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Summary: Background: Ross River virus (RRV), Australia's most notifiable vector-borne disease transmitted through mosquito bites, has seen increased transmission due to rising temperatures. Quantifying the burden of RRV infection attributable to increasing temperatures (both current and future) is pivotal to inform prevention strategies in the context of climate change. Methods: As RRV-related deaths are rare in Australia, we utilised years lived with disability (YLDs) associated with RRV infection data from the Australian Institute of Health and Welfare (AIHW) Burden of Disease database between 2003 and 2018. We obtained relative risks per 1 °C temperature increase in RRV infection from a previous meta-analysis. Exposure distributions for each Köppen-Geiger climate zone were calculated separately and compared with the theoretical-minimum-risk exposure distribution to calculate RRV burden attributable to increasing temperatures during the baseline period (2003–2018), and projected future burdens for the 2030s and 2050s under two greenhouse gas emission scenarios (Representative Concentration Pathways, RCP 4.5 and RCP 8.5), two adaptation scenarios, and different population growth series. Findings: During the baseline period (2003–2018), increasing mean temperatures contributed to 35.8 (±0.5) YLDs (19.1%) of the observed RRV burden in Australia. The mean temperature attributable RRV burden varied across climate zones and jurisdictions. Under both RCP scenarios, the projected RRV burden is estimated to increase in the future despite adaptation scenarios. By the 2050s, without adaptation, the RRV burden could reach 45.8 YLDs under RCP4.5 and 51.1 YLDs under RCP8.5. Implementing a 10% adaptation strategy could reduce RRV burden to 41.8 and 46.4 YLDs, respectively. Interpretation: These findings provide scientific evidence for informing policy decisions and guiding resource allocation for mitigating the future RRV burden. The current findings underscore the need to develop location-specific adaptation strategies for climate-sensitive disease control and prevention. Funding: Australian Research Council Discovery Program.

Background: Ross River virus (RRV) is a zoonotic alphavirus transmitted by several mosquito species. Until recently, endemic transmission was only considered possible in the presence of marsupial reservoirs. Methods: RRV seroprevalence was investigated in placental mammals (including horses, cows, goats, pigs, dogs, rats, and mice) in Fiji, where there are no marsupials. A total of 302 vertebrate serum samples were collected from 86 households from 10 communities in Western Fiji. Results: Neutralizing antibodies against RRV were detected in 28% to 100% of sera depending on the species, and neutralization was strong even at high dilutions. Conclusions: These results are unlikely to be due to cross-reactions. Chikungunya is the only other alphavirus known to be present in the Pacific Islands, but it rarely spills over into non-humans, even during epidemics. The study findings, together with a recent report of high RRV seroprevalence in humans, strongly suggest that RRV is circulating in Fiji in the absence of marsupial reservoirs. Considering that all non-human vertebrates present in Fiji are pan-global in distribution, RRV has the potential to further expand its geographic range. Further surveillance of RRV and access to RRV diagnostics will be critical for the early detection of emergence and outbreaks.

In Tasmania, a temperate island state of Australia, there is little understood about the human health implications of a changing climate. Here, we investigate the hypothesis that human populations in Tasmania might become more vulnerable to Ross River virus (RRV) under climate change, Australia’s most significant vector-borne disease. Importantly, our study considers the complex social-ecological systems based setting that this virus represents, with our approach being underpinned by systems thinking. Specifically, we undertake an integrated and participatory assessment of potential human vulnerability to RRV in a changing climate, and taking account of other parallel, non-climate regional-scale change considerations. We show that projected moderate changes in Tasmania’s climate will have implications for the State’s human health, whereby Tasmania is likely to become more vulnerable to RRV as the 21st Century progresses, shifting this health issue from a relatively low public health risk to one that will become more concerning and costly. The study assists us to contemplate how we frame human health questions as we move into a climatically changing world and reminds us that health impacts will not always be linear or obvious. It demonstrates an approach for scoping indirect and potentially insidious implications of climate change, even in the face of uncertainty, imperfect systems understanding, and limited resources, to inform a range of decision makers.

Abstract Objective: To investigate the relationship between risk of Ross River virus (RRV) infection and proximity to mosquito‐breeding habitat surrounding a tidal wetland ecosystem in south‐west Australia. Methods: Geographic information systems (GIS) were used to spatially map cases of RRV disease in the Leschenault region between July 1995 and June 1996. Half kilometre buffer zones were constructed around the Leschenault Estuary and associated waterways; RRV disease case counts were calculated for each zone. Results: Different relationships between RRV disease incidence and proximity to saltmarsh mosquito habitat were observed east of the Leschenault Estuary compared with an urban region to the south. Disease incidence showed a decreasing trend away from eastern margins of the Estuary, particularly for the first 2 km. In the urban region, RRV disease risk was low close to the Estuary, but increased further out and remained steady across the remainder of that region. Conclusions: The findings support an increased risk of contracting RRV disease for people residing close to eastern margins of the Leschenault Estuary. Implications: This study highlights how historical data combined with GIS can improve understanding of the epidemiology of RRV disease. This has a valuable role in assessing the risk of mosquito‐borne disease for land‐use planning.

