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

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

Author information

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.

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.

PMID:
24362933
PMCID:
PMC4096771
DOI:
10.1038/nm.3424
[Indexed for MEDLINE]
Free PMC Article

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