Lymphatic network drainage resolves cerebral edema and facilitates recovery from experimental cerebral malaria
Michael J. Haley,
Ruben Barroso,
Dhifaf A. Jasim,
Megan Haigh,
Jack Green,
Ben Dickie,
Alister G. Craig,
David Brough,
Kevin N. Couper
Affiliations
Michael J. Haley
Division of Immunology, Immunity to Infection & Respiratory Medicine, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PT, UK; Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester, UK; The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
Ruben Barroso
Division of Immunology, Immunity to Infection & Respiratory Medicine, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PT, UK; Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester, UK; The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
Dhifaf A. Jasim
Nanomedicine Lab, National Graphene Institute and Faculty of Biology, Medicine & Health, The University of Manchester, AV Hill Building, Manchester M13 9PT, UK; Medicines Discovery Catapult (MDC), Alderley Park, Macclesfield SK10 4TG, UK
Megan Haigh
Division of Immunology, Immunity to Infection & Respiratory Medicine, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PT, UK
Jack Green
Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester, UK; The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK; Division of Neuroscience, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PT, UK
Ben Dickie
Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester, UK; Division of Informatics, Imaging & Data Sciences, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PT, UK
Alister G. Craig
Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK
David Brough
Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester, UK; The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK; Division of Neuroscience, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PT, UK
Kevin N. Couper
Division of Immunology, Immunity to Infection & Respiratory Medicine, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PT, UK; Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester, UK; The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK; Corresponding author
Summary: While brain swelling, associated with fluid accumulation, is a known feature of pediatric cerebral malaria (CM), how fluid and macromolecules are drained from the brain during recovery from CM is unknown. Using the experimental CM (ECM) model, we show that fluid accumulation in the brain during CM is driven by vasogenic edema and not by perivascular cerebrospinal fluid (CSF) influx. We identify that fluid and molecules are removed from the brain extremely quickly in mice with ECM to the deep cervical lymph nodes (dcLNs), predominantly through basal routes and across the cribriform plate and the nasal lymphatics. In agreement, we demonstrate that ligation of the afferent lymphatic vessels draining to the dcLNs significantly impairs fluid drainage from the brain and lowers anti-malarial drug recovery from the ECM syndrome. Collectively, our results provide insight into the pathways that coordinate recovery from CM.
