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

PLoS Pathogens

Jimmy Yang¹  W. Conrad Liles²  Kevin C. Kain³  Karlee L. Silver³  Hani Kim³  John G. Sled⁴  Chloë R. McDonald⁴  Keith T. Ho⁵  Lindsay S. Cahill⁶  Peter A. Ward⁶  Howard T. Mount⁶ 

[1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada;Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America;Division of Neurology, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada;Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada;Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada;SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

关键词: Malaria;    Magnetic resonance imaging;    Cognitive impairment;    Mouse models;    Serotonin;    Neurodevelopment;    Biogenic amines;    Parasitic diseases;   

DOI  :  10.1371/journal.ppat.1005140

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY