Abstract
Plasmodium falciparum infection during pregnancy is a major cause of severe maternal illness and neonatal mortality. Mouse models are important for the study of gestational malaria pathogenesis. When infected with Plasmodium chabaudi chabaudi AS in early gestation, several inbred mouse strains abort at midgestation. We report here that outbred Swiss Webster mice infected with P. chabaudi chabaudi AS in early gestation carry their pregnancies to term despite high parasite burden and malarial hemozoin accumulation in the placenta at midgestation, with the latter associated with induction of heme oxygenase 1 expression. Infection yields reduced fetal weight and viability at term and a reduction in pup number at weaning, but does not influence postnatal growth prior to weaning. This novel model allows for the exploration of malaria infection throughout pregnancy, modeling chronic infections observed in pregnant women prior to the birth of underweight infants and enabling the production of progeny exposed to malaria in utero, which is critical for understanding the postnatal repercussions of gestational malaria. The use of outbred mice allows for the exploration of gestational malaria in a genetically diverse model system, better recapitulating the diversity of infection responses observed in human populations.
Highlights
Plasmodium falciparum infection during pregnancy is a major cause of severe maternal illness and neonatal mortality
The poor birth outcomes associated with human gestational P. falciparum malaria are associated with accumulation of parasite-infected red blood cells within the intervillous spaces of the placenta. iRBC sequestration in the placenta is mediated by the expression of the VAR2CSA variant of P. falciparum erythrocyte membrane protein 1 (PfEMP1), which allows the iRBCs to bind to chondroitin sulfate A (CSA)-bearing proteoglycans expressed by the syncytiotrophoblast[14,15,16]
P. berghei interacts with CSA in the murine placenta[34], and recrudescent infections in pregnant animals are associated with enhanced capacity to interact with this glycan in the placenta[35].When initiated in early gestation, P. berghei infection results in abortion and embryo resorption[36,37]
Summary
Plasmodium falciparum infection during pregnancy is a major cause of severe maternal illness and neonatal mortality. Infection of B6 mice on gestational day (GD) 0 results in midgestational pregnancy loss associated with the accumulation of iRBCs in the placenta and the disruption of placental architecture[41,42,43,44,45,46] This infection may better model the trajectory of human infection in pregnancy, as dams develop severe maternal illness but survive. Stasis in weight gain at midgestation is associated with heavy parasite burdens, significant hemozoin accumulation, and an associated heme oxygenase response in placentae This novel model will allow for the exploration of the complex host-parasite interactions that cause significant maternal morbidity and placental damage but allow for fetal survival. This model enables the straightforward production of progeny exposed to malaria infection and malaria-induced maternal responses in utero, facilitating exploration of prenatal exposure to malaria on postnatal development, which is critical because gestational malaria remains a leading cause of preventable infant death[48]
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