Poster Presentation First Malaria World Congress 2018

Targeting host hepatocytes to clear Plasmodium infections and induce immunity (#241)

Gregor Ebert 1 , Sash Lopaticki 1 , Pravin Rajasekaran 1 , Matthew O'Neill 1 , Marcel Doeflinger 1 , Annie Yang 1 , Charlie Jennison 1 , Sara Erickson 1 , Marc Pellegrini 1 , Justin Boddey 1
  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

The pre-erythrocytic stage of Plasmodium infection provides important avenues for antimalarial intervention. The liver stage of mammalian infection involves parasite-mediated inhibition of host cell apoptosis. This allows parasites to evade immune defences and differentiate into merozoites that initiate a blood stage malaria infection. We hypothesised that by antagonising inhibitor of apoptosis proteins (IAPs) with a SMAC mimetic, we would be able to induce immune-mediated killing of malaria parasite-infected hepatocytes, thereby reducing or eliminating the pool of parasites capable of moving into the blood and, as a consequence, promote immunity to prevent re-infection. Here, we have used a clinical-stage SMAC mimetic drug to treat mice after sporozoite challenge and this caused a profound decrease in liver stage infection. IAP-knockout mice phenocopied the drug-treated mice, demonstrating the importance of host cell apoptosis signalling programs during liver infection. The mechanism of parasite clearance involves dis-inhibition of hepatocyte apoptosis through TNF signaling. Most importantly, the induction of apoptosis of malaria-infected hepatocytes promoted protective immunity and prevented re-infection of mice with a lethal sporozoite challenge. This approach provides a novel strategy for the use of SMAC mimetics in combination with other antimalarial drugs in the treatment of people who are infected with malaria and their protection against re-infection.