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.宫内环境对儿童神经发育与行为具有深远影响。非洲有相当比例的孕妇面临妊娠疟疾（malaria in pregnancy, MIP）风险，但宫内暴露于MIP对胎儿神经发育的影响尚不明晰。补体激活，尤其是C5a，可能在MIP病程中参与神经病理改变与不良妊娠结局的发生。本研究采用MIP实验模型，结合标准化神经认知测试、磁共振成像（MRI）、显微计算机断层扫描（micro-CT）以及神经递质水平高效液相色谱（HPLC）分析，旨在验证宫内疟疾暴露通过C5a-C5aR依赖通路改变胎儿神经发育的假说。研究结果显示，与未暴露对照组相比，疟疾暴露子代存在持续的记忆与类情感行为神经认知缺陷。此类缺陷与脑内主要生物源性胺类及脑源性神经营养因子（BDNF）的区域水平降低相关，而通过遗传学与功能学手段阻断C5a-C5aR信号通路可逆转上述改变。本研究结果证实，实验性MIP可导致子代出现神经认知缺陷，并为干预治疗提供了全新靶点。