tetano
Editor, Senior Moderator
J Virol. 2016 Oct 19. pii: JVI.01813-16. [Epub ahead of print]
[h=1]CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza pathogenicity in vivo.[/h] Teng O[SUP]1,[/SUP][SUP]2[/SUP], Chen ST[SUP]3[/SUP], Hsu TL[SUP]4[/SUP], Sia SF[SUP]2[/SUP], Cole S[SUP]2[/SUP], Valkenburg SA[SUP]1,[/SUP][SUP]2[/SUP], Hsu TY[SUP]3[/SUP], Zheng JT[SUP]5[/SUP], Tu W[SUP]5[/SUP], Bruzzone R[SUP]1,[/SUP][SUP]2[/SUP], Peiris JS[SUP]1,[/SUP][SUP]2[/SUP], Hsieh SL[SUP]6,[/SUP][SUP]4,[/SUP][SUP]7[/SUP], Yen HL[SUP]8,[/SUP][SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]IMPORTANCE:[/h] 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
[h=1]CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza pathogenicity in vivo.[/h] Teng O[SUP]1,[/SUP][SUP]2[/SUP], Chen ST[SUP]3[/SUP], Hsu TL[SUP]4[/SUP], Sia SF[SUP]2[/SUP], Cole S[SUP]2[/SUP], Valkenburg SA[SUP]1,[/SUP][SUP]2[/SUP], Hsu TY[SUP]3[/SUP], Zheng JT[SUP]5[/SUP], Tu W[SUP]5[/SUP], Bruzzone R[SUP]1,[/SUP][SUP]2[/SUP], Peiris JS[SUP]1,[/SUP][SUP]2[/SUP], Hsieh SL[SUP]6,[/SUP][SUP]4,[/SUP][SUP]7[/SUP], Yen HL[SUP]8,[/SUP][SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]IMPORTANCE:[/h] 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