Characterization of Ross River Virus Tropism and Virus-Induced Inflammation in a Mouse Model of Viral Arthritis and Myositis

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Journal of Virology (Impact Factor: 4.44). 02/2006; 80(2):737-49. DOI: 10.1128/JVI.80.2.737-749.2006
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Mosquito-borne alphaviruses are a significant cause of both encephalitic and arthritic disease in humans worldwide. In contrast
to the encephalitic alphaviruses, the pathogenesis of alphavirus-induced arthritic disease is not well understood. Utilizing
a mouse model of Ross River virus (RRV) disease, we found that the primary targets of RRV infection are bone, joint, and skeletal
muscle tissues of the hind limbs in both outbred CD-1 mice and adult C57BL/6J mice. Moreover, histological analyses demonstrated
that RRV infection resulted in severe inflammation of these tissues. Characterization of the inflammatory infiltrate within
the skeletal muscle tissue identified inflammatory macrophages, NK cells, and CD4+ and CD8+ T lymphocytes. To determine the contribution of the adaptive immune system, the outcome of RRV-induced disease was examined
in C57BL/6J RAG-1−/− mice, which lack functional T and B lymphocytes. RAG-1−/− and wild-type mice developed similar disease signs, infiltration of inflammatory macrophages and NK cells, and muscle pathology,
suggesting that the adaptive immune response does not play a critical role in the development of disease. These results establish
the mouse model of RRV disease as a useful system for the identification of viral and host factors that contribute to alphavirus-induced
arthritis and myositis.

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    • "Liver and spleen are also considered sites of primary viral replication and contribute to virus dissemination [51]. After dissemination, the virus reaches bones, muscles, and articular tissues, generating the acute phase of the disease, which is strongly associated with a local inflammatory process [34–37, 52]. Host age, the status of the immune system, virus strain virulence, and viral persistence are key determinants for the pathogenesis of alphavirus infection in animals [37, 53, 54]. "
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    ABSTRACT: Arthritogenic alphaviruses, including Ross River virus (RRV), Chikungunya virus (CHIKV), Sindbis virus (SINV), Mayaro virus (MAYV), O'nyong-nyong virus (ONNV), and Barmah Forest virus (BFV), cause incapacitating and long lasting articular disease/myalgia. Outbreaks of viral arthritis and the global distribution of these diseases point to the emergence of arthritogenic alphaviruses as an important public health problem. This review discusses the molecular mechanisms involved in alphavirus-induced arthritis, exploring the recent data obtained with in vitro systems and in vivo studies using animal models and samples from patients. The factors associated to the extension and persistence of symptoms are highlighted, focusing on (a) virus replication in target cells, and tissues, including macrophages and muscle cells; (b) the inflammatory and immune responses with recruitment and activation of macrophage, NK cells and T lymphocytes to the lesion focus and the increase of inflammatory mediators levels; and (c) the persistence of virus or viral products in joint and muscle tissues. We also discuss the importance of the establishment of novel animal models to test new molecular targets and to develop more efficient and selective drugs to treat these diseases.
    08/2013; 2013(2):973516. DOI:10.1155/2013/973516
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    • "With such cytoxicity, methotrexate treatment has been reported to associate with undesired side effects and death in mice [18]. Being the first to report on MTX treatment in the mouse model of RRV disease [19], we performed drug titration experiments with 21-day old C57BL/6 mice and determined a most suitable physiological regimen for this study (0.25 mg/kg/day) (data not shown). With this standardized protocol, we did not observe an ameliorating effect of MTX on acute musculoskeletal disease in the context of virus infection. "
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    ABSTRACT: 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.
    PLoS ONE 08/2013; 8(8):e71146. DOI:10.1371/journal.pone.0071146 · 3.23 Impact Factor
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    • "Viruses may damage muscles directly through the invasion of muscle fibers or indirectly through the activation of the immune response.13-15 Mosquito-borne alphaviruses, such as RRV, have been reported to target bone, joint, and skeletal muscle tissue in a mouse model.16,17 Moreover, histological analyses have demonstrated that RRV infection results in severe inflammation of these tissues by infiltrating macrophages, NK cells, and CD4+ and CD8+ T lymphocytes. "
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    ABSTRACT: Acute rhabdomyolysis is a clinical and laboratory syndrome resulting from the breakdown of skeletal muscle, with the release of intracellular contents into the circulatory system, which can cause potentially lethal complications. Here, we present the case of a patient who developed acute rhabdomyolysis after consumption of meloxicam for jaw pain and experienced generalized myalgias in the context of an acute febrile illness with generalized urticaria. Further investigation indicated elevated muscle enzymes and acute renal failure. Serological analysis revealed that the patient was positive for Ross River virus (RRV) IgM. Genetic studies to detect CYP2C9 polymorphisms were negative. Meloxicam was discontinued. He responded to conservative measures within 2 weeks. Oral aspirin challenge was negative, suggesting a drug-specific effect of meloxicam rather than a class effect. Our case indicates a causative role for meloxicam and/or acute RRV in rhabdomyolysis.
    Allergy, asthma & immunology research 01/2012; 4(1):52-4. DOI:10.4168/aair.2012.4.1.52 · 2.43 Impact Factor
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