Gravidity-dependent Mechanisms of Myeloid Cell-mediated Protection against Placental Malaria

PROJECT SUMMARY/ABSTRACT Malaria in pregnancy is one of the leading causes of infant death globally. Placental malaria (PM) is the main mechanism by which malaria in pregnancy causes birth complications, such as preterm birth, stillbirth, and low birth weight. During PM, Plasmodium falciparum (Pf)-infected red blood cells sequester to syncytiotrophoblasts (STB) within the placental intervillous space, stimulating maternal immune cell recruitment and leading to other placental pathologic changes. With increasing gravidity, the severity of PM decreases and birth outcomes improve as pregnant women acquire Pf-specific antibodies (Abs) against a variant surface protein – VAR2CSA – after repeated Pf exposures. Previous work shows that neutralizing Abs against VAR2CSA are important for protection but do not entirely prevent neonatal complications, which suggests a key role for Ab-mediated effector functions. Work by our group and others demonstrates that Ab-mediated effector functions are crucial for naturally acquired immunity to malaria in children. We hypothesize that myeloid cell state, phagocyte localization at the maternal-fetal interface, and Ab repertoire adapt with repeated Pf exposure in a gravidity-dependent manner, and that Ab-dependent phagocytosis (ADP) is necessary for limiting PM pathogenesis and improving neonatal outcomes. To test this hypothesis, we will leverage an extraordinary biobank of plasma and placental tissue collected from pregnant women enrolled in the DPSP clinical trial (U01 AI1431308). In Aim 1, using novel spatial proteomic (MIBI-TOF) and transcriptomic (NanoString DSP) imaging approaches, we will determine how Pf parasitemia and gravidity shape myeloid cell - STB spatial relationships that drive Pf clearance in placental tissue. We will test whether, with increasing gravidity, inflammatory maternal myeloid cell infiltration will decrease, and maternal phagocytes will preferentially localize to the Pf-infected STB. In Aim 2, we will utilize in vitro models to determine how gravidity-induced Ab modifications influence Fc-mediated protection from malaria in pregnancy. Together, successful completion of these aims will inform vaccine development and therapeutic strategies to reduce the global burden of malaria in pregnancy.