Ross River virus (RRV) infection is one of the emerging and prevalent arboviral diseases in Australia and the Pacific Islands. Although many studies have been conducted to establish the relationship between temperature and RRV infection, there has been no comprehensive review of the association so far. In this study, we performed a systematic review and meta-analysis to assess the effect of temperature on RRV transmission. We searched PubMed, Scopus, Embase, and Web of Science with additional lateral searches from references. The quality and strength of evidence from the included studies were evaluated following the Navigation Guide framework. We have qualitatively synthesized the evidence and conducted a meta-analysis to pool the relative risks (RRs) of RRV infection per 1 °C increase in temperature. Subgroup analyses were performed by climate zones, temperature metrics, and lag periods. A total of 17 studies met the inclusion criteria, of which six were included in the meta-analysis The meta-analysis revealed that the overall RR for the association between temperature and the risk of RRV infection was 1.09 (95% confidence interval (CI): 1.02, 1.17). Subgroup analyses by climate zones showed an increase in RRV infection per 1 °C increase in temperature in humid subtropical and cold semi-arid climate zones. The overall quality of evidence was "moderate" and we rated the strength of evidence to be "limited", warranting additional evidence to reduce uncertainty. The results showed that the risk of RRV infection is positively associated with temperature. However, the risk varies across different climate zones, temperature metrics and lag periods. These findings indicate that future studies on the association between temperature and RRV infection should consider local and regional climate, socio-demographic, and environmental factors to explore vulnerability at local and regional levels., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The acute sickness response (ASR) is a stereotyped set of symptoms including fatigue, pain, and disturbed mood, which are present in most acute infections. The immunological mechanisms of the ASR are conserved, with variations in severity determined partly by the pathogen, but also by polymorphisms in host genes. The ASR was characterised in three different serologically-confirmed acute infections in Caucasians (n = 484) across four symptom domains or endophenotypes (termed 'Fatigue', 'Musculoskeletal pain', 'Mood disturbance', and 'Acute sickness'). Correlations were sought with functional single nucleotide polymorphisms in the NLRP3 inflammasone pathway and severity of the endophenotypes. Individuals with severe Fatigue, Musculoskeletal pain, or Mood endophenotypes were more likely to have prior episodes of significant fatigue (11.4 vs. 3.8%, p = 0.07), pain (14.3 vs. 1.2%, p = 0.001), or Mood disturbance (13 vs 1%, p=0.001), suggesting trait characteristics. The high functioning allele of the rs35829419 SNP in NLRP3 was more common in those with severe Fatigue (OR = 13.3, 95% CI: 1.7-104), particularly in a dominant inheritance pattern (OR = 13.4, 95% CI: 1.8-586.3). In a multivariable analysis assuming dominant inheritance, both rs35829419 and the rs4848306 SNP in Interleukin(IL)-1β, were independently associated with severe Fatigue (OR = 29.6, 95% CI: 2.6-330.9 and OR = 13, 95% CI: 2.7-61.8, respectively). The severity of fatigue in acute infection is influenced by genetic polymorphisms in NLRP3 and IL-1β., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Ross River virus (RRV) is a mosquito-borne arbovirus of the genus Alphavirus that causes disease in humans and horses in Australia. A temporal association of RRV infection in horses with clinical signs including pyrexia, malaise, and polyarthralgia has been reported, along with reduced athletic performance, often for extended periods. Despite these reports, disease due to RRV remains somewhat controversial as experimental infection of horses has resulted in obvious viraemia yet minimal signs of clinical disease. The relatively high viraemia demonstrated by horses infected with RRV has led to speculation that they could act as an important reservoir host of the virus, although this remains unclear. This review sought to appraise the existing literature relating to RRV infection of horses and to summarize the ecological and clinical consequences of RRV of relevance to the equine industry and to public health more broadly., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ross River virus (RRV) is a zoonotic alphavirus transmitted by several mosquito species. Until recently, endemic transmission was only considered possible in the presence of marsupial reservoirs., Methods: RRV seroprevalence was investigated in placental mammals (including horses, cows, goats, pigs, dogs, rats, and mice) in Fiji, where there are no marsupials. A total of 302 vertebrate serum samples were collected from 86 households from 10 communities in Western Fiji., Results: Neutralizing antibodies against RRV were detected in 28% to 100% of sera depending on the species, and neutralization was strong even at high dilutions., Conclusions: These results are unlikely to be due to cross-reactions. Chikungunya is the only other alphavirus known to be present in the Pacific Islands, but it rarely spills over into non-humans, even during epidemics. The study findings, together with a recent report of high RRV seroprevalence in humans, strongly suggest that RRV is circulating in Fiji in the absence of marsupial reservoirs. Considering that all non-human vertebrates present in Fiji are