| First Author | Ebert G | Year | 2020 |
| Journal | Cell Rep | Volume | 30 |
| Issue | 13 | Pages | 4343-4354.e4 |
| PubMed ID | 32234472 | Mgi Jnum | J:287642 |
| Mgi Id | MGI:6416582 | Doi | 10.1016/j.celrep.2020.03.032 |
| Citation | Ebert G, et al. (2020) Targeting the Extrinsic Pathway of Hepatocyte Apoptosis Promotes Clearance of Plasmodium Liver Infection. Cell Rep 30(13):4343-4354.e4 |
| abstractText | 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. |
