Understanding the genetic diversity and identification of pathogenic variants of malaria in pregnancy
Globally, malaria in pregnancy (MiP) remains a significant public health problem. Each year, placental malaria imperils millions of pregnant women and is associated with several adverse birth outcomes, largely owing to Plasmodium falciparum sequestration in the placenta. Currently, efforts are underway to develop a vaccine against MiP by targeting a protein (VAR2CSA) that is critical in this sequestration process. However, there is a lot of genetic diversity in this gene probably as a result of balancing evolutionary selection by the host immune system. To this end, investigations of the causes and consequences of genetic diversity of var2csa can help on-going vaccine development efforts. We will investigate the genetic diversity of var2csa using next-generation deep- sequencing technology, targeting a large 1.5 kb fragment of var2csa in cohorts of Beninese and Malawian pregnant women. We will compare alpha (within group) and beta (between group) diversity among women with and without adverse birth outcomes and look for signatures of balancing selection. Further, we will identify pathogenic variants by estimating their relative effect on fetal growth. This study will integrate new molecular technologies and analytic approaches; the results will help elucidate the role of VAR2CSA in the pathogenesis of MiP and directly inform on- going vaccine development efforts.