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Ross River fever is a mosquito-transmitted viral disease that is endemic to Australia and the surrounding Pacific Islands. Ross River virus (RRV) belongs to the arthritogenic group of alphaviruses, which largely cause disease characterized by debilitating polyarthritis, rash, and fever. There is no specific treatment or licensed vaccine available, and the mechanisms of protective humoral immunity in humans are poorly understood. Here, we describe naturally occurring human mAbs specific to RRV, isolated from subjects with a prior natural infection. These mAbs potently neutralize RRV infectivity in cell culture and block infection through multiple mechanisms, including prevention of viral attachment, entry, and fusion. Some of the most potently neutralizing mAbs inhibited binding of RRV to Mxra8, a recently discovered alpahvirus receptor. Epitope mapping studies identified the A and B domains of the RRV E2 protein as the major antigenic sites for the human neutralizing antibody response. In experiments in mice, these mAbs were protective against cinical disease and reduced viral burden in multiple tissues, suggesting a potential therapeutic use for humans., Author summary Ross River virus (RRV) was first identified in Australia in 1959, and has since caused multiple outbreaks, some affecting tens of thousands of individuals throughout the Pacific Islands, Australia, and Papua New Guinea. In addition, a mean of 4,600 cases of RRV disease occur in Australia each year. RRV is transmitted to humans via the bite of a mosquito, and disease symptoms include rash, fever, and debilitating polyarthritis. Currently, the adaptive immune response during RRV infection is poorly understood, and no human moncoclonal antibodies (mAbs) against the virus exist. In this study, we generated a panel of human mAbs specific for RRV from two donors who had undergone a natural infection with the virus. We then used these mAbs to elucidate antigenic regions of RRV, and to further study mechanisms by which RRV is neutralized. In addition to potently neutralizing virus in vitro, these mAbs significantly reduced mouse death and reducd viral burden in an immunocompromised model. Our study provides new insight into the antibody reponse during a natural infection with RRV, and suggests that therapeutic administration of mAbs may be beneficial in reducing disease burden.

Summary: We find that the spatial scale/aggregation of an analysis influences the apparent importance of ecological drivers of arboviral (Ross River virus) disease; we urge future epidemiological studies to include multiple spatial scales for a more complete picture of disease drivers. Background: Zoonotic vector-borne disease prevalence is affected by vector, human and reservoir host factors, which are influenced by habitat and climate; these five components interact on microhabitat to landscape scales but are often analyzed at a single spatial scale. Methods: We present an information theoretic, multi-scale, multiple regression analysis of the ecological drivers of Ross River virus. We analyze the spatial pattern of 20 years of Ross River virus infections from South Australia (1992-2012; n = 5,261) using variables across these five components of disease ecology at three spatial scales. Results: We found that covariate importance depended on the spatial scale of the analysis; some biotic variables were more important at fine scales and some abiotic variables were more important at coarser spatial scales. The urban score of an area was most predictive of infections and mosquito variables did not improve the explanatory power of these models. Conclusions: Through this multi-scale analysis, we identified novel drivers of the spatial distribution of disease and recommend public health interventions. Our results underline that single-scale analyses may paint an incomplete picture of disease drivers, potentially creating a major flaw in epidemiological analyses. Multi-scale, ecological analyses are needed to better understand infectious disease transmission.

While most mosquito-borne viruses are associated with a narrow range of vector and reservoir host species, some pathogens have much larger vector and host assemblages. One such group is the Alphaviruses (including chikungunya virus [CHIKV]), with Ross River virus (RRV), endemic to Australia, providing a fascinating example of the complicated relationship between vector and reservoir host species across different environments (Fig 1). RRV is responsible for the most commonly reported mosquito-borne disease in Australia, and as both a reservoir host and vector generalist, the virus has complex spatial and temporal activity that makes outbreak prediction, vector and pathogen surveillance, and public health risk mitigation strategies difficult. Here, we review the unique ecology of RRV and the challenges it presents for local health authorities. Fig 1 There are complex relationships between the vectors and the zoonotic reservoirs of Ross River virus across coastal, inland, and metropolitan regions of Australia. Ross River Virus Disease Ross River virus disease (also commonly known as Ross River Fever) is not fatal. However, the associated arthralgia can be seriously debilitating. While there are a wide range of disease symptoms, they typically include arthritic joint pain, usually of the peripheral joints, which affects 83%–98% of patients; fatigue and rash, both of which affect over 50% of patients; and fever, which affects 20%–60% of patients [1]. The severity of symptoms varies, as does their duration, which can range from a few weeks to several months [2]; several studies indicate that chronic joint pain affects over 50% of RRV disease patients, which can persist for years after diagnosis [1]. The public health impacts of RRV disease are significant: it is estimated to cost Australia at least US$4.1–US$4.7 million per year [3]. The incidence of RRV disease varies regionally [2]. Roughly 5,000 cases of RRV disease are officially notified each year [4]. There are generally more cases recorded in northern Australia, but the virus still poses a substantial threat in the temperate southern regions of the country. RRV disease case numbers are generally thought to be an underestimate [5]. Accurately quantifying the scope of RRV disease is difficult, as the variability in symptom severity and the requirement of a blood test to confirm infection may cause many milder cases to go undiagnosed. As a consequence, official statistics may only represent the most severe cases. There are no specific treatments available for the disease; patients are usually given supportive care and prescribed general analgesics and anti-inflammatory agents to treat symptoms [1]. While a vaccine is in development [6], current prevention strategies rely primarily on mosquito avoidance and control.

