Malaria in pregnancy alters foetal neurovascular development

Malaria in pregnancy alters foetal neurovascular development A growing body of evidence has established the importance of the in utero environment on neurodevelopment and long-term cognitive and behavioral outcomes. These data suggest factors that disrupt the tightly regulated in utero environment can modify normal neurodevelopmental processes. Approximately 125 million pregnancies worldwide are at risk of malaria infection every year. However the impact of in utero exposure to malaria in pregnancy on fetal neurodevelopment is unknown.

Researchers used a mouse model of malaria in pregnancy to examine the impact of maternal malaria exposure on neurocognitive outcomes in offspring. They observed impaired learning and memory and depressive-like behavior in malaria-exposed offspring that were neither congenitally infected nor low birth weight. These neurocognitive impairments were associated with decreased tissue levels of neurotransmitters in regions of the brain linked to the observed deficits. Disruption of maternal C5a complement receptor signaling restored the levels of neurotransmitters and rescued the associated cognitive phenotype observed in malaria-exposed offspring. This study provides the first evidence implicating a causal link between pre-natal exposure to malaria, complement signaling and subsequent neurocognitive impairment in offspring.

Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway. (2015) PLoS Pathog 11 (9): e1005140. doi:10.1371/journal.ppat.1005140
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.

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