The C-type Lectin Receptor CLEC12A Recognizes Plasmodial Hemozoin and Contributes to Cerebral Malaria Development

Marie-Kristin Raulf; Timo Johannssen; Svea Matthiesen; Konstantin Neumann; Severin Hachenberg; Sabine Mayer-Lambertz; Fridolin Steinbeis; Jan Hegermann; Peter H Seeberger; Wolfgang Baumgärtner; Christina Strube; Jürgen Ruland; Bernd Lepenies

doi:10.1016/j.celrep.2019.06.015

The C-type Lectin Receptor CLEC12A Recognizes Plasmodial Hemozoin and Contributes to Cerebral Malaria Development

Cell Rep. 2019 Jul 2;28(1):30-38.e5. doi: 10.1016/j.celrep.2019.06.015.

Affiliations

¹ Immunology Unit and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Lower Saxony, Germany; Institute for Parasitology, Centre for Infection Medicine, University of Veterinary Medicine Hannover, 30559 Hannover, Lower Saxony, Germany.
² Immunology Unit and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Lower Saxony, Germany; Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Brandenburg, Germany; Department of Biology, Chemistry and Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
³ Immunology Unit and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Lower Saxony, Germany.
⁴ Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Bavaria, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Lower Saxony, Germany.
⁵ Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Brandenburg, Germany; Charité-Universitätsmedizin Berlin, Klinik mit Schwerpunkt Infektiologie und Pneumologie, 13353 Berlin, Berlin, Germany.
⁶ Research Core Unit Electron Microscopy, Hannover Medical School, 30625 Hannover, Lower Saxony, Germany.
⁷ Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Brandenburg, Germany; Department of Biology, Chemistry and Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
⁸ Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Lower Saxony, Germany.
⁹ Institute for Parasitology, Centre for Infection Medicine, University of Veterinary Medicine Hannover, 30559 Hannover, Lower Saxony, Germany.
¹⁰ Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Bavaria, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Baden-Württemberg, Germany; German Center for Infection Research (DZIF), Partner Site Munich, Munich, Bavaria, Germany.
¹¹ Immunology Unit and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Lower Saxony, Germany; Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Brandenburg, Germany; Department of Biology, Chemistry and Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany. Electronic address: bernd.lepenies@tiho-hannover.de.

Abstract

Malaria represents a major cause of death from infectious disease. Hemozoin is a Plasmodium-derived product that contributes to progression of cerebral malaria. However, there is a gap of knowledge regarding how hemozoin is recognized by innate immunity. Myeloid C-type lectin receptors (CLRs) encompass a family of carbohydrate-binding receptors that act as pattern recognition receptors in innate immunity. In the present study, we identify the CLR CLEC12A as a receptor for hemozoin. Dendritic cell-T cell co-culture assays indicate that the CLEC12A/hemozoin interaction enhances CD8⁺ T cell cross-priming. Using the Plasmodium berghei Antwerpen-Kasapa (ANKA) mouse model of experimental cerebral malaria (ECM), we find that CLEC12A deficiency protects mice from ECM, illustrated by reduced ECM incidence and ameliorated clinical symptoms. In conclusion, we identify CLEC12A as an innate sensor of plasmodial hemozoin.

Keywords: C-type lectin receptor; MICL/CLEC12A; Plasmodium berghei; cerebral malaria; hemozoin.

Publication types

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

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology
Cross-Priming
Dendritic Cells / immunology
Disease Models, Animal
Granzymes / metabolism
Hemeproteins / immunology*
Immunity, Innate
Lectins, C-Type / genetics
Lectins, C-Type / immunology*
Malaria, Cerebral / immunology*
Mice
Mice, Inbred C57BL
Plasmodium berghei / pathogenicity*
Receptors, Mitogen / genetics
Receptors, Mitogen / immunology*
T-Lymphocytes

Substances

CLEC12A protein, human
CLEC12A protein, mouse
Hemeproteins
Lectins, C-Type
Receptors, Mitogen
hemozoin
Granzymes