Epidemic Polyarthritis Research Articles

Identification of T Cell and B Cell Specific Peptide Vaccine for the Treatment of Ross River Virus

Ross River virus, also known as Ross River fever and epidemic polyarthritis, is an infection that is spread to humans through mosquitoes.Ross River virus infection can cause fever, rash, joint inflammation and pain, fatigue and muscle aches. Most people recover completely within 3 to 6 months, although some people have intermittent symptoms for a year or more. Ross River virus infection is caused by an alphavirus(RNA Virus).Ross River virus is named after the Ross River in Townsville, which is the place where it was first identified. Ross River fever is the most common mosquito-borne disease in Australia, and nearly 5000 people are reported to be infected with the virus each year.The T and B lymphocytes (T and B Cells) are involved in the acquired or antigen-specific immune response given that they are the only cells in the organism able to recognize and respond specifically to each antigenic epitope.Developing a B-cell and T-cell specific peptide vaccine for Ross River Virus (RRV) would involve identifying specific antigenic targets that can stimulate the immune response.

An "Uncharacterized" Australian Virus Is the Earliest Known Example of Ross River Virus with Changes in the nsP3 Protein Associated with the Explosive Outbreak of Ross River Virus Infection in the Pacific Region from 1979 to 1980.

ABSTRACTRoss River virus recovered from a South Australian patient during an outbreak of epidemic polyarthritis in 1971 is the earliest known genome sequence with the duplicated 12-amino-acid motif in the nsP3 protein that was found in strains responsible for the outbreak of epidemic polyarthritis in the Pacific region from 1979 to 1980.

Localized Outbreaks of Epidemic Polyarthritis among Military Personnel Caused by Different Sublineages of Ross River Virus, Northeastern Australia, 2016-2017.

Two outbreaks of epidemic polyarthritis occurred among Australian Defence Force personnel during and following short military exercises in the Shoalwater Bay Training Area, northeastern Australia, in 2016 and 2017. Ross River virus (RRV) IgM was detected in acute-phase serum samples from most patients (28/28 in 2016 and 25/31 in 2017), and RRV was recovered from 4/38 serum samples assayed (1/21 in 2016 and 3/17 in 2017). Phylogenetic analyses of RRV envelope glycoprotein E2 and nonstructural protein nsP3 nucleotide sequences segregated the RRV isolates obtained in 2016 and 2017 outbreaks into 2 distinct sublineages, suggesting that each outbreak was caused by a different strain of RRV. The spatiotemporal characteristics of the 2016 outbreak suggested that some of the infections involved human-mosquito-human transmission without any intermediate host. These outbreaks highlight the importance of personal protective measures in preventing vectorborne diseases for which no vaccine or specific prophylaxis exists.

Increased Proinflammatory Cytokine Levels in Prolonged Arthralgia in Ross River Virus Infection.

Ross River virus, a mosquitoborne alphavirus, causes epidemic polyarthritis in Australia and the Pacific region. We analyzed serum cytokine, chemokine, and growth factor levels in travelers returning to Germany from Australia. Serum samples showed elevated concentrations in the acute phase of the illness and, more pronounced, in the long-lasting convalescent phase.

Surveillance should be strengthened to improve epidemiological understandings of mosquito-borne Barmah Forest virus infection

Barmah Forest virus (BFV) is a mosquito-borne virus causing epidemic polyarthritis in Australia. This study used case follow-up of cases from the surveillance system to demonstrate that routinely collected BFV notification data were an unreliable indicator of the true location of exposure. BFV notifications from June 2001 to May 2011 were extracted from the New South Wales (NSW) Notifiable Conditions Information Management System to study case distribution. Disease cluster analysis was performed using spatial scan statistics. Exposure history data were collected from cases notified in 2010 and 2011 to accurately determine travel to high-risk areas. Cluster analysis using address data identified an area of increased BFV disease incidence in the mid-north coast of NSW contiguous with estuarine wetlands. When travel to this area was investigated, 96.7% (29/30) cases reported having visited coastal regions within four weeks of developing symptoms. Along the central NSW coastline, extensive wetlands occur in close proximity to populated areas. These wetlands provide ideal breeding habitats for a range of mosquito species implicated in the transmission of BFV. This is the first study to fully assess case exposure with findings suggesting that sporadic cases of BFV in people living further away from the coast do not reflect alternative exposure sites but are likely to result from travel to coastal regions. Spatial analysis by case address alone may lead to inaccurate understandings of the true distribution of arboviral diseases. Subsequently, this information has important implications for the collection of mosquito-borne disease surveillance information and public health response strategies.

