title: Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria.
abstract: Human cerebral malaria (HCM) is a serious complication ofPlasmodium falciparuminfection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale magnetic resonance imaging (MRI) study in humans identified brain swelling as the most prominent predictor of fatal HCM. Therefore, in this study, we sought to define the mechanism controlling brain edema through the use of the murine experimental cerebral malaria (ECM) model. Specifically, we investigated the ability of CD8 T cells to initiate brain edema during ECM. We determined that areas of blood-brain barrier (BBB) permeability colocalized with a reduction of the cerebral endothelial cell tight-junction proteins claudin-5 and occludin. Furthermore, through small-animal MRI, we analyzed edema and vascular leakage. Using gadolinium-enhanced T1-weighted MRI, we determined that vascular permeability is not homogeneous but rather confined to specific regions of the brain. Our findings show that BBB permeability was localized within the brainstem, olfactory bulb, and lateral ventricle. Concurrently with the initiation of vascular permeability, T2-weighted MRI revealed edema and brain swelling. Importantly, ablation of the cytolytic effector molecule perforin fully protected against vascular permeability and edema. Furthermore, perforin production specifically by CD8 T cells was required to cause fatal edema during ECM. We propose that CD8 T cells initiate BBB breakdown through perforin-mediated disruption of tight junctions. In turn, leakage from the vasculature into the parenchyma causes brain swelling and edema. This results in a breakdown of homeostatic maintenance that likely contributes to ECM pathology.
authors.affiliation: Immunology Program, Mayo Graduate School, Rochester, Minnesota, USA.|Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Huggins
authors.affiliation: Neurobiology of Disease Program, Mayo Graduate School, Rochester, Minnesota, USA.
authors.forename: Holly L
authors.initials: HL
authors.lastname: Johnson
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Jin
authors.affiliation: Neurobiology of Disease Program, Mayo Graduate School, Rochester, Minnesota, USA.
authors.forename: Aurelie
authors.initials: A
authors.lastname: N Songo
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hanson
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: LaFrance
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Noah S
authors.initials: NS
authors.lastname: Butler
authors.affiliation: Department of Microbiology, Department of Pathology, and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA Johnson.Aaron2@mayo.edu.|Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000000981:diagnostic imaging / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008279:Magnetic Resonance Imaging; D016779:Malaria, Cerebral / Q000150:complications* / Q000000981:diagnostic imaging; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052899:Pore Forming Cytotoxic Proteins / Q000096:biosynthesis*
chemical_list: D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse
keywords: CD8 T cell; blood-brain barrier; experimental cerebral malaria; perforin