Disturbances in neurocognitive performance are a core feature of the acute sickness response to infection; however the underlying mechanisms remain unclear. The current study used a computerised battery to assess neurocognitive functioning in subjects enrolled in the Dubbo Infection Outcomes Study (n=107) - a prospective cohort of subjects followed from documented acute infection with Epstein Barr virus, Ross River virus, or Coxiella burnetii until recovery. Subjects were assessed when ill, and a subset again after complete recovery. Associations between sickness-related cognitive disturbances and single nucleotide polymorphisms (SNPs) in cytokine (interleukin [IL]-6, IL-10, tumor necrosis factor-α and interferon-γ) and neurobehavioral genes (serotonin transporter and catechol-O-methyltransferase) were explored. During acute infection, subjects exhibited slower matching-to-sample responses (p=0.03), poorer working memory capacity (p=0.014), mental planning (p=0.045), and dual attention task performance (p=0.02), and required longer to complete discordant Stroop trials (p=0.01) compared to recovery. Objective impairments correlated significantly with self-reported symptoms (p

Newborn mice inoculated sc with a minimally lethal strain of Ross River virus had severe paralysis from days 5 to 6, but only 25% died. Small foci of infection in ependyma and very few infected neurons in the cerebral cortex were detected, but there were no other evidences of acute infection in the central nervous system. From day 10, there was thinning of the cerebral cortex, with appearance of fluidfilled spaces by day 18. Paralysis was apparently due to severe necrosis of muscle; mice recovered and appeared normal by days 25-35, despite persistent cortical lesions still present in apparently healthy mice surviving for one and a half years. Intracerebrally inoculated newborn mice had necrosis of infected ependymal cells; in many instances this resulted in aqueductal stenosis and hydrocephalus. Semliki Forest virus, in contrast to Ross River virus, produced widespread infection and necrosis in the central nervous system, including foci in the retina. Death was attributed to neuronal destruction. Extraneural tissues were also infected, but mice died before there had been time for evolution of pathologic changes seen with Ross River virus.

In newborn mice infected subcutaneously with the NB5092 strain of Ross River virus there was early and extensive growth of virus in extraneural tissues, especially striate muscle, brown fat, and smooth muscle. Several days after peak titers had been attained in muscle, infected mice developed widespread muscle necrosis with paralysis of hind limbs, but recovery was complete by 35 days. In brown fat, lesions became calcified and were surrounded by giant cells; some lesions were not resolved by 60 days. The T48 strain of Ross River virus, unlike the NB5092 strain, regularly infected the heart and caused myocardial necrosis, and later, calcification. Both strains infected perichondrium, periosteum, and skin. Semliki Forest virus infected, with acute necrotic changes, the same extraneural tissues of newborn mice as did Ross River virus, but the infection was generally less extensive. Ross River virus (RRV) has been described as an etiologic agent of human epidemic polyarthritis in Australia [1]. RRV causes a paralytic disease in infant mice, and the studies on pathogenesis reported in the preceeding paper failed to implicate a neurologic mechanism for this paralysis. In the present paper the pathogenesis of lesions in striate, smooth, and cardiac muscle, as well as in connective tissue and brown fat, are described. The distribution of RRV in murine tissues has been briefly described [2], but in the present study the integrated use of immunofluorescence, light microscopic histology, electron microscopy, and viral assay of organs has allowed more comprehensive analysis of pathogenetic mechanisms.

An outbreak of Ross River virus infection (epidemic polyarthritis), which occurred in American Samoa between August 1979 and January 1980, is described. On the basis of a serological survey performed near the end of the epidemic, it is estimated that at least 13,500 people were infected. Ross River virus was isolated from the blood of a single polyarthritis patient. Plaque reduction neutralization tests, using this virus strain, were done on 393 human and 143 animal sera collected on Tutuila island. Over-all, 43.8% of the people sampled had evidence of infection. Sera from 100 adult residents of the same island, collected in 1972, had no Ross River antibody, suggesting recent introduction of the virus. In contrast to the human serological data, the prevalence of Ross River antibodies among animals was relatively low. Dogs and pigs had the highest rates with 20% and 15%, respectively. Results of this study suggest that the Ross River virus cycle during the epidemic in American Samoa involved primarily humans and mosquitoes with animals less frequently infected. These observations plus the recent introduction of Ross River virus into new areas of the South Pacific suggest that a major change has occurred in the epidemiology of epidemic polyarthritis.

19 strains of 6 viruses (Kunjin, Kokobera, MRM3929, Koongol, Kowanyama and MRM3630) were isolated from 40,508 mosquitoes collected on 8 occasions from March 1963 to November 1966, at Mitchell River Mission in Cape York Peninsula, Queensland. Isolation rates were lower than in earlier collections in the same area, varied markedly between years, and were very low in each dry season (October–November) when only 4 strains were isolated, all from Anopheline mosquitoes. One virus isolated, Kowanyama, appears to be unrelated to all agents with which it has been compared; one, MRM3630, is related to but easily distinguishable from Mapputta virus; one, MRM3929, was previously isolated from a bird from the same area, but the isolation reported is the first from mosquitoes. Serological tests of children and domestic fowls gave supporting evidence of the occurrence of infections with Group B arboviruses, and also demonstrated infections with Sindbis and Ross River virus. The findings do not indicate the mode of survival of arboviruses in the markedly seasonal environment in this area.