Over half of all pregnant women world-wide are at risk for malaria, but little is known about possible consequences for the neurodevelopment of children exposed to malaria in pregnancy. A study published on September 24th in PLOS Pathogens reports a causal link between pre-natal exposure to malaria and subsequent neurocognitive impairment in offspring in a mouse model of experimental malaria in pregnancy. The research also identifies some of the molecular mechanisms involved.
Kevin Kain, from the University of Toronto, Canada, and colleagues are interested in health consequences for children exposed to malaria in pregnancy. In this study, they specifically examined neurocognitive function in mice of normal birth weight that had been exposed to–but not themselves infected with–malaria in the uterus (both low birth weight and fetal malaria might also affect neurodevelopment, and were therefore eliminated as possible complicating factors).
The researchers found that young mice that had been exposed to malaria in pregnancy have impaired learning and memory and show depressive-like behavior that persists to adulthood. These neurocognitive impairments are associated with decreased tissue levels of major neurotransmitters (serotonin, dopamine, and norepinephrine) in specific regions of the brain. Pushing the technology by imaging blood vessels in the uterus, the researchers also saw changes in neurovascular development in the brain of malaria-exposed mouse fetuses (see image).
Because a specific immune system factor called C5a had previously been linked to both neurodevelopment and adverse birth outcomes after malaria-exposure in pregnancy, the researchers next tested whether C5a signaling played a role in the link between malaria during pregnancy and neurocognitive impairment they discovered. They found that genetic and functional disruption of maternal C5a signaling restored neurotransmitter levels and completely rescued the neurocognitive defects in the offspring. In other words, mothers with defective C5a signaling that had malaria in pregnancy gave birth to malaria-exposed pups without detectable neurocognitive abnormalities.
These results, the researchers say, “highlight a novel mechanism by which malaria in pregnancy may alter the neurocognitive development of millions of children prior to birth”. They mention that “a prospective study is underway to confirm these findings in African children exposed to malaria in utero”. Stressing that “it is essential to identify preventable risk factors that can be modified to decrease the risk of developmental delay in children”, they say, “this study suggests that malaria in pregnancy is one such factor that can be targeted [and FDA-approved anti-C5a strategies exist] in order to improve cognitive development and school performance in malaria-endemic regions”.
Source: Kevin Kain – PLOS
Image Source: The image is credited to McDonald et al./PLOS Pathogens
Original Research: Full open access research for “Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway” by Chloë R. McDonald, Lindsay S. Cahill, Keith T. Ho, Jimmy Yang, Hani Kim, Karlee L. Silver, Peter A. Ward, Howard T. Mount, W. Conrad Liles, John G. Sled, and Kevin C. Kain in PLOS Pathogens. Published online September 24 2015 doi:10.1371/journal.ppat.1005140
Abstract
Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway
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.
“Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway” by Chloë R. McDonald, Lindsay S. Cahill, Keith T. Ho, Jimmy Yang, Hani Kim, Karlee L. Silver, Peter A. Ward, Howard T. Mount, W. Conrad Liles, John G. Sled, and Kevin C. Kain in PLOS Pathogens. Published online September 24 2015 doi:10.1371/journal.ppat.1005140
