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PLoS Pathog. 2015 Sep 24;11(9):e1005140. doi: 10.1371/journal.ppat.1005140. eCollection 2015 Sep.

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

Author information

1
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
2
Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
3
Division of Neurology, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
4
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
5
Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America.
6
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
7
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
8
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

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.

PMID:
26402732
PMCID:
PMC4581732
DOI:
10.1371/journal.ppat.1005140
[Indexed for MEDLINE]
Free PMC Article

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