Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection

Peter Liehl; Vanessa Zuzarte-Luís; Jennie Chan; Thomas Zillinger; Fernanda Baptista; Daniel Carapau; Madlen Konert; Kirsten K Hanson; Céline Carret; Caroline Lassnig; Mathias Müller; Ulrich Kalinke; Mohsan Saeed; Angelo Ferreira Chora; Douglas T Golenbock; Birgit Strobl; Miguel Prudêncio; Luis P Coelho; Stefan H Kappe; Giulio Superti-Furga; Andreas Pichlmair; Ana M Vigário; Charles M Rice; Katherine A Fitzgerald; Winfried Barchet; Maria M Mota

doi:10.1038/nm.3424

Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection

Nat Med. 2014 Jan;20(1):47-53. doi: 10.1038/nm.3424. Epub 2013 Dec 22.

Authors

Peter Liehl¹, Vanessa Zuzarte-Luís¹, Jennie Chan², Thomas Zillinger³, Fernanda Baptista¹, Daniel Carapau¹, Madlen Konert¹, Kirsten K Hanson¹, Céline Carret¹, Caroline Lassnig⁴, Mathias Müller⁴, Ulrich Kalinke⁵, Mohsan Saeed⁶, Angelo Ferreira Chora¹, Douglas T Golenbock⁷, Birgit Strobl⁴, Miguel Prudêncio¹, Luis P Coelho¹, Stefan H Kappe⁸, Giulio Superti-Furga⁹, Andreas Pichlmair⁹, Ana M Vigário¹⁰, Charles M Rice⁶, Katherine A Fitzgerald⁷, Winfried Barchet¹¹, Maria M Mota¹

Affiliations

¹ Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
² 1] Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [2].
³ 1] Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, Germany. [2].
⁴ Institute of Animal Breeding and Genetics and Biomodels, Austria University of Veterinary Medicine Vienna, Vienna, Austria.
⁵ Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover Medical School and Helmholtz Centre for Infection Research, Hannover, Germany.
⁶ Laboratory of Virology and Infectious Diseases, Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, USA.
⁷ Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
⁸ Seattle Biomedical Research Institute, Seattle, Washington, USA.
⁹ CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
¹⁰ 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.
¹¹ Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, Germany.

PMID: 24362933
PMCID: PMC4096771
DOI: 10.1038/nm.3424

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Animals
Blotting, Western
DEAD-box RNA Helicases / immunology
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Gene Expression Profiling
Green Fluorescent Proteins
Immunity, Innate / immunology*
Immunohistochemistry
Interferon Regulatory Factor-3 / metabolism
Interferon Regulatory Factor-7 / metabolism
Interferon Type I / immunology*
Interferon-Induced Helicase, IFIH1
Liver / immunology
Liver / parasitology*
Luciferases
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microarray Analysis
Oligonucleotides / genetics
Plasmodium / genetics
Plasmodium / immunology*
Real-Time Polymerase Chain Reaction
Signal Transduction / immunology*
Statistics, Nonparametric

Substances

Adaptor Proteins, Signal Transducing
IPS-1 protein, mouse
Interferon Regulatory Factor-3
Interferon Regulatory Factor-7
Interferon Type I
Irf3 protein, mouse
Irf7 protein, mouse
Oligonucleotides
Green Fluorescent Proteins
Luciferases
Ifih1 protein, mouse
DEAD-box RNA Helicases
Interferon-Induced Helicase, IFIH1

Abstract

Publication types

MeSH terms

Substances

Grants and funding