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Alphaviruses, such as chikungunya virus and Ross River virus (RRV), are associated with outbreaks of infectious rheumatic disease in humans worldwide. Using an established mouse model of disease that mimics RRV disease in humans, we showed that macrophage-derived factors are critical in the development of striated muscle and joint tissue damage. Histologic analyses of muscle and ankle joint tissues demonstrated a substantial reduction in inflammatory infiltrates in infected mice depleted of macrophages (i.e., "macrophage-depleted mice"). Levels of the proinflammatory factors tumor necrosis factor-alpha, interferon-gamma, and macrophage chemoattractant protein-1 were also dramatically reduced in tissue samples obtained from infected macrophage-depleted mice, compared with samples obtained from infected mice without macrophage depletion. These factors were also detected in the synovial fluid of patients with RRV-induced polyarthritis. Neutralization of these factors reduced the severity of disease in mice, whereas blocking nuclear factor kappaB by treatment with sulfasalazine ameliorated RRV inflammatory disease and tissue damage. To our knowledge, these findings are the first to demonstrate that macrophage-derived products play important roles in the development of arthritis and myositis triggered by alphavirus infection.
Dendritic cells (DCs) are an important early target cell for many mosquito-borne viruses, and in many cases mosquito-cell-derived arboviruses more efficiently infect DCs than viruses derived from mammalian cells. However, whether mosquito-cell-derived viruses differ from mammalian-cell-derived viruses in their ability to induce antiviral responses in the infected dendritic cell has not been evaluated. In this report, alphaviruses, which are mosquito-borne viruses that cause diseases ranging from encephalitis to arthritis, were used to determine whether viruses grown in mosquito cells differed from mammalian-cell-derived viruses in their ability to induce type I interferon (IFN) responses in infected primary dendritic cells. Consistent with previous results, mosquito-cell-derived Ross River virus (mos-RRV) and Venezuelan equine encephalitis virus (mos-VEE) exhibited enhanced infection of primary myeloid dendritic cells (mDCs) compared to mammalian-cellderived virus preparations. However, unlike the mammalian-cell-derived viruses, which induced high levels of type I IFN in the infected mDC cultures, mos-RRV and mos-VEE were poor IFN inducers. Furthermore, the poor IFN induction by mos-RRV contributed to the enhanced infection of mDCs by mos-RRV. These results suggest that the viruses initially delivered by the mosquito vector differ from those generated in subsequent rounds of replication in the host, not just with respect to their ability to infect dendritic cells but also in their ability to induce or inhibit antiviral type I IFN responses. This difference may have an important impact on the mosquito-borne virus's ability to successfully make the transition from the arthropod vector to the vertebrate host.
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.Interleukin-6 | Ross River virus disease | viral arthritis | osteoclastogenesis A rthritogenic alphaviruses including Ross River virus (RRV), chikungunya virus (CHIKV), Sindbis virus (SINV), o'nyongnyong virus (ONNV), and Barmah Forest virus (BFV) are classified under the genus Alphavirus ("Old World" alphaviruses) of the Togaviridae family (1). RRV is a small, enveloped, positivesense single-stranded RNA virus transmitted by mosquitoes (2, 3). RRV disease (RRVD) in humans commonly affects the ankles, knees, and peripheral joints. The hallmarks of RRVD include incapacitating joint pain and polyarthralgias, with a level of disability comparable to rheumatoid arthritis (RA) (4, 5). Similar to RA, the onset of RRVD can be sudden and debilitating, and the prolonged manifestations of RRVD in some patients have been proposed to be due to the actions of proinflammatory mediators including interleukin-6 (IL-6), interleukin-1 (IL-1), and chemokine (C-C motif) ligand 2; monocyte chemotactic protein-1 (CCL2; MCP-1) (6-8).Recently, bone lesions in joints of CHIKV-infected patients have been reported (9), providing evidence that alphavirusinduced disease can result in bone pathologies (10, 11). In physiological conditions, osteoblasts (OBs) form bone, and this cell lineage also expresses both receptor activator of nuclear factorkappaB ligand (RANKL) and its soluble decoy receptor, osteoprotegerin (OPG). The expression of RANKL by the OB lineage is stimulated by IL-6 and IL-1β among other proinflammatory cytokines (12, 13), whereas CCL2 is thought to be an important chemoattractant for monocytic precursors during inflammatory processes (14,15). Together with an elevation in RANKL/OPG...
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