Exploring the etiology of oxidative damage and cell death in placental malaria

Malaria is a major public health problem for many regions of the world, affecting mainly pregnant women and young children. Plasmodium falciparum infection during pregnancy results in significant fetal compromise and contributes to hundreds of thousands of infant deaths each year. These outcomes are associated with a number of malaria-induced placental pathologies, including infiltration of maternal inflammatory cells into the placenta in response to the infection. This, in turn, is linked to significant damage to the villous placenta, including necrotic death of syncytiotrophoblast. Complete understanding of the critical cellular and molecular mechanisms that drive placental damage and dysfunction in placental malaria, however, remains elusive. Evidence suggests that neutrophils and monocytes accumulate in inflammatory placental malaria, and neutrophils in particular are also implicated in severe malaria in non-pregnant patients. However, few details of the roles of these cells in placental malaria pathogenesis are available. Motivated by exciting preliminary data that show profound lipid peroxidation in placental malaria, we hypothesize that activated innate immune cells, through oxidative mechanisms, directly contribute to syncytiotrophoblast stress and death in placental malaria, thereby precipitating poor birth outcomes via placental dysfunction. The objective of this application is to address this hypothesis using placenta tissue from a malaria endemic population, villous explants and a mouse model that recapitulates key aspects of placental malaria. The study objectives will be achieved through three Specific Aims. First, preserved placental tissues from Kenyan women exposed to malaria will be assessed by spatial transcriptomics to establish the extent to which trophoblast oxidative stress and necroptosis are coincident in natural infection. Second, the impact of trophoblast exposure to activated neutrophils and monocytes will be characterized in an in vitro simulation of placental malaria. Oxidative damage, necroptosis and other cell death mechanisms, and syncytiotrophoblast destruction will be monitored in villous explants exposed to neutrophils and monocytes undergoing respiratory burst. Third the role of neutrophil and monocyte oxidative burst, and the relative role of pro-oxidant malarial hemozoin, in driving placental oxidative stress and damage will be investigated in an outbred mouse model for placental malaria. Successful completion of this research will expand understanding of the mechanistic basis of malaria-induced placental damage and fetal compromise, leading to identification of new targets for adjunctive therapies in malaria during pregnancy. By advancing fundamental knowledge of mediators of syncytiotrophoblast compromise and death, this work will have implications for other pregnancy conditions associated with maternal monocyte and neutrophil activity, placental oxidative damage, and cell death-related placental dysfunction.

Project details

Enabling Technologies & Assays

Sep 2022 — Jul 2027

$411,997

United States