Targeting the extrinsic pathway of hepatocyte apoptosis promotes clearance of Plasmodium liver infection
- Author(s)
- Ebert, G; Lopaticki, S; O'Neill, MT; Steel, RWJ; Doerflinger, M; Rajasekaran, P; Yang, ASP; Erickson, S; Ioannidis, L; Arandjelovic, P; Mackiewicz, L; Allison, C; Silke, J; Pellegrini, M; Boddey, JA;
- Details
- Publication Year 2020-03-31,Volume 30,Issue #13,Page 4343-4354 e4
- Journal Title
- Cell Reports
- Publication Type
- Journal Article
- 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 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.
- Publisher
- Cell Press
- Research Division(s)
- Infectious Diseases And Immune Defence; Inflammation
- PubMed ID
- 32234472
- Publisher's Version
- https://doi.org/10.1016/j.celrep.2020.03.032
- Open Access at Publisher's Site
https://doi.org/10.1016/j.celrep.2020.03.032- NHMRC Grants
- NHMRC/1049811, NHMRC/1139153, NHMRC/1006592, NHMRC/1045549, NHMRC/1065626, NHMRC/1123727, NHMRC/1107149,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-04-07 01:20:07
Last Modified: 2020-04-07 01:35:00