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Immunity to Malaria and Vaccine Strategies

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.00371

Human TLR8 senses RNA from Plasmodium falciparum-infected red blood cells which is uniquely required for the IFN-γ response in NK cells

 Christoph Coch1, 2*, Benjamin Hommertgen1, 2,  Thomas Zillinger1, 2, Juliane Daßler-Plenker1, 2,  Bastian Putchli1, 2,  Maximilian Nastaly1, 2, Beate M. Kümmerer1, 3,  Johanna Scheunemann1, 4,  Beatrix Schumak1, 4, Sabine Specht1, 4,  Martin Schlee1, 2, Winfried Barchet1, 2, Achim Hoerauf1, 4,  Eva Bartok1, 2 and Gunther Hartmann1, 2
  • 1Universität Bonn, Germany
  • 2Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Germany
  • 3Department of Virology, Germany
  • 4Institut für Medizinische Mikrobiologie, Immunologie und Parasitologie, Universität Bonn, Germany

During blood-stage malaria, the innate immune system initiates the production of pro-inflammatory cytokines, including IFN-γ, that are critical to host defense and responsible for severe disease. Nonetheless, the innate immune pathways activated during this process in human malaria remain poorly understood. Here, we identify TLR8 as an essential sensor of Plasmodium falciparum-infected red blood cells (iRBC). In human immune cells, iRBC and RNA purified from iRBC were detected by TLR8 but not TLR7 leading to IFN-γ induction in NK cells. While TLR7 and 9 have been shown to lead to IFN-γ in mice, our data demonstrate that TLR8 was the only TLR capable of inducing IFN-γ release in human immune cells. This unique capacity was mediated by the release of IL-12p70 and bioactive IL-18 from monocytes, the latter via a hitherto undescribed pathway. Altogether, our data are the first reported activation of TLR8 by protozoan RNA and demonstrate both the critical role of TLR8 in human blood-stage malaria and its unique functionality in the human immune system. Moreover, our study offers important evidence that mouse models alone may not be sufficient to describe the human innate immune response to malaria.

Keywords: Innate immune system, Toll-Like Receptor 8, interleukin 12p70, Interleukin 18, Interferon gamma (IFNγ), NK cells, Malaria, Plasmodium falciparum

Received: 25 Jul 2018; Accepted: 14 Feb 2019.

Edited by:

Julius Clemence Hafalla, London School of Hygiene and Tropical Medicine (LSHTM), United Kingdom

Reviewed by:

Roland Lang, University Hospital Erlangen, Germany
Eleanor Riley, Roslin Institute, University of Edinburgh, United Kingdom
Martin R. Goodier, London School of Hygiene and Tropical Medicine (LSHTM), United Kingdom  

Copyright: © 2019 Coch, Hommertgen, Zillinger, Daßler-Plenker, Putchli, Nastaly, Kümmerer, Scheunemann, Schumak, Specht, Schlee, Barchet, Hoerauf, Bartok and Hartmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD. Christoph Coch, Universität Bonn, Bonn, Germany,