Pentosan polysulfate: a novel glycosaminoglycan-like molecule for the effective treatment of alphavirus-induced cartilage destruction and inflammatory disease
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Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease and have been progressively expanding their global distribution. Since its introduction in July 2014, CHIKV now circulates in the USA . The hallmark of alphavirus disease is crippling pain and inflammation of the joints, a similar immunopathology to rheumatoid arthritis. The use of glycans as novel therapeutics is an area of research that has increased in recent years. Here we describe the promising therapeutic potential of the glycosaminoglycan (GAG)-like molecule pentosan polysulfate (PPS) to alleviate viral-induced arthritis. Mouse models of RRV and CHIKV disease were used to characterise the extent of cartilage damage in infection and investigate the potential of PPS to treat disease. This was assessed using histological analysis, real-time PCR and FACS. Alphaviral-infection resulted in cartilage destruction, the severity of which was alleviated by PPS therapy during RRV and CHIKV clinical disease. Reduction in cartilage damage corresponded with a significant reduction in immune infiltrates. Using multiplex analysis, PPS treatment significantly increased the anti-inflammatory cytokine interleukin-10 and reduced pro-inflammatory cytokines, typically correlated with disease severity. Furthermore, we reveal that the severe RRV-induced joint pathology, including thinning of articular cartilage and loss of proteoglycans in the cartilage matrix, was diminished with treatment. PPS is a promising new therapy for alphavirus induced arthritis acting to preserve the cartilage matrix, which is damaged during alphavirus infection. Overall the data demonstrate the potential of glycotherapeutics as a new class of treatment for infectious arthritis. Importance The hallmark of alphavirus disease is crippling pain and joint arthritis, which often has an extended duration. In the past year, CHIKV has expanded into the Americas with approximately 1-million cases reported to date, whereas RRV continues to circulate in the South Pacific. Currently there is no licenced specific treatment for alphavirus disease and the increasing spread of infection highlights an urgent need for therapeutic intervention strategies. Pentosan polysulfate (PPS) is a glycan derivative that is orally bioavailable, has few toxic side effects and is currently licensed under the name Elmironor the treatment of cystitis in the USA. Our findings show RRV infection damages the articular cartilage including a loss of proteoglycans within joint. Furthermore, treatment with PPS reduced the severity of both RRV- and CHIKV-induced musculoskeletal disease, including a reduction in inflammation and joint swelling, suggesting PPS is a promising candidate for drug-repurposing for the treatment of alphavirus-induced arthritis.
Journal of Virology
Copyright 2015 American Society for Microbiology. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.