Ross River virus Evolution: Implications for Vaccine Development

Ross River virus is a mosquito-borne alphavirus that causes approximately 5000 cases of epidemic polyarthritis in Australia each year and has direct medical-associated costs of approximately US$15 million annually. While mosquito control programs are able, at best, to contain rather than prevent this disease, natural infection with Ross River virus confers lifelong protection against subsequent clinical infection. A killed-virus vaccine has been developed, which is in Phase III clinical trials. Analyses of intra-host genetic diversity and of long-term evolutionary changes in Ross River virus populations suggest that antigenic variation is unlikely to pose a threat to the efficacy of this vaccine.

Role of Proinflammatory Cytokines and Chemokines in Chronic Arthropathy in CHIKV Infection

Chikungunya virus (CHIKV) has caused large outbreaks worldwide in recent years. Acute-phase CHIKV infection has been reported to cause mild to severe febrile illness, and in some patients, this may be followed by long-lasting polyarthritis. The mainstay of treatment includes nonsteroidal anti-inflammatory drugs and other disease-modifying agents, the use of which is based on the assumption of an immunological interference mechanism in the pathogenesis. The present study has been designed to generate preliminary evidence to test this hypothesis. The levels of 30 cytokines were estimated in serum samples of acute CHIKV-infected patients, fully-recovered patients, patients with chronic CHIKV arthritis, and controls, using a quantitative multiplex bead ELISA. The levels of the proinflammatory cytokines IL-1 and IL-6 were elevated in acute patients, but IFN-γ/β and TNF-α levels remained stable. IL-10, which might have an anti-inflammatory effect, was also elevated, indicating a predominantly anti-inflammatory response in the acute phase of infection. Elevation of MCP-1, IL-6, IL-8, MIP-1α, and MIP-1β was most prominent in the chronic phase. These cytokines and chemokines have been shown to play important roles in other arthritides, including epidemic polyarthritis (EPA) caused by Ross River virus (RRV) and rheumatoid arthritis (RA).The immunopathogenesis of chronic CHIKV arthritis might have similarities to these arthritides. The novel intervention strategies being developed for EPA and RA, such as IL-6 and IL-8 signaling blockade, may also be considered for chronic CHIKV arthritis.

Evaluation of an inactivated Ross River virus vaccine in active and passive mouse immunization models and establishment of a correlate of protection

Ross River Virus has caused reported outbreaks of epidemic polyarthritis, a chronic debilitating disease associated with significant long-term morbidity in Australia and the Pacific region since the 1920s. To address this public health concern, a formalin- and UV-inactivated whole virus vaccine grown in animal protein-free cell culture was developed and tested in preclinical studies to evaluate immunogenicity and efficacy in animal models. After active immunizations, the vaccine dose-dependently induced antibodies and protected adult mice from viremia and interferon α/β receptor knock-out (IFN-α/βR −/−) mice from death and disease. In passive transfer studies, administration of human vaccinee sera followed by RRV challenge protected adult mice from viremia and young mice from development of arthritic signs similar to human RRV-induced disease. Based on the good correlation between antibody titers in human sera and protection of animals, a correlate of protection was defined. This is of particular importance for the evaluation of the vaccine because of the comparatively low annual incidence of RRV disease, which renders a classical efficacy trial impractical. Antibody-dependent enhancement of infection, did not occur in mice even at low to undetectable concentrations of vaccine-induced antibodies. Also, RRV vaccine-induced antibodies were partially cross-protective against infection with a related alphavirus, Chikungunya virus, and did not enhance infection. Based on these findings, the inactivated RRV vaccine is expected to be efficacious and protect humans from RRV disease.

Lineage replacement accompanying duplication and rapid fixation of an RNA element in the nsP3 gene in a species of alphavirus

A sequence of thirty-six nucleotides in the nsP3 gene of Ross River virus (RRV), coding for the amino acid sequence HADTVSLDSTVS, was duplicated some time between 1969 and 1979 coinciding with the appearance of a new lineage of this virus and with a major outbreak of Epidemic Polyarthritis among residents of the Pacific Islands. This lineage of RRV continues to circulate throughout Australia and both earlier lineages, which lacked the duplicated element, now are extinct. Multiple copies of several other elements also were observed in this region of the nsP3 gene in all lineages of RRV. Multiple copies of one of these, coding for the amino acid sequence P*P*PR, were detected in the C-terminal region of the nsP3 protein of all alphaviruses except those of African origin. The fixation of duplications and insertions in 3′ region of nsP3 genes from all lineages of alphaviruses, suggests they provide some fitness advantage.

