Pentosan polysulfate: A novel glycosaminoglycan-like molecule for effective treatment of alphavirus-induced cartilage destruction and inflammatory disease
Autor(es): Herrero Lara J, Foo Suan-Sin, Sheng Kuo-Ching, Chen Weiqiang, Forwood Mark R, Bucala Richard, Mahalingam Suresh
Resumo: Arthritogenic alphaviruses such as Ross River virus (RRV) - chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease - have been progressively exp-ing their global distribution. Since its introduction in July 2014, CHIKV now circulates in the United States. The hallmark of alphavirus disease is crippling pain - 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 - CHIKV disease were used to characterize the extent of cartilage damage in infection - investigate the potential of PPS to treat disease. This was assessed using histological analysis, real-time PCR, - fluorescence-activated cell sorting (FACS). Alphaviral infection resulted in cartilage destruction, the severity of which was alleviated by PPS therapy during RRV - 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 - reduced proinflammatory cytokines, typically correlated with disease severity. Furthermore, we reveal that the severe RRV-induced joint pathology, including thinning of articular cartilage - 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. The hallmark of alphavirus disease is crippling pain - joint arthritis, which often has an extended duration. In the past year, CHIKV has exp-ed 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, - 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, - 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- - CHIKV-induced musculoskeletal disease, including a reduction in inflammation - joint swelling, suggesting that PPS is a promising c-idate for drug repurposing for the treatment of alphavirus-induced arthritis.
Imprenta: Journal of Virology, v. 89, n. 15, p. 8063-8076, 2015
Identificador do objeto digital: 10.1128/JVI.00224-15
Descritores: Chikungunya virus - Cell ; Chikungunya virus - Cytopathology ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Cytokines ; Chikungunya virus - Immunopathology ; Chikungunya virus - Infectious diseases ; Chikungunya virus - Inflammation ; Chikungunya virus - Viral infections ; Chikungunya virus - Real Time PCR ; Chikungunya Virus - Virus ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Epidemic ; Chikungunya virus - Immunology
Data de publicação: 2015
