title: The Deubiquitinating Enzyme Cylindromatosis Dampens CD8+T Cell Responses and Is a Critical Factor for Experimental Cerebral Malaria and Blood-Brain Barrier Damage.
abstract: Cerebral malaria is a severe complication of human malaria and may lead to death ofPlasmodium falciparum-infected individuals. Cerebral malaria is associated with sequestration of parasitized red blood cells within the cerebral microvasculature resulting in damage of the blood-brain barrier and brain pathology. Although CD8+T cells have been implicated in the development of murine experimental cerebral malaria (ECM), several other studies have shown that CD8+T cells confer protection against blood-stage infections. Since the role of host deubiquitinating enzymes (DUBs) in malaria is yet unknown, we investigated how the DUB cylindromatosis (CYLD), an important inhibitor of several cellular signaling pathways, influences the outcome of ECM. Upon infection withPlasmodium bergheiANKA (PbA) sporozoites orPbA-infected red blood cells, at least 90% ofCyld-/-mice survived the infection, whereas all congenic C57BL/6 mice displayed signatures of ECM, impaired parasite control, and disruption of the blood-brain barrier integrity.Cylddeficiency prevented brain pathology, including hemorrhagic lesions, enhanced activation of astrocytes and microglia, infiltration of CD8+T cells, and apoptosis of endothelial cells. Furthermore,PbA-specific CD8+T cell responses were augmented in the blood ofCyld-/-mice with increased production of interferon-γ and granzyme B and elevated activation of protein kinase C-θ and nuclear factor "kappa light-chain enhancer" of activated B cells. Importantly, accumulation of CD8+T cells in the brain ofCyld-/-mice was significantly reduced compared to C57BL/6 mice. Bone marrow chimera experiments showed that the absence of ECM signatures in infectedCyld-/-mice could be attributed to hematopoietic and radioresistant parenchymal cells, most likely endothelial cells that did not undergo apoptosis. Together, we were able to show that host deubiqutinating enzymes play an important role in ECM and that CYLD promotes ECM supporting it as a potential therapeutic target for adjunct therapy to prevent cerebral complications of severe malaria.
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg , Magdeburg , Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Schmid
authors.affiliation: Department of Neuropathology, Charite , Berlin , Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg , Magdeburg , Germany.
authors.forename: Josephin
authors.initials: J
authors.lastname: Koschel
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg , Magdeburg , Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Raptaki
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg , Magdeburg , Germany.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg , Magdeburg , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Naumann
authors.affiliation: Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany; Department of Molecular Parasitology, Humboldt University, Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; Organ-Specific Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schlüter
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg , Magdeburg , Germany.
authors.forename: Gopala
authors.initials: G
authors.lastname: Nishanth
keywords: CYLD; T cells; blood–brain barrier; deubiquitinating enzymes; malaria