was defined as TNF-TNFR1-mediated apoptosis via caspases 3 and 8 to clear parasites. This study reveals the importance of cIAPs to Plasmodium infection and demonstrates that host-directed antimalarial drugs can eliminate liver parasites and induce immunity while likely providing a high barrier to resistance in the parasite.
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