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 United States. 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 virus-induced
arthritis. Mouse models of RRV and CHIKV disease were used to characterize 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 fluorescence-activated cell sorting (FACS). Alphaviral
infection resulted in cartilage destruction, the severity of which was alleviated by PPS
therapy during RRV and CHIKV clinical disease. The reduction in cartilage damage corresponded with a significant reduction in immune infiltrates. Using multiplex bead arrays, PPS treatment was found to have significantly increased the anti-inflammatory
cytokine interleukin-10 and reduced proinflammatory
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 licensed 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
Elmiron for the treatment of
cystitis in the United States. Our findings show that RRV
infection damages the articular cartilage, including a loss of
proteoglycans within the 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 that PPS is a promising candidate for
drug repurposing for the treatment of alphavirus-induced
arthritis.