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

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

    J Virol. 2016 Oct 19. pii: JVI.01813-16. [Epub ahead of print]
    CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza pathogenicity in vivo.

    Teng O1,2, Chen ST3, Hsu TL4, Sia SF2, Cole S2, Valkenburg SA1,2, Hsu TY3, Zheng JT5, Tu W5, Bruzzone R1,2, Peiris JS1,2, Hsieh SL6,4,7, Yen HL8,2.
    Author information

    Abstract

    Human infections with influenza viruses exhibit mild to severe clinical outcome 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 member 5A (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 pro-inflammatory 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 TNF-α and IP-10 but elevated IFN-α compared to wild-type mice. The heightened type-I IFN response in the macrophages of CLEC5A-deficient mice was associated with up-regulated TLR3 mRNA after treatment with double stranded RNA. Upon lethal challenges with a recombinant H5N1 virus, CLEC5A-deficient mice showed reduced levels of pro-inflammatory 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 as 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 at gate 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 pro-inflammatory 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 than 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 may reduce immunopathogenesis after influenza infections.
    Copyright ? 2016 Teng et al.


    PMID: 27795434 DOI: 10.1128/JVI.01813-16
    [PubMed - as supplied by publisher] Free full text
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