title: Chemical attenuation of Plasmodium in the liver modulates severe malaria disease progression.
abstract: Cerebral malaria is one of the most severe complications of malaria disease, attributed to a complicated series of immune reactions in the host. The syndrome is marked by inflammatory immune responses, margination of leukocytes, and parasitized erythrocytes in cerebral vessels leading to breakdown of the blood-brain barrier. We show that chemical attenuation of the parasite at the very early, clinically silent liver stage suppresses parasite development, delays the time until parasites establish blood-stage infection, and provokes an altered host immune response, modifying immunopathogenesis and protecting from cerebral disease. The early response is proinflammatory and cell mediated, with increased T cell activation in the liver and spleen, and greater numbers of effector T cells, cytokine-secreting T cells, and proliferating, proinflammatory cytokine-producing T cells. Dendritic cell numbers, T cell activation, and infiltration of CD8(+) T cells to the brain are decreased later in infection, possibly mediated by the anti-inflammatory cytokine IL-10. Strikingly, protection can be transferred to naive animals by adoptive transfer of lymphocytes from the spleen at very early times of infection. Our data suggest that a subpopulation belonging to CD8(+) T cells as early as day 2 postinfection is responsible for protection. These data indicate that liver stage-directed early immune responses can moderate the overall downstream host immune response and modulate severe malaria outcome.
authors: Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, D 69120 Heidelberg, Germany; German Centre for Infection Research, D 69120 Heidelberg, Germany;
authors: Matthew D
authors: MD
authors: Lewis
authors: Core Facility Fluorescence Cytometry, Research Center Borstel, D 23845 Borstel, Germany;
authors: Jochen
authors: J
authors: Behrends
authors: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal;
authors: Cláudia
authors: C
authors: Sá E Cunha
authors: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal;
authors: António M
authors: AM
authors: Mendes
authors: German Centre for Infection Research, D 69120 Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, D 69120 Heidelberg, Germany;
authors: Felix
authors: F
authors: Lasitschka
authors: Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, D 69120 Heidelberg, Germany;
authors: Julia M
authors: JM
authors: Sattler
authors: Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, D 69120 Heidelberg, Germany; MalVa GmbH, D 69121 Heidelberg, Germany;
authors: Kirsten
authors: K
authors: Heiss
authors: Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands; Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands; and.
authors: Taco W A
authors: TW
authors: Kooij
authors: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal;
authors: Miguel
authors: M
authors: Prudêncio
authors: Institute for Organic Chemistry, University of Würzburg, 97074 Würzburg, Germany.
authors: Gerhard
authors: G
authors: Bringmann
authors: Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, D 69120 Heidelberg, Germany;
authors: Friedrich
authors: F
authors: Frischknecht
authors: Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, D 69120 Heidelberg, Germany; German Centre for Infection Research, D 69120 Heidelberg, Germany; ann-kristin.mueller@uni-heidelberg.de.
authors: Ann-Kristin
authors: AK
authors: Mueller
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008099:Liver / Q000276:immunology* / Q000821:virology*; D008288:Malaria / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000634:Aminoquinolines; D000998:Antiviral Agents; C015955:isopentaquine