Host-cell Sensors for Plasmodium Activate Innate Immunity Against Liver-stage Infection

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2013 Dec 24

PMID 24362933

Citations 162

Authors

Peter Liehl

Vanessa Zuzarte-Luis

Jennie Chan

Thomas Zillinger

Fernanda Baptista

Daniel Carapau

Madlen Konert

Kirsten K Hanson

Celine Carret

Caroline Lassnig

Mathias Muller

Ulrich Kalinke

Mohsan Saeed

Angelo Ferreira Chora

Douglas T Golenbock

Birgit Strobl

Miguel Prudencio

Luis P Coelho

Stefan H Kappe

Giulio Superti-Furga

Andreas Pichlmair

Ana M Vigario

Charles M Rice

Katherine A Fitzgerald

Winfried Barchet

Maria M Mota

Affiliations

Soon will be listed here.

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.

Citing Articles

Exploring the role of mitochondrial antiviral signaling protein in cardiac diseases.

Qi Y, Yin J, Xia W, Yang S Front Immunol. 2025; 16:1540774.

PMID: 40040697 PMC: 11876050. DOI: 10.3389/fimmu.2025.1540774.

Cytoadhesion of Plasmodium falciparum-Infected Red Blood Cells Changes the Expression of Cytokine-, Histone- and Antiviral Protein-Encoding Genes in Brain Endothelial Cells.

Allweier J, Bartels M, Torabi H, Tauler M, Metwally N, Roeder T Mol Microbiol. 2024; 122(6):948-967.

PMID: 39630601 PMC: 11658792. DOI: 10.1111/mmi.15331.

Role of inflammasomes in Toxoplasma and Plasmodium infections.

Wang Z, Jiao W, Yang Y, Liu H, Wang H Parasit Vectors. 2024; 17(1):466.

PMID: 39548522 PMC: 11566176. DOI: 10.1186/s13071-024-06529-6.

Host-pathogen interactions in the Plasmodium-infected mouse liver at spatial and single-cell resolution.

Hildebrandt F, Iturritza M, Zwicker C, Vanneste B, Van Hul N, Semle E Nat Commun. 2024; 15(1):7105.

PMID: 39160174 PMC: 11333755. DOI: 10.1038/s41467-024-51418-2.

Hepatocytes and the art of killing Plasmodium softly.

Marques-da-Silva C, Schmidt-Silva C, Kurup S Trends Parasitol. 2024; 40(6):466-476.

PMID: 38714463 PMC: 11156546. DOI: 10.1016/j.pt.2024.04.004.

References

Tsuji M, Mattei D, Nussenzweig R, Eichinger D, Zavala F . Demonstration of heat-shock protein 70 in the sporozoite stage of malaria parasites. Parasitol Res. 1994; 80(1):16-21. DOI: 10.1007/BF00932618. View

Barbalat R, Lau L, Locksley R, Barton G . Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands. Nat Immunol. 2009; 10(11):1200-7. PMC: 2821672. DOI: 10.1038/ni.1792. View

Goncalves L, Vigario A, Penha-Goncalves C . Improved isolation of murine hepatocytes for in vitro malaria liver stage studies. Malar J. 2007; 6:169. PMC: 2244635. DOI: 10.1186/1475-2875-6-169. View

Decker T, Muller M, Stockinger S . The yin and yang of type I interferon activity in bacterial infection. Nat Rev Immunol. 2005; 5(9):675-87. DOI: 10.1038/nri1684. View

Mueller A, Camargo N, Kaiser K, Andorfer C, Frevert U, Matuschewski K . Plasmodium liver stage developmental arrest by depletion of a protein at the parasite-host interface. Proc Natl Acad Sci U S A. 2005; 102(8):3022-7. PMC: 548321. DOI: 10.1073/pnas.0408442102. View

Shirey K, Nhu Q, Yim K, Roberts Z, Teijaro J, Farber D . The anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces IFN-beta-mediated antiviral activity in vitro and in vivo. J Leukoc Biol. 2010; 89(3):351-7. PMC: 3040469. DOI: 10.1189/jlb.0410216. View

Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M . The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004; 5(7):730-7. DOI: 10.1038/ni1087. View

Andrade B, Santos C, Camargo L, Souza-Neto S, Reis-Filho A, Clarencio J . Hepatitis B infection is associated with asymptomatic malaria in the Brazilian Amazon. PLoS One. 2011; 6(5):e19841. PMC: 3097216. DOI: 10.1371/journal.pone.0019841. View

Leiriao P, Mota M, Rodriguez A . Apoptotic Plasmodium-infected hepatocytes provide antigens to liver dendritic cells. J Infect Dis. 2005; 191(10):1576-81. DOI: 10.1086/429635. View

10.

Sriprawat K, Kaewpongsri S, Suwanarusk R, Leimanis M, Lek-Uthai U, Phyo A . Effective and cheap removal of leukocytes and platelets from Plasmodium vivax infected blood. Malar J. 2009; 8:115. PMC: 2694833. DOI: 10.1186/1475-2875-8-115. View

11.

Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R . Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005; 437(7062):1167-72. DOI: 10.1038/nature04193. View

12.

Honda K, Taniguchi T . IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol. 2006; 6(9):644-58. DOI: 10.1038/nri1900. View

13.

Sadler A, Williams B . Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008; 8(7):559-68. PMC: 2522268. DOI: 10.1038/nri2314. View

14.

Schoggins J, Wilson S, Panis M, Murphy M, Jones C, Bieniasz P . A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011; 472(7344):481-5. PMC: 3409588. DOI: 10.1038/nature09907. View

15.

Liehl P, Mota M . Innate recognition of malarial parasites by mammalian hosts. Int J Parasitol. 2012; 42(6):557-66. DOI: 10.1016/j.ijpara.2012.04.006. View

16.

Lopes da Silva M, Thieleke-Matos C, Cabrita-Santos L, Ramalho J, Wavre-Shapton S, Futter C . The host endocytic pathway is essential for Plasmodium berghei late liver stage development. Traffic. 2012; 13(10):1351-63. DOI: 10.1111/j.1600-0854.2012.01398.x. View

17.

Manel N, Hogstad B, Wang Y, Levy D, Unutmaz D, Littman D . A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature. 2010; 467(7312):214-7. PMC: 3051279. DOI: 10.1038/nature09337. View

18.

Xu L, Wang Y, Han K, Li L, Zhai Z, Shu H . VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005; 19(6):727-40. DOI: 10.1016/j.molcel.2005.08.014. View

19.

Schlee M, Roth A, Hornung V, Hagmann C, Wimmenauer V, Barchet W . Recognition of 5' triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity. 2009; 31(1):25-34. PMC: 2824854. DOI: 10.1016/j.immuni.2009.05.008. View

20.

Takeuchi O, Akira S . Pattern recognition receptors and inflammation. Cell. 2010; 140(6):805-20. DOI: 10.1016/j.cell.2010.01.022. View