Targeting the extrinsic pathway of hepatocyte apoptosis promotes clearance of Plasmodium liver infection
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
WEHI Research Division(s)
Infectious Diseases And Immune Defence; Inflammation
PubMed ID
32234472
Open Access at Publisher's Site
https://doi.org/10.1016/j.celrep.2020.03.032
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
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