Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway

Chloë R Mcdonald,Karlee L Silver,John G Sled,Keith T Ho,Hani Kim,Lindsay S Cahill,Peter A Ward,Kevin C Kain,Howard T Mount,W Conrad Liles,Jimmy Yang,Maria M Mota

doi:10.1371/journal.ppat.1005140

Abstract

The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

Highlights

Each year, an estimated 125 million pregnancies worldwide are at risk of malaria infection [1]
Since malaria in pregnancy (MIP) may cause low birth weight infants (LBW), these infants would be expected to experience an increased risk of neurocognitive impairment; the majority of fetuses exposed to malaria in utero do not develop LBW
In order to avoid LBW as a confounder and isolate the effects of malaria exposure alone on offspring neurodevelopment, we reduced the inoculum given to dams in a validated model of experimental MIP (EMIP) [28] from 106 to 105 parasitized erythrocytes (PEs)

Summary

Introduction

An estimated 125 million pregnancies worldwide are at risk of malaria infection [1]. Plasmodium falciparum infections during pregnancy are more frequent, and associated with higher parasite burdens and worse clinical outcomes than those of non-pregnant individuals [2,3]. MIP has profound maternal and fetal health consequences including increased risk of maternal anemia, preterm birth, stillbirth, fetal growth restriction (FGR) and low birth weight infants (LBW), resulting in an estimated 200,000 infant deaths annually [4]. MIP is characterized by the accumulation of parasitized erythrocytes (PEs) and monocytes/macrophages in the placenta [2,3]. While it is believed that this localized placental immune response contributes to adverse birth outcomes, the precise mechanism by which parasite and monocyte accumulation in the placenta results in poor pregnancy outcomes remains unknown. Recent evidence supports a role for altered angiogenesis and resulting placental vascular insufficiency [5,6]

Methods

Results

Conclusion