pan-global in distribution, RRV has the potential to further expand its geographic range. Further surveillance of RRV and access to RRV diagnostics will be critical for the early detection of emergence and outbreaks., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ross River virus (RRV) is Australia's most epidemiologically important mosquito-borne disease. During RRV epidemics in the State of Victoria (such as 2010/11 and 2016/17) notifications can account for up to 30% of national RRV notifications. However, little is known about factors which can forecast RRV transmission in Victoria. We aimed to understand factors associated with RRV transmission in epidemiologically important regions of Victoria and establish an early warning forecast system. We developed negative binomial regression models to forecast human RRV notifications across 11 Local Government Areas (LGAs) using climatic, environmental, and oceanographic variables. Data were collected from July 2008 to June 2018. Data from July 2008 to June 2012 were used as a training data set, while July 2012 to June 2018 were used as a testing data set. Evapotranspiration and precipitation were found to be common factors for forecasting RRV notifications across sites. Several site-specific factors were also important in forecasting RRV notifications which varied between LGA. From the 11 LGAs examined, nine experienced an outbreak in 2011/12 of which the models for these sites were a good fit. All 11 LGAs experienced an outbreak in 2016/17, however only six LGAs could predict the outbreak using the same model. We document similarities and differences in factors useful for forecasting RRV notifications across Victoria and demonstrate that readily available and inexpensive climate and environmental data can be used to predict epidemic periods in some areas. Furthermore, we highlight in certain regions the complexity of RRV transmission where additional epidemiological information is needed to accurately predict RRV activity. Our findings have been applied to produce a Ross River virus Outbreak Surveillance System (ROSS) to aid in public health decision making in Victoria., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The circulation of arthropod-borne viruses (arboviruses) throughout the Pacific is no exception in French Polynesia (FP). We review here the mosquito vectors involved or potentially involved in the transmission of arboviruses in FP. We highlight Aedes aegypti and Aedes polynesiensis ; species that are widely distributed in FP and whose ability to transmit dengue, zika and chikungunya viruses is well known. In addition, we discuss the contribution of those species and the abundant Culex annulirostris to the silent circulation of Ross River virus in FP. As these mosquito species and others present in FP are known to be vectors of a large panel of arboviruses, there is a high risk for new emergences.

Ross River virus (RRV) is an arthitogenic alphavirus capable of causing outbreaks of debilitating musculoskeletal inflammatory disease in humans. RRV is the most common mosquito-borne disease in Australia, with outbreaks of RRV generally occurring during seasonal wet and warm conditions. Patients with Ross River virus disease (RRVD) typically present with fever, polyarthralgia, myalgia and a maculopapular erythematous rash. Treatment of the disease is usually palliative with no licensed vaccines or antiviral therapies currently available. In an effort to better inform therapeutic design, much progress has been made to understand the pathogenesis of RRVD. Progress has been largely driven by clinical evaluations supported by research using established murine models of RRVD, able to accurately replicate human disease. In this review we describe RRVD pathogenesis and the role of the host immune response, with particular focus on insights from studying animal models. We also discuss prospects for effective vaccines, preclinical development of therapeutic strategies and raise important questions for future RRV research., (Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Alphaviruses such as Chikungunya virus (CHIKV), O'Nyong-Nyong virus (ONNV), Ross River virus (RRV), Eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), and Western equine encephalitis virus (WEEV), are mosquito-transmitted viruses that can cause fevers, rash, and rheumatic diseases (CHIKV, ONNV, RRV) or potentially fatal encephalitis (EEEV, VEEV, WEEV) in humans. These diseases are considered neglected tropical diseases for which there are no current antiviral therapies or vaccines available. The alphavirus non-structural protein 2 (nsP2) contains a papain-like protease, which is considered to be a promising target for antiviral drug discovery. In this work, molecular docking analyses have been carried out on a library of 2174 plant-derived natural products (290 alkaloids, 664 terpenoids, 1060 polyphenolics, and 160 miscellaneous phytochemicals) with the nsP2 proteases of CHIKV, ONNV, RRV, EEEV, VEEV, WEEV, as well as Aura virus (AURV), Barmah Forest Virus (BFV), Semliki Forest virus (SFV), and Sindbis virus (SINV) in order to identity structural scaffolds for inhibitor design or discovery. Of the 2174 phytochemicals examined, a total of 127 showed promising docking affinities and poses to one or more of the nsP2 proteases, and this knowledge can be used to guide experimental investigation of potential inhibitors., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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<0.05) as well as levels of the inflammation marker, C-reactive protein (p=0.001). Linear