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

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 A. J., Robertson, Avril A. B., King, Nicholas J., Suhrbier, Andreas, Cooper, Matthew A., Ng, Lisa F. P. and Mahalingam, Suresh (2017) Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation. Nature Microbiology, 2 10: 1-11. doi:10.1038/s41564-017-0015-4

Author 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 A. J.
Robertson, Avril A. B.
King, Nicholas J.
Suhrbier, Andreas
Cooper, Matthew A.
Ng, Lisa F. P.
Mahalingam, Suresh
Title Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation
Journal name Nature Microbiology   Check publisher's open access policy
ISSN 2058-5276
Publication date 2017-08-28
Year available 2017
Sub-type Article (original research)
DOI 10.1038/s41564-017-0015-4
Open Access Status Not yet assessed
Volume 2
Issue 10
Start page 1
End page 11
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 2404 Microbiology
2403 Immunology
2402 Applied Microbiology and Biotechnology
1311 Genetics
2726 Microbiology (medical)
1307 Cell Biology
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 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.
Keyword Immunology
Microbiology (medical)
Applied Microbiology and Biotechnology
Cell Biology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1079086
Institutional Status UQ

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Created: Thu, 07 Sep 2017, 13:40:00 EST by Richard Gordon on behalf of School of Biomedical Sciences