Molecular evolutionary dynamics of Ross River virus and implications for vaccine efficacy

Ross River virus (RRV) is a mosquito-borne member of the genus Alphavirus that causes epidemic polyarthritis in humans, costing the Australian health system at least US$10 million annually. Recent progress in RRV vaccine development requires accurate assessment of RRV genetic diversity and evolution, particularly as they may affect the utility of future vaccination. In this study, we provide novel RRV genome sequences and investigate the evolutionary dynamics of RRV from time-structured E2 gene datasets. Our analysis indicates that, although RRV evolves at a similar rate to other alphaviruses (mean evolutionary rate of approx. 8x10(-4) nucleotide substitutions per site year(-1)), the relative genetic diversity of RRV has been continuously low through time, possibly as a result of purifying selection imposed by replication in a wide range of natural host and vector species. Together, these findings suggest that vaccination against RRV is unlikely to result in the rapid antigenic evolution that could compromise the future efficacy of current RRV vaccines.

Ross River virus infection in a traveller returning from northern Australia

Ross River virus is an arthropod-borne alphavirus (family Togaviridae) causing epidemic polyarthritis in the Australia-Pacific region. The infection causes substantial morbidity due to long-lasting arthralgia. Despite being the most common arboviral infection in Australia, reports in travellers are scarce. Here, we describe the disease in a German traveller who was not aware of the prevalence of this infection in his holiday destination, the Northern Territory and Queensland, Australia. The patient had neither fever nor rash, but presented with chills, watery diarrhoea and severe, prolonged arthritis.

Infections in travellers arriving from Australia

An unwell traveller whose itinerary has included Australia may be infected with agents that are uniquely found in that country or by more cosmopolitan agents that exist there. This brief review will discuss some of the more common or important infectious disease diagnoses and discuss some features that can be elicited on examination or from the history that would be useful in directing investigation and treatment. Diseases discussed include epidemic polyarthritis, dengue fever, Murray Valley encephalitis, melioidosis, leptospirosis, Buruli ulcer, scrub typhus and spotted fever.

The preclinical testing of a formaldehyde inactivated Ross River virus vaccine designed for use in humans

Ross River virus was grown in industrial facilities in vaccine-certified Vero cells in the absence of serum, inactivated using standard formalin-inactivation protocols, treated with Benzonase to digest host cell DNA and purified on a sucrose gradient. Mice given two subcutaneous injections of 0.625 microg of this vaccine or two doses of 0.156 microg vaccine with aluminium hydroxide adjuvant failed to develop a detectable viraemia after intravenous challenge with 10(6)TCID50 of the prototype strain of Ross River virus (T48). Guinea pigs immunised with one or two10 microg doses of vaccine with adjuvant also failed to develop a detectable viraemia following a similar challenge. The levels of neutralising antibody (neutralisation index 1.9-3.1) in the mice protected against challenge with 10(6)TCID50 Ross River virus were similar to those in 16 former epidemic polyarthritis patients (1.1-3.5) who had not experienced a second clinical infection with Ross River virus in the 20 years following their initial infection.

Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study

Objective To delineate the risk factors, symptom patterns, and longitudinal course of prolonged illnesses after a variety of acute infections.Design Prospective cohort study following patients from the time of acute...

Risk of mosquito-borne epidemic polyarthritis disease among international visitors to Queensland, Australia.

Risk of mosquito-borne epidemic polyarthritis disease among international visitors to Queensland, Australia.

An arthritogenic alphavirus uses the α1β1 integrin collagen receptor

Ross River (RR) virus is an alphavirus endemic to Australia and New Guinea and is the aetiological agent of epidemic polyarthritis or RR virus disease. Here we provide evidence that RR virus uses the collagen-binding α1β1 integrin as a cellular receptor. Infection could be inhibited by collagen IV and antibodies specific for the β1 and α1 integrin proteins, and fibroblasts from α1-integrin −/− mice were less efficiently infected than wild-type fibroblasts. Soluble α1β1 integrin bound immobilized RR virus, and peptides representing the α1β1 integrin binding-site on collagen IV inhibited virus binding to cells. We speculate that two highly conserved regions within the cell-receptor binding domain of E2 mimic collagen and provide access to cellular collagen-binding receptors.

Sindbis viruses and other alphaviruses as cause of human arthritic disease

Amongst the arthritis-causing arboviruses, i.e. those spread by insects, the alphavirus group is of special interest. These viruses occasionally cause vast outbreaks, such as O'nyong-nyong in Africa in 1959. In Fennoscandia, Sindbis-related Ockelbo, Pogosta, or Karelian fever viruses have been found to cause significant morbidity. The major symptoms in addition to joint inflammation are fever, fatigue, headache and rash. The joint symptoms may persist for weeks, even months. The diagnosis is based on the clinical picture and serology. The causative viruses are closely related but not identical. It appears that at least in Finland the Pogosta disease is more common than thought, and the symptoms may often be overlooked. Several factors related to the viruses, their hosts, and global environmental changes may affect the spread of these viruses. All over the world arbovirus-caused diseases have increased, because of global changes.

