Malaria is a global health problem and a leading cause of deaths worldwide. Many efforts have been made to eradicate malaria. However, it is difficult because the mechanism behind some parts of parasite life cycle are still obscure, especially the liver stage which is essential for parasite development and maturation. Upon invasion of the hepatocyte it is likely that the parasite prevents liver cell death. This is especially relevant for Plasmodium vivax as the hypnozoite can lay dormant in a liver cell for months even years.
Many Plasmodium proteins show little sequence similarity to known proteins and so it is difficult to infer function. To identify similarities based on tertiary predicted structure of proteins we used the computer algorithm i-TASSER, and identified several P. vivax proteins which are predicted to have a similar structure to human proteins involved in apoptosis, such as Apaf-1 and cIAP-1. Apaf-1 (Apoptotic protease activating factor 1) forms an apoptosome with cytochrome C which leads to activation of caspase-9 and cell death. cIAP1 (Cellular Inhibitor of Apoptosis) is a multi-functional protein playing an important role in cell death. We inducibly expressed these P. vivax proteins, and predicted functionally null mutants, in a human liver cancer cell line. We investigate the death phenotype of cells expressing these proteins.
Identification of P. vivax proteins that influence host cell death would improve understanding of how P. vivax can survive for prolonged periods in the host cell during liver stage and may accelerate the development of new drugs for malaria liver stage, which is necessary for the ultimate goal of eliminating malaria.