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The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein
- Source :
- PLoS Pathogens, PLOS Pathogens, PLoS Pathogens, Vol 12, Iss 3, p e1005542 (2016), PLoS Pathogens, Vol 12, Iss 3, p e1005487 (2016)
- Publication Year :
- 2016
- Publisher :
- Public Library of Science, 2016.
-
Abstract
- Fatal Ebola virus infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is involved in this process through activating dendritic cells (DCs) and macrophages. However, the mechanism is unclear. Here, we showed that LSECtin (also known as CLEC4G) plays an important role in GP-mediated inflammatory responses in human DCs. Anti-LSECtin mAb engagement induced TNF-α and IL-6 production in DCs, whereas silencing of LSECtin abrogated this effect. Intriguingly, as a pathogen-derived ligand, Ebola GP could trigger TNF-α and IL-6 release by DCs through LSECtin. Mechanistic investigations revealed that LSECtin initiated signaling via association with a 12-kDa DNAX-activating protein (DAP12) and induced Syk activation. Mutation of key tyrosines in the DAP12 immunoreceptor tyrosine-based activation motif abrogated LSECtin-mediated signaling. Furthermore, Syk inhibitors significantly reduced the GP-triggered cytokine production in DCs. Therefore, our results demonstrate that LSECtin is required for the GP-induced inflammatory response, providing new insights into the EBOV-mediated inflammatory response.<br />Author Summary Ebola virus (EBOV), a highly virulent pathogen, causes a severe hemorrhagic fever syndrome. The fatal infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is thought to contribute to disease pathogenesis, as high amounts of shed GP from virus-infected cells are detected in patients, and activate macrophages and dendritic cells (DCs) to produce proinflammatory cytokines. Here, we show that LSECtin plays an important role in GP-mediated inflammatory responses in human DCs. LSECtin is a DAP12-coupled receptor able to initiate specific signaling events in human DCs. LSECtin interacts with Ebola GP and results in DAP12 phosphorylation. LSECtin knockdown impairs the production of proinflammatory cytokines induced by Ebola GP. Thus, this study suggests that LSECtin may contribute to Ebola GP-mediated pathogenicity.
- Subjects :
- 0301 basic medicine
RNA viruses
Viral Diseases
Physiology
medicine.medical_treatment
Syk
Ligands
medicine.disease_cause
Pathology and Laboratory Medicine
Biochemistry
Mice
0302 clinical medicine
Immune Physiology
Medicine and Health Sciences
Small interfering RNAs
Post-Translational Modification
Phosphorylation
Enzyme-Linked Immunoassays
lcsh:QH301-705.5
Immune Response
Mice, Inbred BALB C
Innate Immune System
biology
hemic and immune systems
Ebolavirus
Recombinant Proteins
Cell biology
Nucleic acids
Cytokine
Infectious Diseases
Medical Microbiology
Filoviruses
Viral Pathogens
Viruses
Cytokines
Tumor necrosis factor alpha
medicine.symptom
Signal transduction
Pathogens
Ebola Virus
Signal Transduction
Research Article
Neglected Tropical Diseases
lcsh:Immunologic diseases. Allergy
Immunology
Immunoblotting
Molecular Probe Techniques
Inflammation
Research and Analysis Methods
Ebola Hemorrhagic Fever
Microbiology
03 medical and health sciences
Signs and Symptoms
Virology
medicine
Genetics
Animals
Humans
Gene silencing
Lectins, C-Type
Interleukin 6
Non-coding RNA
Immunoassays
Molecular Biology Techniques
Molecular Biology
Microbial Pathogens
Adaptor Proteins, Signal Transducing
Glycoproteins
Viral Hemorrhagic Fevers
Ebola virus
Biology and life sciences
Interleukin-6
Tumor Necrosis Factor-alpha
Hemorrhagic Fever Viruses
Macrophages
Organisms
Correction
Membrane Proteins
Proteins
Dendritic Cells
Hemorrhagic Fever, Ebola
Molecular Development
Tropical Diseases
Gene regulation
030104 developmental biology
lcsh:Biology (General)
Immune System
biology.protein
Immunologic Techniques
RNA
Parasitology
Gene expression
lcsh:RC581-607
030215 immunology
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 12
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....57d5e1dd226a7ab3356b9f669a90e4e2