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  • Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation

    Author(s)
    Chen, Weiqiang
    Foo, Suan-Sin
    Zaid, Ali
    Teng, Terk-Shin
    Herrero, Lara J
    Wolf, Stefan
    Tharmarajah, Kothila
    Vu, Luan D
    van Vreden, Caryn
    Taylor, Adam
    Freitas, Joseph R
    Li, Rachel W
    Woodruff, Trent M
    Gordon, Richard
    Ojcius, David M
    Nakaya, Helder I
    Kanneganti, Thirumala-Devi
    O'Neill, Luke AJ
    Robertson, Avril AB
    King, Nicholas J
    Suhrbier, Andreas
    Cooper, Matthew A
    Ng, Lisa FP
    Mahalingam, Suresh
    Griffith University Author(s)
    Wolf, Stefan
    Mahalingam, Suresh
    Herrero, Lara J.
    Foo, Jolin
    Chen, Javier
    Taylor, Adam
    Freitas, Joseph R.
    Zaid, Ali
    Tharmarajah, Kothila
    Year published
    2017
    Metadata
    Show full item record
    Abstract
    Mosquito-borne viruses can cause severe inflammatory diseases and there are limited therapeutic solutions targeted specifically at virus-induced inflammation. Chikungunya virus (CHIKV), a re-emerging alphavirus responsible for several outbreaks worldwide in the past decade, causes debilitating joint inflammation and severe pain. Here, we show that CHIKV infection activates the NLRP3 inflammasome in humans and mice. Peripheral blood mononuclear cells isolated from CHIKV-infected patients showed elevated NLRP3, caspase-1 and interleukin-18 messenger RNA expression and, using a mouse model of CHIKV infection, we found that high ...
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    Mosquito-borne viruses can cause severe inflammatory diseases and there are limited therapeutic solutions targeted specifically at virus-induced inflammation. Chikungunya virus (CHIKV), a re-emerging alphavirus responsible for several outbreaks worldwide in the past decade, causes debilitating joint inflammation and severe pain. Here, we show that CHIKV infection activates the NLRP3 inflammasome in humans and mice. Peripheral blood mononuclear cells isolated from CHIKV-infected patients showed elevated NLRP3, caspase-1 and interleukin-18 messenger RNA expression and, using a mouse model of CHIKV infection, we found that high NLRP3 expression was associated with peak inflammatory symptoms. Inhibition of NLRP3 activation using the small-molecule inhibitor MCC950 resulted in reduced CHIKV-induced inflammation and abrogated osteoclastogenic bone loss and myositis, but did not affect in vivo viral replication. Mice treated with MCC950 displayed lower expression levels of the cytokines interleukin-6, chemokine ligand 2 and tumour necrosis factor in joint tissue. Interestingly, MCC950 treatment abrogated disease signs in mice infected with a related arthritogenic alphavirus, Ross River virus, but not in mice infected with West Nile virus—a flavivirus. Here, using mouse models of alphavirus-induced musculoskeletal disease, we demonstrate that NLRP3 inhibition in vivo can reduce inflammatory pathology and that further development of therapeutic solutions targeting inflammasome function could help treat arboviral diseases.
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    Journal Title
    Nature Microbiology
    Volume
    2
    DOI
    https://doi.org/10.1038/s41564-017-0015-4
    Subject
    Microbiology
    Microbiology not elsewhere classified
    Medical microbiology
    Publication URI
    http://hdl.handle.net/10072/374720
    Collection
    • Journal articles

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