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2017 ; 91
(1
): ä Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
CLEC5A-Mediated Enhancement of the Inflammatory Response in Myeloid Cells
Contributes to Influenza Virus Pathogenicity In Vivo
#MMPMID27795434
Teng O
; Chen ST
; Hsu TL
; Sia SF
; Cole S
; Valkenburg SA
; Hsu TY
; Zheng JT
; Tu W
; Bruzzone R
; Peiris JSM
; Hsieh SL
; Yen HL
J Virol
2017[Jan]; 91
(1
): ä PMID27795434
show ga
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-?) and IP-10 but elevated alpha interferon
(IFN-?) 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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