Specific Inhibition of NLRP3 in Chikungunya Disease Reveals a Role for Inflammasome in Alphavirus-Induced Inflammation
Ali Zaid1, Weiqiang Chen1, Suan Sin Foo1, Avril A.B. Robertson2, Nicholas J King3, Andreas Suhrbier4, Matthew A Cooper2, Lisa F.P. Ng2 and Suresh Mahalingam1 1Institute for Glycomics, Griffith University, Gold Coast, QLD4215, Australia; 2 School of Biomedical Science, The University of Queensland, Australia, St Lucia, QLD 4072, Australia; 3Discipline of Pathology, Bosch Institute, School of Medical Sciences, Sydney Medical School, Charles Perkins Centre, University of Sydney, Camperdown, NSW 2006, Australia; 4Inflammation Biology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; 5Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138632, Singapore
Mosquito-borne viruses such as Alphaviruses and Flaviviruses have been the cause of several outbreaks worldwide in the past 10 years. In some cases, the risk to public health was significant, as was seen with recent Chikungunya and Zika virus epidemics. Chikungunya virus (CHIKV) is an alphavirus that causes severe, debilitating arthritis, arthralgia and fever, and has emerged in various parts of the world since a landmark outbreak in the Indian Ocean in 2006. Inflammation in CHIKV disease has been attributed to host innate immune system, but the specific mechanisms remain to be elucidated. Cellular responses to pathogens or damage have been shown to involve inflammasome activation, leading to subsequent release of pro-inflammatory cytokines. We found that the NLRP3 inflammasome was activated during CHIKV infection in humans suffering acute disease, with showed high serum levels of IL-18 and IL-1b, and this observation was replicated in a mouse model of CHIKV infection. Administration of a specific, small-molecule inhibitor of NLRP3 to CHIKV-infected mice reduced inflammation score, and modulated the pro-inflammatory cytokine expression profile in inflamed tissue. In addition, NLRP3 inhibition reduced osteoclastogenic bone loss and muscle inflammation in CHIKV-infected mice. Importantly, while similar results were observed in mice infected with Ross River virus, an Australian Alphavirus, NLRP3 inhibition had no effect in a model of West Nile virus encephalitis, indicating both virus and tissue-specific mechanisms of inflammasome-driven responses. Our data shows that the NLRP3 inflammasome is a key driver of alphavirus-induced musculoskeletal inflammation, and that specific targeting of NLRP3 offers a viable therapeutic approach in light of past recent alphavirus outbreaks.
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