regression analysis identified an association between neurocognitive disturbance during acute illness and functional polymorphisms in inflammatory cytokine genes. Specifically, the high cytokine producing G allele of the IL-6-174G/C SNP was associated with poorer neurocognitive performance when subjects were ill (p=0.027). These findings confirm that acute infection impacts on neurocognitive performance, manifesting as slowed responses and impaired performance on complex tasks requiring higher-order functioning which has important real-world implications. The data provide the first preliminary evidence for a role of a genetic predisposition to more intense inflammatory responses in objective neurocognitive disturbances during acute infections. These associations require replication in a larger sample size., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To investigate the relationship between risk of Ross River virus (RRV) infection and proximity to mosquito-breeding habitat surrounding a tidal wetland ecosystem in south-west Australia., Methods: Geographic information systems (GIS) were used to spatially map cases of RRV disease in the Leschenault region between July 1995 and June 1996. Half kilometre buffer zones were constructed around the Leschenault Estuary and associated waterways; RRV disease case counts were calculated for each zone., Results: Different relationships between RRV disease incidence and proximity to saltmarsh mosquito habitat were observed east of the Leschenault Estuary compared with an urban region to the south. Disease incidence showed a decreasing trend away from eastern margins of the Estuary, particularly for the first 2 km. In the urban region, RRV disease risk was low close to the Estuary, but increased further out and remained steady across the remainder of that region., Conclusions: The findings support an increased risk of contracting RRV disease for people residing close to eastern margins of the Leschenault Estuary., Implications: This study highlights how historical data combined with GIS can improve understanding of the epidemiology of RRV disease. This has a valuable role in assessing the risk of mosquito-borne disease for land-use planning., (© 2012 The Authors. ANZJPH © 2012 Public Health Association of Australia.)

The acute sickness response to infection is a conserved set of changes in physiology and behaviour, featuring fever, fatigue, musculo-skeletal pain, disturbed mood, and cognitive difficulties. The manifestations differ somewhat between individuals, including those infected with pathogens which do not have genetic variability--suggesting host determinants. Principal components analysis (PCA) was applied to acute phase, self-report symptom data from subjects in the Dubbo Infection Outcomes Study (n=296) to empirically derive indices of fatigue, pain, neurocognitive difficulties, and mood disturbance, as well as overall illness severity. Associations were sought with functional single nucleotide polymorphisms (SNPs) in the cytokine genes, interleukin (IL)-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-10. The summed individual symptom indices correlated with overall severity and also with functional status. The relative contribution of individual symptom domains to the overall illness was stable over time within subjects, but varied between subjects with the same infection. The T allele of the IFN-γ +874 T/A SNP was associated with increased fatigue (p=0.0003; OR: 3.3). The C allele of the IL-10 -592 C/A SNP exerted a protective effect on neurocognitive difficulties (p=0.017; OR: 0.52); while the A allele for the IL-10 -592 SNP was associated with increased mood disturbance (p=0.044; OR: 1.83), as was the G allele of the IL-6 -174 G/C SNP (p=0.051; OR: 1.83). The acute sickness response has discrete symptom domains including fatigue, which have unique genetic associations. These data provide novel insights into the pathophysiology of fatigue states., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A retrospective follow-up survey was undertaken of residents of the North Coast of New South Wales infected with Ross River virus in 1992. The aims of the study were to describe the epidemiology and acute symptomatology of Ross River virus infection, its natural history during the first 12 months of infection, and its effects on those infected. Questionnaires were distributed to both cases and their medical practitioners. Of 129 people infected, aged between six and 85 years, 81 (63 per cent) were male and 48 (37 per cent) were female. The peak age-specific incidence was in the age group 50 to 59 years. The most common symptoms were arthralgia (95 per cent) and tiredness (91 per cent). Over 60 per cent took time off work. At 12 months follow-up, over 50 per cent reported persistent arthralgia, 35 per cent reported persistent tiredness and 15 per cent were still unable to carry out their normal activities. The median duration of symptoms was in the range 7 to 12 months, and of incapacity was in the range five weeks to three months. There were some differences from previous reports of Ross River virus outbreaks, in the incidence of major symptoms and the duration of illness and incapacity. These are likely to be at least partly due to inconsistent measurement methods. In this study, there were systematic differences between medical practitioners' and patients' estimates of periods of incapacity. Previous estimates of the direct economic costs and indirect human costs of infection based on data obtained from medical practitioners, although alarming, are almost certainly underestimates.