Targeting the extrinsic pathway of hepatocyte apoptosis promotes clearance of Plasmodium liver infection Academic Article uri icon

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.

authors

  • Ebert, G
  • Lopaticki, S
  • O'Neill, MT
  • Steel, RWJ
  • Doerflinger, Marcel
  • Rajasekaran, P
  • Yang, ASP
  • Erickson, S
  • Ioannidis, L
  • Arandjelovic, P
  • Mackiewicz, L
  • Allison, C
  • Silke, John
  • Pellegrini, M
  • Boddey, JA

publication date

  • 2020