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

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.

Systems Analysis of Subjects Acutely Infected with Chikungunya Virus

“…Importantly, these data account to explain our previous demonstration that NLRP3 inhibitors can interfere with the pathogenesis of CHIKV virus (24).…”

“…As the inflammasome-related genes are exclusively up-regulated in CHIKV infection and was described before in this context (24), we decided to provide a deeper proof-of-concept related to these findings. The murine bone marrow-derived macrophages were infected with CHIKV virus and the readouts of the inflammasome activation were measured.…”

“…It has been shown recently that the activation of NLRP3 leads to IL-1β and IL-18 production and was linked to the alphaviral disease severity in an animal model (24).…”

A potent prolyl tRNA synthetase inhibitor antagonizes Chikungunya and Dengue viruses

“…The typical vector responsible for transmission of CHIKV was Aedes aegypti , but a mutation in the viral envelope led to enhanced replication in the Aedes albopictus mosquitos present in temperate regions, potentially expanding the range of transmission (Tsetsarkin et al, 2007). CHIKV-induced arthropathy is due to viral replication and the ensuing host inflammatory response (Suhrbier et al, 2012), including inflammasome activation (Chen et al, 2017) and T-cell mediated pathogenesis (Amdekar et al, 2017). …”

“…Recently, it was shown that treatment of murine macrophages with halofuginone leads to sequestration of IL-1β mRNA into translationally inactive riboclusters, thereby suppressing the inflammasome (Battu et al, 2018). Since inflammasome activation plays a significant role in CHIKV pathogenesis (Chen et al, 2017), halofuginone may be efficacious against both viral replication and the subsequent arthralgia-inducing host inflammation. Furthermore, halofuginone downregulates NF-κB signaling pathway (Luo et al, 2018), which contributes to DENV-induced hemorrhage (Lin et al, 2014).…”