Background: Cellular inhibitor of apoptosis proteins (cIAPs) are critically required for the promotion of cell survival downstream of TNF receptor engagement. Drug or genetic targeting of cIAPs results in programmed cell death downstream of death receptor signalling. Small molecule inhibitors of cIAPs (Smac mimetics) were originally developed to promote immune / TNF mediated killing of cancer cells. We hypothesized that by antagonizing cIAPs 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 blood stage and as a consequence, promote immunity to prevent re-infection.
Design: We antagonized cIAPs through gene targeting and by using the clinical stage Smac mimetic birinapant in mice infected with the malaria parasite Plasmodium berghei. We examined effects on liver and blood stage malaria and investigated the underlying and contributing immune-mediated mechanisms. Moreover, we characterized the capability of cell death induced and immune mediated protection against re-infection with malaria parasites.
Results: Modulation of cIAP function, through gene-targeting or treatment with birinapant, reduced parasite numbers in the liver of mice by over 90% and significantly delayed the progression of parasites into the blood stages. Most importantly, the induction of apoptosis of malaria infected hepatocytes promoted protective immunity and prevented re-infection of mice with malaria.
Conclusion: cIAPs are central regulators of immune-mediated host responses to malaria parasite infection and are critical determinants of infectious outcomes. Collectively, our data shows that antagonizing the function of cIAPs by a Smac mimetic such as birinapant can promote the control of malaria infection and induce immunity to prevent re-infection in vivo. This approach provides a novel strategy and has implications for the use of SMAC mimetics in combination with other drugs in the treatment of people who are infected with malaria.