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

Nature Microbiology volume 2, pages 1435–1445 (2017)Cite this article

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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.

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Fig. 1: NLRP3, IL-18 and IL-1β expression is highly elevated in CHIKV-infected patients.
Fig. 2: CHIKV infection leads to rapid induction of inflammasomes in the ankle joints of mice.
Fig. 3: Treatment with NLRP3 and caspase-1 inhibitor ameliorates CHIKV-induced footpad swelling.
Fig. 4: Inhibition of inflammasome activation with MCC950 and Z-YVAD-FMK reduces pathological bone loss in CHIKV-infected mice.
Fig. 5: MCC950 and Z-YVAD-FMK treatment suppresses CHIKV-induced osteoclastogenesis.
Fig. 6: MCC950 and Z-YVAD-FMK treatment downregulates the expression of inflammasome components in CHIKV-infected mice.

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Acknowledgements

We thank S. Masters (the Walter and Eliza Hall Institute of Medical Research) for kindly providing the caspase-1–/– and ASC–/– mice. This study was supported by grants from the Australian National Health and Medical Research Council (NHMRC) to S.M. (APP1079086). S.M. is the recipient of an NHMRC Senior Research Fellowship (APP1059167) and A.S. is the recipient of an NHMRC Principal Research Fellowship (APP1058391).

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Author notes

  1. Weiqiang Chen & Suan-Sin Foo

    Present address: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA

  2. Weiqiang Chen, Suan Sin Foo and Ali Zaid contributed equally to this work.

Authors and Affiliations

  1. Emerging Viruses and Inflammation Research Group, Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia

    Weiqiang Chen, Suan-Sin Foo, Ali Zaid, Lara J. Herrero, Stefan Wolf, Kothila Tharmarajah, Adam Taylor, Joseph R. Freitas & Suresh Mahalingam

  2. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, 138632, Singapore

    Terk-Shin Teng & Lisa F. P. Ng

  3. Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK

    Terk-Shin Teng & Lisa F. P. Ng

  4. Discipline of Pathology, Bosch Institute, School of Medical Sciences, Sydney Medical School, Charles Perkins Centre, University of Sydney, Camperdown, NSW, 2006, Australia

    Luan D. Vu, Caryn van Vreden & Nicholas J. King

  5. The Medical School, The Australian National University, Acton, ACT, 2601, Australia

    Rachel W. Li

  6. Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Acton, ACT, 2601, Australia

    Rachel W. Li

  7. School of Biomedical Science, The University of Queensland, Australia, St Lucia, QLD, 4072, Australia

    Trent M. Woodruff & Richard Gordon

  8. Department of Biomedical Sciences, University of the Pacific, San Francisco, CA, 94103, USA

    David M. Ojcius

  9. Department of Pathophysiology and Toxicology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, CEP 05508-000, Brazil

    Helder I. Nakaya

  10. Department of Immunology, St Jude’s Children’s Hospital, Memphis, TN, 38105, USA

    Thirumala-Devi Kanneganti

  11. Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, College Green, Dublin, 2, Ireland

    Luke A. J. O’Neill

  12. Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia

    Avril A. B. Robertson & Matthew A. Cooper

  13. Inflammation Biology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia

    Andreas Suhrbier

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Contributions

W.C., L.F.P.N. and S.M. conceptualized and designed the study. W.C., S-S.F., A.Z., S.W., L.J.H., K.T., A.T. and J.R.F. performed the mouse CHIKV and RRV experiments and analysed the data. L.D.V. and C.v.V. performed the mouse WNV experiments and analysed the data. R.W.L. performed the bone computed tomography experiments and analysed the data. T.M.W. and R.G. performed MCC950 pharmacokinetics experiments and analysed the data. D.M.O., H.I.N., T-D.K., L.A.J.O., A.A.B.R., N.J.K., A.S. and M.A.C. provided the materials and analysis methods. A.Z. wrote the manuscript. A.Z., R.W.L., N.J.K., A.S., L.F.P.N., M.A.C. and S.M. reviewed and revised the manuscript.

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Correspondence to Suresh Mahalingam.

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Chen, W., Foo, SS., Zaid, A. et al. Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation. Nat Microbiol 2, 1435–1445 (2017). https://doi.org/10.1038/s41564-017-0015-4

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