Innate-adaptive immune bridging in gravidity-dependent immunity against placental malaria: a multi-omics approach

/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 demonstrate that Ab-mediated effector functions are crucial for naturally acquired immunity to malaria in children. We hypothesize that the myeloid compartment, phagocyte localization at the materno-fetal milieu, and Ab repertoire adapt with repeated Pf exposure in a gravidity-dependent manner, and that antibody-dependent phagocytosis is necessary for limiting PM pathogenesis and improving neonatal outcomes. To test this hypothesis, we will leverage an extraordinary biobank of peripheral and placental blood, plasma, and placental tissue collected from pregnant women enrolled in the DPSP clinical trial (U01 AI1431308). In Aim 1, we will determine how malaria and gravidity impact the circulating and placental blood myeloid compartment in pregnancy using single cell proteomic (CyTOF) and transcriptomic (scRNAseq) approaches. We will test whether Pf infections and increasing gravidity result in an enrichment of circulating, FcγR-expressing phagocytes. In Aim 2, we will determine how Pf parasitemia and gravidity shape myeloid cell - STB spatial relationships in placental tissue using novel spatial proteomic (MIBI-TOF) and transcriptomic (NanoString DSP) imaging approaches. We will test whether, with increasing gravidity, inflammatory maternal myeloid cell infiltration will decrease and maternal phagocytes will preferentially localize to the STB. Finally, in Aim 3, 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 studies will inform vaccine development and therapeutic strategies to reduce the global burden of malaria in pregnancy. Project Number: 1R01AI189963-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Prasanna Jagannathan (+1 co-PI) | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $789,442 | Activity Code: R01 | Study Section: Immunity and Host Defense Study Section[IHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18996301