Natural history of Ross River virus-induced epidemic polyarthritis.

To describe the natural history, treatment and cost of Ross River virus-induced epidemic polyarthritis (RRV disease). Questionnaire-based longitudinal prospective study. Patients in the greater Brisbane area, Queensland, diagnosed with RRV disease by their general practitioners based on clinical symptoms and paired serological tests between November 1997 and April 1999. Scores on two validated quality-of-life questionnaires (Clinical Health Assessment Questionnaire and Medical Outcomes Study Short Form 36) were obtained soon after diagnosis and one, two, three, six and 12 months thereafter. Scores were compared between patients diagnosed with RRV disease alone and those with RRV disease plus other conditions. 67 patients were enrolled. Most patients with RRV disease alone had severe acute symptoms, but followed a consistent path to recovery within three to six months. Other conditions, often chronic rheumatic diseases or depression, were identified in half the cohort; their quality-of-life scores suggested stable chronic illness between six and 12 months after diagnosis. Non-steroidal anti-inflammatory drugs (NSAIDs) were taken by 58% of patients (average use, 7.6 weeks; range, 2-22 weeks). Time off work averaged 1.9 days, and direct cost to the community was estimated as 1018 Australian dollars per patient. Symptom duration and frequency of long-term symptoms may have been overestimated by previous studies of RRV disease. Disease persisting six to 12 months after RRV diagnosis was largely attributable to other conditions, highlighting the need to seek other diagnoses in RRV patients with persistent symptoms.

Ross River virus transmission, infection, and disease: a cross-disciplinary review.

Ross River virus (RRV) is a fascinating, important arbovirus that is endemic and enzootic in Australia and Papua New Guinea and was epidemic in the South Pacific in 1979 and 1980. Infection with RRV may cause disease in humans, typically presenting as peripheral polyarthralgia or arthritis, sometimes with fever and rash. RRV disease notifications in Australia average 5,000 per year. The first well-described outbreak occurred in 1928. During World War II there were more outbreaks, and the name epidemic polyarthritis was applied. During a 1956 outbreak, epidemic polyarthritis was linked serologically to a group A arbovirus (Alphavirus). The virus was subsequently isolated from Aedes vigilax mosquitoes in 1963 and then from epidemic polyarthritis patients. We review the literature on the evolutionary biology of RRV, immune response to infection, pathogenesis, serologic diagnosis, disease manifestations, the extraordinary variety of vertebrate hosts, mosquito vectors, and transmission cycles, antibody prevalence, epidemiology of asymptomatic and symptomatic human infection, infection risks, and public health impact. RRV arthritis is due to joint infection, and treatment is currently based on empirical anti-inflammatory regimens. Further research on pathogenesis may improve understanding of the natural history of this disease and lead to new treatment strategies. The burden of morbidity is considerable, and the virus could spread to other countries. To justify and design preventive programs, we need accurate data on economic costs and better understanding of transmission and behavioral and environmental risks.

Specific ablation of antiviral gene expression in macrophages by antibody-dependent enhancement of Ross River virus infection.

Ross River virus (RRV) is an indigenous Australian arthropod-borne alphavirus responsible for epidemic polyarthritis (EPA), myalgia, and lethargy in humans. Macrophages and monocytes have been associated with human RRV disease, and previous studies have shown that RRV is capable of infecting macrophages via both a natural virus receptor and by Fc receptor-mediated antibody-dependent enhancement (ADE). Similar to other viruses, such as human immunodeficiency virus and dengue virus, ADE infection results in dramatic RRV growth increases for in vitro macrophage cultures. This study demonstrates that RRV could resist lipopolysaccharide (LPS)-induced antiviral activity in macrophage cultures when infection was via the ADE pathway. Investigation of this infection pathway found that RRV was able to suppress the transcription and translation of key antiviral genes (tumor necrosis factor and inducible nitric oxide synthase) in LPS-stimulated macrophages by disrupting the transcription into mRNA of the genes coding for the associated transcription factors IRF-1 and NF-kappaB. The transcription of non-antiviral control genes was not perturbed by RRV-ADE infection, and de novo protein synthesis also was not significantly affected in RRV-ADE infected cells. The ADE pathway of infection allowed RRV to specifically target antiviral genes in macrophages, resulting in unrestricted virus replication. As ADE has been observed for several virus families and associated with disease and adverse vaccination outcomes, these findings may have broad relevance to viral disease formation and antiviral vaccination strategies.