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Article: CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza virus pathogenicity in vivo

TitleCLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza virus pathogenicity in vivo
Authors
KeywordsC-type lectins
CLEC5A
Influenza virus
Macrophages
Spleen tyrosine kinase (Syk)
Issue Date2017
PublisherAmerican Society for Microbiology. The Journal's web site is located at http://jvi.asm.org/
Citation
Journal of Virology, 2017, v. 91 n. 1, p. e01813-16:1-16 How to Cite?
AbstractHuman infections with influenza viruses exhibit mild to severe clinical outcomes as a result of complex virus-host interactions. Induction of inflammatory mediators via pattern recognition receptors may dictate subsequent host responses for pathogen clearance and tissue damage. We identified that human C-type lectin domain family 5 member A (CLEC5A) interacts with the hemagglutinin protein of influenza viruses expressed on lentiviral pseudoparticles through lectin screening. Silencing CLEC5A gene expression, blocking influenza-CLEC5A interactions with anti-CLEC5A antibodies, or dampening CLEC5A-mediated signaling using a spleen tyrosine kinase inhibitor consistently reduced the levels of proinflammatory cytokines produced by human macrophages without affecting the replication of influenza A viruses of different subtypes. Infection of bone marrow-derived macrophages from CLEC5A-deficient mice showed reduced levels of tumor necrosis factor alpha (TNF-α) and IP-10 but elevated alpha interferon (IFN-α) compared to those of wild-type mice. The heightened type I IFN response in the macrophages of CLEC5A-deficient mice was associated with upregulated TLR3 mRNA after treatment with double-stranded RNA. Upon lethal challenges with a recombinant H5N1 virus, CLEC5A-deficient mice showed reduced levels of proinflammatory cytokines, decreased immune cell infiltration in the lungs, and improved survival compared to the wild-type mice, despite comparable viral loads noted throughout the course of infection. The survival difference was more prominent at a lower dose of inoculum. Our results suggest that CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza pathogenicity in vivo and may be considered a therapeutic target in combination with effective antivirals. Well-orchestrated host responses together with effective viral clearance are critical for optimal clinical outcome after influenza infections.
Persistent Identifierhttp://hdl.handle.net/10722/237730
ISSN
2019 Impact Factor: 4.501
2015 SCImago Journal Rankings: 3.347
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTeng, O-
dc.contributor.authorChen, ST-
dc.contributor.authorHsu, TL-
dc.contributor.authorSia, SF-
dc.contributor.authorCole, SL-
dc.contributor.authorDoak, SA-
dc.contributor.authorHsu, TY-
dc.contributor.authorZheng, JT-
dc.contributor.authorTu, W-
dc.contributor.authorBruzzone, R-
dc.contributor.authorPeiris, JSM-
dc.contributor.authorHsieh, SAL-
dc.contributor.authorYen, H-
dc.date.accessioned2017-01-20T02:27:36Z-
dc.date.available2017-01-20T02:27:36Z-
dc.date.issued2017-
dc.identifier.citationJournal of Virology, 2017, v. 91 n. 1, p. e01813-16:1-16-
dc.identifier.issn0022-538X-
dc.identifier.urihttp://hdl.handle.net/10722/237730-
dc.description.abstractHuman infections with influenza viruses exhibit mild to severe clinical outcomes as a result of complex virus-host interactions. Induction of inflammatory mediators via pattern recognition receptors may dictate subsequent host responses for pathogen clearance and tissue damage. We identified that human C-type lectin domain family 5 member A (CLEC5A) interacts with the hemagglutinin protein of influenza viruses expressed on lentiviral pseudoparticles through lectin screening. Silencing CLEC5A gene expression, blocking influenza-CLEC5A interactions with anti-CLEC5A antibodies, or dampening CLEC5A-mediated signaling using a spleen tyrosine kinase inhibitor consistently reduced the levels of proinflammatory cytokines produced by human macrophages without affecting the replication of influenza A viruses of different subtypes. Infection of bone marrow-derived macrophages from CLEC5A-deficient mice showed reduced levels of tumor necrosis factor alpha (TNF-α) and IP-10 but elevated alpha interferon (IFN-α) compared to those of wild-type mice. The heightened type I IFN response in the macrophages of CLEC5A-deficient mice was associated with upregulated TLR3 mRNA after treatment with double-stranded RNA. Upon lethal challenges with a recombinant H5N1 virus, CLEC5A-deficient mice showed reduced levels of proinflammatory cytokines, decreased immune cell infiltration in the lungs, and improved survival compared to the wild-type mice, despite comparable viral loads noted throughout the course of infection. The survival difference was more prominent at a lower dose of inoculum. Our results suggest that CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza pathogenicity in vivo and may be considered a therapeutic target in combination with effective antivirals. Well-orchestrated host responses together with effective viral clearance are critical for optimal clinical outcome after influenza infections.-
dc.languageeng-
dc.publisherAmerican Society for Microbiology. The Journal's web site is located at http://jvi.asm.org/-
dc.relation.ispartofJournal of Virology-
dc.rightsJournal of Virology. Copyright © American Society for Microbiology.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectC-type lectins-
dc.subjectCLEC5A-
dc.subjectInfluenza virus-
dc.subjectMacrophages-
dc.subjectSpleen tyrosine kinase (Syk)-
dc.titleCLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza virus pathogenicity in vivo-
dc.typeArticle-
dc.identifier.emailTeng, O: oo1ean@hku.hk-
dc.identifier.emailSia, SF: sfsia@hkucc.hku.hk-
dc.identifier.emailCole, SL: scole@hku.hk-
dc.identifier.emailDoak, SA: sophiev@hku.hk-
dc.identifier.emailTu, W: wwtu@hku.hk-
dc.identifier.emailBruzzone, R: bruzzone@hkucc.hku.hk-
dc.identifier.emailPeiris, JSM: malik@hkucc.hku.hk-
dc.identifier.emailYen, H: hyen@hku.hk-
dc.identifier.authorityDoak, SA=rp02141-
dc.identifier.authorityTu, W=rp00416-
dc.identifier.authorityBruzzone, R=rp01442-
dc.identifier.authorityPeiris, JSM=rp00410-
dc.identifier.authorityYen, H=rp00304-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1128/JVI.01813-16-
dc.identifier.scopuseid_2-s2.0-85008150063-
dc.identifier.hkuros271027-
dc.identifier.volume91-
dc.identifier.issue1-
dc.identifier.spagee01813-
dc.identifier.epage16:1-
dc.identifier.isiWOS:000393189200030-
dc.publisher.placeUnited States-
dc.identifier.issnl0022-538X-

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