Article ; Online: CLEC5A-Mediated Enhancement of the Inflammatory Response in Myeloid Cells Contributes to Influenza Virus Pathogenicity In Vivo.
2016 Volume 91, Issue 1
Abstract: ... in myeloid cells contributes to influenza pathogenicity in vivo and may be considered a therapeutic target ... that dampening CLEC5A-mediated inflammatory responses in myeloid cells reduces immunopathogenesis after influenza ... in myeloid cells after influenza infections. CLEC5A-deficient mice infected with influenza virus showed reduced ...
| Abstract | Human 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. Importance: Multiple pattern recognition receptors work in synergy to sense viral RNA or proteins synthesized during influenza replication and mediate host responses for viral control. Well-orchestrated host responses may help to maintain the inflammatory response to minimize tissue damage while inducing an effective adaptive immune response for viral clearance. We identified that CLEC5A, a C-type lectin receptor which has previously been reported to mediate flavivirus-induced inflammatory responses, enhanced induction of proinflammatory cytokines and chemokines in myeloid cells after influenza infections. CLEC5A-deficient mice infected with influenza virus showed reduced inflammation in the lungs and improved survival compared to that of the wild-type mice despite comparable viral loads. The survival difference was more prominent at a lower dose of inoculum. Collectively, our results suggest that dampening CLEC5A-mediated inflammatory responses in myeloid cells reduces immunopathogenesis after influenza infections. |
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| MeSH term(s) | Animals ; Antibodies/pharmacology ; Chemokine CXCL10/genetics ; Chemokine CXCL10/immunology ; Gene Expression Regulation ; Hemagglutinin Glycoproteins, Influenza Virus/genetics ; Hemagglutinin Glycoproteins, Influenza Virus/immunology ; Host-Pathogen Interactions ; Humans ; Influenza A Virus, H1N1 Subtype/growth & development ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza A Virus, H1N1 Subtype/pathogenicity ; Influenza A Virus, H5N1 Subtype/growth & development ; Influenza A Virus, H5N1 Subtype/immunology ; Influenza A Virus, H5N1 Subtype/pathogenicity ; Interferon-alpha/genetics ; Interferon-alpha/immunology ; Lectins, C-Type/antagonists & inhibitors ; Lectins, C-Type/genetics ; Lectins, C-Type/immunology ; Lentivirus/genetics ; Lentivirus/immunology ; Lung/drug effects ; Lung/immunology ; Lung/virology ; Macrophages/drug effects ; Macrophages/immunology ; Macrophages/virology ; Macrophages, Alveolar/drug effects ; Macrophages, Alveolar/immunology ; Macrophages, Alveolar/virology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Orthomyxoviridae Infections/genetics ; Orthomyxoviridae Infections/immunology ; Orthomyxoviridae Infections/mortality ; Orthomyxoviridae Infections/virology ; Primary Cell Culture ; Protein Binding ; Protein Isoforms/genetics ; Protein Isoforms/immunology ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Receptors, Cell Surface/antagonists & inhibitors ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/immunology ; Survival Analysis ; Toll-Like Receptor 3/genetics ; Toll-Like Receptor 3/immunology ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/immunology | |||||
| Chemical Substances | Antibodies ; CLEC5A protein, human ; Chemokine CXCL10 ; Cxcl10 protein, mouse ; Hemagglutinin Glycoproteins, Influenza Virus ; Interferon-alpha ; Lectins, C-Type ; Protein Isoforms ; RNA, Small Interfering ; Receptors, Cell Surface ; TLR3 protein, mouse ; Toll-Like Receptor 3 ; Tumor Necrosis Factor-alpha ; hemagglutinin, human influenza A virus | |||||
| Language | English | |||||
| Publishing date | 2016-12-16 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 80174-4 | |||||
| ISSN | 1098-5514 ; 0022-538X | |||||
| ISSN (online) | 1098-5514 | |||||
| ISSN | 0022-538X | |||||
| DOI | 10.1128/JVI.01813-16 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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