title: Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection.
abstract: Before they infect red blood cells and cause malaria, Plasmodium parasites undergo an obligate and clinically silent expansion phase in the liver that is supposedly undetected by the host. Here, we demonstrate the engagement of a type I interferon (IFN) response during Plasmodium replication in the liver. We identified Plasmodium RNA as a previously unrecognized pathogen-associated molecular pattern (PAMP) capable of activating a type I IFN response via the cytosolic pattern recognition receptor Mda5. This response, initiated by liver-resident cells through the adaptor molecule for cytosolic RNA sensors, Mavs, and the transcription factors Irf3 and Irf7, is propagated by hepatocytes in an interferon-α/β receptor-dependent manner. This signaling pathway is critical for immune cell-mediated host resistance to liver-stage Plasmodium infection, which we find can be primed with other PAMPs, including hepatitis C virus RNA. Together, our results show that the liver has sensor mechanisms for Plasmodium that mediate a functional antiparasite response driven by type I IFN.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Peter
authors.initials: P
authors.lastname: Liehl
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zuzarte-Luís
authors.affiliation: 1] Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [2].
authors.forename: Jennie
authors.initials: J
authors.lastname: Chan
authors.affiliation: 1] Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, Germany. [2].
authors.forename: Thomas
authors.initials: T
authors.lastname: Zillinger
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Baptista
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carapau
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Madlen
authors.initials: M
authors.lastname: Konert
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Kirsten K
authors.initials: KK
authors.lastname: Hanson
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Céline
authors.initials: C
authors.lastname: Carret
authors.affiliation: Institute of Animal Breeding and Genetics and Biomodels, Austria University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lassnig
authors.affiliation: Institute of Animal Breeding and Genetics and Biomodels, Austria University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover Medical School and Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.affiliation: Laboratory of Virology and Infectious Diseases, Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, USA.
authors.forename: Mohsan
authors.initials: M
authors.lastname: Saeed
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Angelo Ferreira
authors.initials: AF
authors.lastname: Chora
authors.affiliation: Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.affiliation: Institute of Animal Breeding and Genetics and Biomodels, Austria University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Luis P
authors.initials: LP
authors.lastname: Coelho
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, USA.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Kappe
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Giulio
authors.identifier: 0000000205701768
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pichlmair
authors.affiliation: 1] Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal. [2] Unidade de Ciências Médicas, Centro de compentência de ciências da vida, Universidade da Madeira, Funchal, Portugal.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Vigário
authors.affiliation: Laboratory of Virology and Infectious Diseases, Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D053487:DEAD-box RNA Helicases / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology*; D000072640:Interferon-Induced Helicase, IFIH1; D008099:Liver / Q000276:immunology / Q000469:parasitology*; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009841:Oligonucleotides / Q000235:genetics; D010961:Plasmodium / Q000235:genetics / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D018709:Statistics, Nonparametric
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053487:DEAD-box RNA Helicases; D049452:Green Fluorescent Proteins; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D000072640:Interferon-Induced Helicase, IFIH1; D008156:Luciferases; D009841:Oligonucleotides; C512612:MAVS protein, mouse; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C510592:Ifih1 protein, mouse