Interleukin-17 contributes to Ross River virus-induced arthritis and myositis

Arthritogenic alphaviruses are mosquito-borne viruses that are a major cause of infectious arthropathies worldwide, and recent outbreaks of chikungunya virus and Ross River virus (RRV) infections highlight the need for robust intervention strategies. Alphaviral arthritis can persist for months after the initial acute disease, and is mediated by cellular immune responses. A common strategy to limit inflammation and pathology is to dampen the overwhelming inflammatory responses by modulating proinflammatory cytokine pathways. Here, we investigate the contribution of interleukin-17 (IL-17), a cytokine involved in arthropathies such as rheumatoid arthritis, in the development RRV-induced arthritis and myositis. IL-17 was quantified in serum from RRV-infected patients, and mice were infected with RRV and joints and muscle tissues collected to analyse cellular infiltrates, tissue mRNA, cytokine expression, and joint and muscle histopathology. IL-17 expression was increased in musculoskeletal tissues and serum of RRV-infected mice and humans, respectively. IL-17-producing T cells and neutrophils contributed to the cellular infiltrate in the joint and muscle tissue during acute RRV disease in mice. Blockade of IL-17A/F using a monoclonal antibody (mAb) reduced disease severity in RRV-infected mice and led to decreased proinflammatory proteins, cellular infiltration in synovial tissues and cartilage damage, without affecting viral titers in inflamed tissues. IL-17A/F blockade triggered a shift in transcriptional profile of both leukocyte infiltrates and musculoskeletal stromal cells by downregulating proinflammatory genes. This study highlights a previously uncharacterized role for an effector cytokine in alphaviral pathology and points towards potential therapeutic benefit in targeting IL-17 to treat patients presenting with RRV-induced arthropathy. Author summarySome viruses transmitted by mosquitoes cause painful and debilitating arthritis, which manifests both as an acute form shortly following infection, and a chronic form long after the initial symptoms have subsided. These viruses, termed arboviruses, are difficult to control and there are currently no specific treatments to alleviate the pain and loss of mobility. Arthritis caused by arboviruses shares similarities with a non-infectious, autoimmune form of arthritis called rheumatoid arthritis (RA). In RA, an immune molecule termed interleukin-17, or IL-17, has been shown to drive arthritis and treatments that target or block IL-17 are being developed to treat RA. Here, we asked whether arthritis caused by an arbovirus, Ross River virus (RRV), was also associated with elevated IL-17 in humans and mice. Disease severity in mice was associated with high IL-17 expression in the feet and muscle, and blocking IL-17 using an anti-IL-17 monoclonal antibody ameliorated disease in mice infected with RRV. Our study provides new information on a molecule that is implicated in arthritic inflammation, and could be targeted to treat disease caused by arthritogenic arboviruses.