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Nat Microbiol. 2017 Oct;2(10):1435-1445. doi: 10.1038/s41564-017-0015-4. Epub 2017 Aug 28.

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

Author information

1
Emerging Viruses and Inflammation Research Group, Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia.
2
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
3
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, 138632, Singapore.
4
Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK.
5
Discipline of Pathology, Bosch Institute, School of Medical Sciences, Sydney Medical School, Charles Perkins Centre, University of Sydney, Camperdown, NSW, 2006, Australia.
6
The Medical School, The Australian National University, Acton, ACT, 2601, Australia.
7
Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Acton, ACT, 2601, Australia.
8
School of Biomedical Science, The University of Queensland, Australia, St Lucia, QLD, 4072, Australia.
9
Department of Biomedical Sciences, University of the Pacific, San Francisco, CA, 94103, USA.
10
Department of Pathophysiology and Toxicology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, CEP 05508-000, Brazil.
11
Department of Immunology, St Jude's Children's Hospital, Memphis, TN, 38105, USA.
12
Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, College Green, Dublin, 2, Ireland.
13
Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia.
14
Inflammation Biology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
15
Emerging Viruses and Inflammation Research Group, Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia. s.mahalingam@griffith.edu.au.

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.

PMID:
28848230
DOI:
10.1038/s41564-017-0015-4
[Indexed for MEDLINE]

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