Exploring the posttranslational modifications and interactome of the VAR2CSA placental malaria vaccine candidate – VAR2PTM

According to the latest WHO’s World Malaria Report, there were a total of 241 million cases of malaria in 2020 leading to 627 000 deaths, mostly children under five years of age, principally associated with Plasmodium falciparum infection occurring in sub-Saharan Africa. Human malaria severe disease results from the capacity of Plasmodium falciparum to express variant adhesive PfEMP1 on the infected erythrocyte surface, enabling them to adhere to host receptors and sequester to critical target organs such as the brain, the lung and the placenta. Placental malaria is characterized by the massive accumulation of Plasmodium falciparum infected erythrocytes in the placenta and causes adverse birth outcomes, notably low birth weight and increased perinatal and maternal mortality. VAR2CSA is responsible for infected erythrocytes cytoadhesion to placental CSA and is the leading vaccine candidate to protect pregnant women against placental malaria. Although we have now acquired a deeper knowledge on VAR2CSA-CSA interaction, many gaps remain in our knowledge on VAR2CSA function and adhesive properties. Among the main deficits is the lack of knowledge on other putative interactions involved in placental sequestration, such as the molecular interactions between VAR2CSA and other malaria/host proteins, as well as the role of post-translational modifications that could regulate VAR2CSA trafficking and the interaction of infected erythrocytes with Host receptors. We will perform a comprehensive analysis of VAR2CSA post-translational modifications that modulate its function, and will identify the interacting partners associated with VAR2CSA trafficking and infected erythrocytes surface display to dissect their contribution in the parasite biology and virulence. This project will therefore provide novel insights into the parasite biology and virulence during placental malaria and may have a considerable impact on future vaccine and therapeutic strategies.