title: Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway.
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.
authors.affiliation: 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.
authors.forename: Chloë R
authors.initials: CR
authors.lastname: McDonald
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Cahill
authors.affiliation: Division of Neurology, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Ho
authors.affiliation: Division of Neurology, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Yang
authors.affiliation: SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hani
authors.initials: H
authors.lastname: Kim
authors.affiliation: SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Karlee L
authors.initials: KL
authors.lastname: Silver
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Howard T
authors.initials: HT
authors.lastname: Mount
authors.affiliation: 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.
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Sled
authors.affiliation: 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.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002560:Cerebrovascular Circulation; D015936:Complement C5a / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D047109:Fetal Development; D006790:Host-Parasite Interactions; D008288:Malaria / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000503:physiopathology*; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019965:Neurocognitive Disorders / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010962:Plasmodium berghei / Q000276:immunology / Q000502:physiology; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000503:physiopathology*; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001679:Biogenic Amines; D019208:Brain-Derived Neurotrophic Factor; C000591759:C5ar1 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a