Chikungunya Virus Arthritis in Adult Wild-Type Mice

Abstract

Chikungunya virus is a mosquito-borne arthrogenic alphavirus that has recently reemerged to produce the largest epidemic ever documented for this virus. Here we describe a new adult wild-type mouse model of chikungunya virus arthritis, which recapitulates the self-limiting arthritis, tenosynovitis, and myositis seen in humans. Rheumatic disease was associated with a prolific infiltrate of monocytes, macrophages, and NK cells and the production of monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-␣), and gamma interferon (IFN-␥). Infection with a virus isolate from the recent Reunion Island epidemic induced significantly more mononuclear infiltrates, proinflammatory mediators, and foot swelling than did an Asian isolate from the 1960s. Primary mouse macrophages were shown to be productively infected with chikungunya virus; however, the depletion of macrophages ameliorated rheumatic disease and prolonged the viremia. Only 1 g of an unadjuvanted, inactivated, whole-virus vaccine derived from the Asian isolate completely protected against viremia and arthritis induced by the Reunion Island isolate, illustrating that protection is not strain specific and that low levels of immunity are sufficient to mediate protection. IFN-␣ treatment was able to prevent arthritis only if given before infection, suggesting that IFN-␣ is not a viable therapy. Prior infection with Ross River virus, a related arthrogenic alphavirus, and anti-Ross River virus antibodies protected mice against chikungunya virus disease, suggesting that individuals previously exposed to Ross River virus should be protected from chikungunya virus disease. This new mouse model of chikungunya virus disease thus provides insights into pathogenesis and a simple and convenient system to test potential new interventions.

A Mouse Model of Chikungunya Virus–Induced Musculoskeletal Inflammatory Disease

“…Recently, evidence of arthritis, tenosynovitis, and myositis after inoculation of adult C57BL/6 mice with a Reunion Island CHIKV isolate (LR2006-OPY1) or a presumably mouse-adapted Asian CHIKV isolate was reported. 33 Similar to our findings, Gardner et al 33 observed that CHIKV-induced swelling was restricted to the inoculated foot, suggesting that neither the SL15649 virus used in our studies nor the LR2006-OPY1 virus used by Gardner et al disseminated efficiently in the mouse. Interestingly, some of the findings from Gardner et al differed from our findings.…”

Arthrogenic Alphaviruses and Inflammatory Myopathies

“…The selective depletion of macrophages by treatment of mice with macrophage-toxic agents such as silica or carrageenan, was found to almost entirely abrogate disease and the clearance of macrophages from damaged tissue correlated with recovery (Lidbury et al, 2000). The high degree of macrophage and monocyte infiltration into infected tissues and joints has also been confirmed in the models of CHIKV infection (Gardner et al, 2010;Morrison et al, 2011).…”

“…Subcutaneous infection of adult C57BL/6 mice leads to a self-limiting disease characterised by arthritis, tenosynovitis and myositis. Histological studies revealed a pronounced infiltration of monocytes, macrophages and natural killer (NK) cells in muscle tissues and synovial membranes indicative of myositis and arthritis (Gardner et al, 2010). Finally, adult mice partially deficient in the type I interferon (IFN) receptor (IFN-/R+/-) developed mild CHIKV infection which closely resembles the course of human infection, with virus recovered from muscles, joints and skin (Couderc et al, 2008).…”

“…In animal models of RRV and CHIKV infection, virus initially replicates at the site of inoculation before being disseminated through the blood stream to other tissues such as skeletal muscle and joint tissues (Gardner et al, 2010;Labadie et al, 2010;Morrison et al, 2011;Morrison et al, 2006). Replication in skeletal muscle results in severe necrotic myositis with extensive myofibre destruction (Couderc & Lecuit, 2009).…”

Recent progress on chikungunya virus research

“…(C) Symptoms in WT mice with CHIKV infection. In acute phase of post-infected WT mice, viremia occurs and lasts for 4 days, followed by arthritis appearing in day 6-8 (Gardner et al, 2010). In chronic phase, persistent synovitis exists at least for 84 days (Hawman et al, 2013).…”