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The Journal of Infectious Diseases 08/2011; 204(3):489-91. · 6.41 Impact Factor
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ABSTRACT: Alphaviruses, such as chikungunya virus, o'nyong-nyong virus, and Ross River virus (RRV), cause outbreaks of human rheumatic disease worldwide. RRV is a positive-sense single-stranded RNA virus endemic to Australia and Papua New Guinea. In this study, we sought to establish an in vitro model of RRV evolution in response to cellular antiviral defense mechanisms. RRV was able to establish persistent infection in activated macrophages, and a small-plaque variant (RRV(PERS)) was isolated after several weeks of culture. Nucleotide sequence analysis of RRV(PERS) found several nucleotide differences in the nonstructural protein (nsP) region of the RRV(PERS) genome. A point mutation was also detected in the E2 gene. Compared to the parent virus (RRV-T48), RRV(PERS) showed significantly enhanced resistance to beta interferon (IFN-β)-stimulated antiviral activity. RRV(PERS) infection of RAW 264.7 macrophages induced lower levels of IFN-β expression and production than infection with RRV-T48. RRV(PERS) was also able to inhibit type I IFN signaling. Mice infected with RRV(PERS) exhibited significantly enhanced disease severity and mortality compared to mice infected with RRV-T48. These results provide strong evidence that the cellular antiviral response can direct selective pressure for viral sequence evolution that impacts on virus fitness and sensitivity to alpha/beta IFN (IFN-α/β).
Journal of Virology 03/2011; 85(11):5651-63. · 5.40 Impact Factor
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ABSTRACT: Mosquito-borne alphaviruses such as chikungunya virus, o'nyong-nyong virus, and Ross River virus (RRV) cause sporadic, sometimes large, outbreaks of rheumatic disease worldwide. This study was designed to test the effect of treating RRV-induced arthritis using the anti-tumor necrosis factor (anti-TNF) drug etanercept in a mouse model of rheumatic disease.
Mice were infected with RRV and treated with etanercept. Weight gain was measured, tissue viral titers were determined, and histologic changes in muscle and joint tissues were assessed.
RRV-infected mice treated with etanercept showed decreased weight gain, higher viral titers in muscle, joints, and blood, and more tissue damage and inflammatory cell recruitment than RRV-infected mice without treatment.
Anti-TNF therapy is unlikely to be useful in treating alphaviral arthritides. During alphaviral epidemics, careful monitoring of patients being treated with anti-TNF agents may be warranted.
Arthritis & Rheumatism 02/2011; 63(2):488-91. · 7.87 Impact Factor
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ABSTRACT: OBJECTIVES.: Mosquito-borne alphaviruses such as chikungunya virus, O'nyong-nyong virus and Ross River virus (RRV) cause sporadic, sometimes large, outbreaks of rheumatic disease worldwide. Here we test the effect of treating RRV-induced arthritis using the anti-TNF drug, etanercept, in a mouse model of rheumatic disease. METHODS.: Mice were infected with RRV and treated with etanercept. Weight loss, tissue viral titers and histological examination of muscle and joint tissues were undertaken. RESULTS.: RRV-infected mice treated with etanercept showed increased weight loss, higher viral titres in muscle, joints and blood, more tissue damage and inflammatory cell recruitment than RRV-infected mice without treatment. CONCLUSION.: Anti-TNF therapy is unlikely to have utility in treating alphaviral arthritides. During alphaviral epidemics careful monitoring of patients being treated with anti-TNF drugs may be warranted.
Arthritis & Rheumatism 10/2010; · 7.87 Impact Factor
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ABSTRACT: 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.
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.
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-kappaB and tumor necrosis factor alpha, which are involved in mediating tissue damage.
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.
Arthritis & Rheumatism 08/2009; 60(8):2513-23. · 7.87 Impact Factor
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ABSTRACT: Human metapneumovirus (HMPV) is a recently discovered pathogen first identified in respiratory specimens from young children suffering from clinical respiratory syndromes ranging from mild to severe lower respiratory tract illness. HMPV has worldwide prevalence, and is a leading cause of respiratory tract infection in the first years of life, with a spectrum of disease similar to respiratory syncytial virus (RSV). The disease burden associated with HMPV infection has not been fully elucidated; however, studies indicate that HMPV may cause upper or lower respiratory tract illness in patients between ages 2 months and 87 years, may co-circulate with RSV, and HMPV infection may be associated with asthma exacerbation. The mechanisms and effector pathways contributing to immunity or disease pathogenesis following infection are not fully understood; however, given the clinical significance of HMPV, there is a need for a fundamental understanding of the immune and pathophysiological processes that occur following infection to provide the foundation necessary for the development of effective vaccine or therapeutic intervention strategies. This review provides a current perspective on the processes associated with HMPV infection, immunity, and disease pathogenesis.
Microbes and Infection 02/2006; 8(1):285-93. · 3.10 Impact Factor
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ABSTRACT: Ross River virus (RRV) is a mosquito-borne alphavirus indigenous to Australia and the Western Pacific region and is responsible for several thousand cases of human RRV disease (RRVD) per annum. The disease primarily involves polyarthritis/arthralgia, with many patients also presenting with rash, myalgia, fever, and/or lethargy. The symptoms can be debilitating at onset, but they usually resolve within 3-6 months. Recent insights into the RRV-host relationship, associated pathology, and molecular biology of infection have generated a number of potential avenues for improved treatment. Although vaccine development has been proposed, the small market size and potential for antibody-dependent enhancement (ADE) of disease make this approach unattractive. Recent insights into the molecular basis of RRV-ADE and the virus's ability to manipulate host inflammatory and immune responses create potential new opportunities for therapeutic invention. Such interventions should overcome virus-induced dysregulation of protective host responses to promote viral clearance and/or ameliorate inflammatory immunopathology.
Pharmacology [?] Therapeutics 10/2005; 107(3):329-42. · 8.56 Impact Factor
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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 Yes Yes
