TY - JOUR
T1 - Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection
AU - Liehl, Peter
AU - Zuzarte-Luís, Vanessa
AU - Chan, Jennie
AU - Zillinger, Thomas
AU - Baptista, Fernanda
AU - Carapau, Daniel
AU - Konert, Madlen
AU - Hanson, Kirsten K.
AU - Carret, Céline
AU - Lassnig, Caroline
AU - Müller, Mathias
AU - Kalinke, Ulrich
AU - Saeed, Mohsan
AU - Chora, Angelo Ferreira
AU - Golenbock, Douglas T.
AU - Strobl, Birgit
AU - Prudêncio, Miguel
AU - Coelho, Luis P.
AU - Kappe, Stefan H.
AU - Superti-Furga, Giulio
AU - Pichlmair, Andreas
AU - Vigário, Ana M.
AU - Rice, Charles M.
AU - Fitzgerald, Katherine A.
AU - Barchet, Winfried
AU - Mota, Maria M.
N1 - Funding Information:
grant agreement 242095 to M.M.M., US National Institutes of Health grant AI079293 to K.A.F. and D.T.G., Austrian Science Fund grant SFB F28 to M.M. and B.S., Deutsche Forschungs Gesellschaft grants BA3544/1-1 and SFB704 (to W.B.), the Starr Foundation, the Greenberg Medical Research Institute and Bill & Melinda Gates Foundation grant OPP1021571 (subcontract R10291, M11R11017, all to C.M.R.). P.L. was supported by Fondation pour la Recherche Médicale and FCT (fellowship SFRH/BPD/41547/2007). V.Z.-L. was supported by European Molecular Biology Organization fellowship ALTF357-2009. D.C. and C.C. were supported by FCT fellowships (SFRH/BPD/64626/2009 and SFRH/BPD/40965/2007, respectively). M.S. was supported in part by a Helmsley Postdoctoral Fellowship for Basic and Translational Research on Disorders of the Digestive System at The Rockefeller University.
Funding Information:
Mavs−/− mice were from Z.J. Chen (South Western Medical School). Mda5−/− mice were from M. Colonna (Washington University). Rig-I−/−, Tlr3−/−, Tlr4−/−, Trif−/− and Myd88−/− mice were a gift from S. Akira (Osaka University). Trif−/− and Myd88−/− mice were used for generating Trif−/−; Myd88−/− mice. Irf7−/− and Irf3−/− mice were kindly provided by T. Taniguchi (University of Tokyo). We would like to thank A. Parreira for Anopheles stephensi production and infection, M. Rebelo for help with P. falciparum in vitro cultures, J. Ribot for help with chimeric mice and A. Zaidman-Rémy for critical reading of the manuscript. We are grateful to M. Seabra (CEDOC, Faculdade de Ciências Médicas) and A. Holder (UK Medical Research Council National Institute for Medical Research) for providing antisera. This work was supported by Fundação para a Ciência e Tecnologia (FCT, Portugal) grants (PTDC/SAU-GMG/100313/2008 to M.M.M., PTDC/SAU-GMG/104392/2008 to C.C. and PTDC/SAU-MIC/113697/2009 to V.Z.-L., and also by the European Research Council grant ERC-2012-StG_20111109 to M.M.M., the European Community’s Seventh Framework Programme (FP7/2007-2013)
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84891874162&partnerID=8YFLogxK
U2 - 10.1038/nm.3424
DO - 10.1038/nm.3424
M3 - Article
C2 - 24362933
AN - SCOPUS:84891874162
SN - 1078-8956
VL - 20
SP - 47
EP - 53
JO - Nature Medicine
JF - Nature Medicine
IS - 1
ER -
