Amelioration of alphavirus-induced arthritis and myositis in a mouse model by treatment with bindarit, an inhibitor of monocyte chemotactic proteins

Abstract

Objective Alphaviruses such as chikungunya virus, Sindbis virus, o'nyong-nyong virus, Mayaro virus, and Ross River virus (RRV), are commonly associated with arthralgias and overt arthritides worldwide. Understanding the processes by which arthritogenic viruses cause disease is a prerequisite in the quest for better treatments. In this regard, we have recently established that monocyte/macrophages are mediators of alphavirus-induced arthritis in mice. We hypothesized that chemokines associated with monocyte/macrophage recruitment may play an important role in disease. The aim of the present investigations was to determine whether bindarit, an inhibitor of monocyte chemotactic protein (MCP) synthesis, could ameliorate alphavirus-induced rheumatic disease in mice. Methods Using our recently developed mouse model of RRV-induced arthritis, which has many characteristics of RRV disease (RRVD) in humans, the effects of bindarit treatment on RRVD in mice were determined via histologic analyses, immunohistochemistry, flow cytometry, real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and electrophoretic mobility shift assay. Results Bindarit-treated RRV-infected mice developed mild disease and had substantially reduced tissue destruction and inflammatory cell recruitment as compared with untreated RRV-infected mice. The virus load in the tissues was not affected by bindarit treatment. Bindarit exhibited its activity by down-regulating MCPs, which in turn led to inhibition of cell infiltration and lower production of NF-κB and tumor necrosis factor , which are involved in mediating tissue damage. Conclusion Our data support the use of inhibitors of MCP production in the treatment of arthritogenic alphavirus syndromes and suggest that bindarit may be useful in treating RRVD and other alphavirus-induced arthritides in humans.

Mosquito-borne arthritogenic alphaviruses, such as the Sindbis group of viruses, the Asian/African chikungunya virus, the African o'nyong-nyong virus, the South American Mayaro virus, and the Australian Barmah Forest virus and Ross River virus (RRV), are frequently associated with outbreaks of polyarthritis and/or polyarthralgia in humans (1). For example, a recent chikungunya virus epidemic in the Indian Ocean resulted in ∼250,000 cases on La Réunion Island (2), >3 million cases in India (3), and ∼200 cases in Italy (4). Between 1959 and 1962, an epidemic of o'nyong-nyong fever in Africa affected at least 2 million people (5), and RRV caused a large epidemic of RRV disease (RRVD) in 1979–1980, resulting in ∼60,000 cases in the South Pacific (6).

RRV is a positive-sense single-stranded alphavirus. It is transmitted by mosquitoes and is endemic in Australia and Papua New Guinea, causing up to 8,000 cases of RRVD annually in Australia in recurrent seasonal epidemics (7). In humans, the dominant symptom of RRVD is arthralgia and/or arthritis, with many patients also experiencing myalgia and fatigue and some experiencing fever and rash (8). Joint symptoms most commonly involve the fingers, knees, and ankles, but many joints can be affected. The disease is often severe and debilitating at onset, and it progressively resolves over 3–6 months in the majority of patients (9, 10). Using validated quality-of-life questionnaires, the severity of RRVD at onset was shown to be comparable with that seen in patients with osteoarthritis awaiting hip or knee replacements or in patients with chronic rheumatoid arthritis (RA) or Lyme arthritis (9).

The pathologic and/or immunopathologic mechanisms responsible for viral arthropathies are poorly understood, largely because of the absence of small animal models of disease. Recently, we established a mouse model of RRVD that recapitulates many aspects of RRVD in humans and thus provides one of the first mouse models for the study of viral arthritis (11, 12). RRV infection in mice results in inflammation of the joints and skeletal muscles and a