Summary auto-generated
Ross River virus (RRV), an arbovirus causing epidemic polyarthritis in Australia and the Pacific, can productively infect macrophages and monocyte cell lines. This study demonstrates for the first time that macrophages support RRV replication and that subneutralizing levels of anti-RRV IgG antibodies enhance infection through classical antibody-dependent enhancement (ADE), though this mechanism appears to occur via Fc receptors rather than complement receptors. Notably, RRV-infected macrophage cultures maintained virus production for over 50 days, indicating persistent infection in the absence of overt cytopathic effects. Unexpectedly, RRV-infected monocytes and macrophages did not produce tumor necrosis factor-alpha, distinguishing RRV-induced arthritis from rheumatoid arthritis pathogenesis. While ADE was demonstrated in vitro, no correlation was found between pre-existing ADE antibody titers and development of epidemic polyarthritis in patients, and cross-reactive antibodies from related Barmah Forest virus did not enhance RRV infection. The authors propose that RRV-induced arthritis may result from persistent macrophage infection, potentially established transiently through ADE when rising subneutralizing antibodies coincide with viremia early in infection.
Key findings
- Macrophages can be productively infected by Ross River virus and maintain persistent viral replication for over 50 days
- Subneutralizing anti-RRV IgG antibodies mediate antibody-dependent enhancement of RRV infection in macrophage and monocyte cell lines via Fc receptors
- No direct correlation exists between pre-existing ADE antibody titers and development of epidemic polyarthritis in infected patients
- RRV-infected macrophages do not produce tumor necrosis factor-alpha, distinguishing viral arthritis from autoimmune rheumatoid arthritis
- Persistent macrophage infection established early through ADE may be the primary mechanism driving RRV-associated arthritis
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Abstract
Ross River virus (RRV) is the aetiological agent of epidemic polyarthritis (EPA) a predominantly rheumatic disease afflicting up to 5000 Australians annually. We show here for the first time that macrophages can be productively infected by RRV. Subneutralizing titres of anti-RRV IgG (but not IgM) also showed classical antibody-dependent enhancement (ADE) of RRV infection in macrophage and monocyte cell lines. No correlation between development of EPA and the preexistence of ADE titres was apparent, nor could sera raised against a related arbovirus, Barmah Forest, enhance RRV infection. Tumour necrosis factor-α, implicated in the immunopathogenesis of rheumatoid arthritis, was not secreted by RRV-infected monocytes or macrophages. Macrophage cell lines infected with RRV were, however, capable of producing virus for over 50 days. RRV-induced arthritis may therefore be due to the persistent productive infection of macrophages, perhaps established by a brief period of ADE early in infection.
* Author for correspondence. Fax +61 7 33620106. e-mail andreasS@qimr.edu.au