Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss

Arthritogenic alphaviruses including Ross River virus (RRV), Sindbis virus, and chikungunya virus cause worldwide outbreaks of musculoskeletal disease. The ability of alphaviruses to induce bone pathologies remains poorly defined. Here we show that primary human osteoblasts (hOBs) can be productively infected by RRV. RRV-infected hOBs produced high levels of inflammatory cytokine including IL-6. The RANKL/OPG ratio was disrupted in the synovial fluid of RRV patients, and this was accompanied by an increase in serum Tartrate-resistant acid phosphatase 5b (TRAP5b) levels. Infection of bone cells with RRV was validated using an established RRV murine model. In wild-type mice, infectious virus was detected in the femur, tibia, patella, and foot, together with reduced bone volume in the tibial epiphysis and vertebrae detected by microcomputed tomographic (μCT) analysis. The RANKL/OPG ratio was also disrupted in mice infected with RRV; both this effect and the bone loss were blocked by treatment with an IL-6 neutralizing antibody. Collectively, these findings provide previously unidentified evidence that alphavirus infection induces bone loss and that OBs are capable of producing proinflammatory mediators during alphavirus-induced arthralgia. The perturbed RANKL/OPG ratio in RRV-infected OBs may therefore contribute to bone loss in alphavirus infection

Methotrexate treatment causes early onset of disease in a mouse model of Ross River virus-induced inflammatory disease through increased monocyte production.

Part of the Togaviridae family, alphaviruses, including chikungunya virus (CHIKV), Sindbis virus (SINV) and Ross River virus (RRV), are able to cause significant inflammatory pathologies ranging from arthritis to encephalitis. Following symptomatic infection with arthritis-associated alphaviruses, patients often experience severe joint pain, affecting distal and small joints, which can last six months or longer. Recently, methotrexate (MTX), a disease modifying anti-rheumatic drug (DMARD), was used to treat patients experiencing chronic rheumatic symptoms following infection with CHIKV. Here, the effect of MTX on Ross River virus disease (RRVD) in mice was examined to better understand its therapeutic potential for alphaviral-induced musculoskeletal disease and to further our knowledge of the development of alphaviral pathologies. Using a mouse model, we analyzed the effect of MTX on RRVD. RRV disease pathogenesis in response to MTX treatment was determined by measuring levels of proinflammatory factors, cellular infiltrates, viral titer and histological analysis of infected tissues. RRV-infected mice receiving MTX treatment rapidly developed musculoskeletal disease, which correlated with a significant influx of inflammatory cell infiltrates into the skeletal muscle tissue. Although no difference was observed in the level of proinflammatory cytokines and chemokines, the viral load increased at early time points post infection in the serum and quadriceps of MTX treated mice, possibly contributing to disease pathogenesis. Results suggest that MTX treatment of acute RRVD in mice provides no therapeutic benefit and underline the importance of inflammatory monocytes in alphaviral induced arthritides

Ross River Virus: An Arthritogenic Alphavirus of Significant Importance in the Asia Pacific

Ross River virus is a mosquito transmitted disease endemic in tropical Australia, Papua New Guinea, East Timor, adjacent islands of Indonesia and the Solomon islands. It occurs epidemically in temperate Australia and sporadically in Pacific Islands, such as Fiji, Tonga, Samoa and the Cook Islands. It is the most common arbovirus disease in Australia. The disease occurs mainly in adults, with clinical symptoms rare before puberty. The symptoms are rash, joint pain and general effects such as fatigue, fever and muscle pain, which appear from 3 to 21 days post-infection and can persist for 3-6 months. In Australia, Ross River virus is responsible for an average of 8,000 cases annually. The long-term effects of Ross River virus disease are thought to be due to the virus's ability to evade the patient's immune system. Antibodies produced against the virus may be insufficient to neutralise it and may even improve the ability of the virus to infect host cells (antibody-dependent enhancement). The virus is also capable of persisting for long periods in macrophages and may be reactivated during times of stress. Various human host proteins may also increase Ross River virus infection rates and contribute to disease symptoms.No Full Tex

Ross River virus: molecular and cellular aspects of disease pathogenesis

Ross River virus (RRV) is a mosquito-borne alphavirus indigenous to Australia and the Western Pacific region and is responsible for several thousand cases of human RRV disease (RRVD) per annum. The disease primarily involves polyarthritis/arthralgia, with many patients also presenting with rash, myalgia, fever, and/or lethargy. The symptoms can be debilitating at onset, but they usually resolve within 3-6 months. Recent insights into the RRV-host relationship, associated pathology, and molecular biology of infection have generated a number of potential avenues for improved treatment. Although vaccine development has been proposed, the small market size and potential for antibody-dependent enhancement (ADE) of disease make this approach unattractive. Recent insights into the molecular basis of RRV-ADE and the virus's ability to manipulate host inflammatory and immune responses create potential new opportunities for therapeutic invention. Such interventions should overcome virus-induced dysregulation of protective host responses to promote viral clearance and/or ameliorate inflammatory immunopathology