CLEC5A is critical for dengue-virus-induced lethal disease.
Dengue haemorrhagic fever and dengue shock syndrome, the most severe responses to dengue virus (DV) infection, are characterized by plasma leakage (due to increased vascular permeability) and low platelet counts. CLEC5A (C-type lectin domain family 5, member A; also known as myeloid DAP12-associating lectin (MDL-1)) contains a C-type lectin-like fold similar to the natural-killer T-cell C-type lectin domains and associates with a 12-kDa DNAX-activating protein (DAP12) on myeloid cells. Here we show that CLEC5A interacts with the dengue virion directly and thereby brings about DAP12 phosphorylation. The CLEC5A-DV interaction does not result in viral entry but stimulates the release of proinflammatory cytokines. Blockade of CLEC5A-DV interaction suppresses the secretion of proinflammatory cytokines without affecting the release of interferon-alpha, supporting the notion that CLEC5A acts as a signalling receptor for proinflammatory cytokine release. Moreover, anti-CLEC5A monoclonal antibodies inhibit DV-induced plasma leakage, as well as subcutaneous and vital-organ haemorrhaging, and reduce the mortality of DV infection by about 50% in STAT1-deficient mice. Our observation that blockade of CLEC5A-mediated signalling attenuates the production of proinflammatory cytokines by macrophages infected with DV (either alone or complexed with an enhancing antibody) offers a promising strategy for alleviating tissue damage and increasing the survival of patients suffering from dengue haemorrhagic fever and dengue shock syndrome, and possibly even other virus-induced inflammatory diseases.
Chen
Szu-Ting
ST
Department and Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan.
Lin
Yi-Ling
YL
Huang
Ming-Ting
MT
Wu
Ming-Fang
MF
Cheng
Shih-Chin
SC
Lei
Huan-Yao
HY
Lee
Chien-Kuo
CK
Chiou
Tzyy-Wen
TW
Wong
Chi-Huey
CH
Hsieh
Shie-Liang
SL
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003716:Dengue Virus / Q000378:metabolism* / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000821:virology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014779:Virus Replication; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D016898:Interferon-alpha; D037181:Lectins, C-Type; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C509771:CLEC5A protein, human; C494080:Stat1 protein, mouse; C110546:TYROBP protein, human