Abstract
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.
Highlights
Mosquito-borne viruses, or arboviruses, are a group of pathogens of major public health concern highlighted by several recent outbreaks of regional and global significance
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 River virus (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
Summary
Mosquito-borne viruses, or arboviruses, are a group of pathogens of major public health concern highlighted by several recent outbreaks of regional and global significance. Re-emerging arboviruses comprise two major families of RNA viruses, including flaviviruses (e.g. Zika) and alphaviruses (e.g. chikungunya, Ross River, Mayaro), each with their specific geographic distribution, mosquito vector specificity and disease aetiology. Arthritogenic alphaviruses, which include chikungunya (CHIKV), Ross River (RRV), Barmah Forest (BFV), Mayaro (MAYV) and o’nyong’nyong (ONNV) viruses cause severe joint and muscle inflammation leading to painful and debilitating arthritic disease [1–3]. Ross River virus (RRV) is an arthritogenic alphavirus endemic to Australia that is responsible for seasonal outbreaks that account for approximately 5000 cases each year, with recent, larger outbreaks affecting over 9000 people in 2015 [5], it is known to circulate in nearby southern Pacific islands [6]. Chronic arthralgia is common in RRVD patients and can persist for years, though the factors that trigger these persistent symptoms are not known. In the absence of vaccine, antivirals or targeted therapeutic solutions, RRV disease is generally treated with non-steroidal anti-inflammatory drugs (NSAIDs) or analgesics such as paracetamol, and recent clinical trials have shown some efficacy of pentosan polysulfate sodium (PPS), a sulphated polysaccharide, which is available as a prescription in Australia [10,11]
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