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Arthritogenic alphaviruses are mosquito-borne arboviruses that include several re-emerging human pathogens, including the chikungunya (CHIKV), Ross River (RRV), Mayaro (MAYV), and o’nyong-nyong (ONNV) virus. Arboviruses are transmitted via a mosquito bite to the skin. Herein, we describe intradermal RRV infection in a mouse model that replicates the arthritis and myositis seen in humans with Ross River virus disease (RRVD). We show that skin infection with RRV results in the recruitment of inflammatory monocytes and neutrophils, which together with dendritic cells migrate to draining lymph nodes (LN) of the skin. Neutrophils and monocytes are productively infected and traffic virus from the skin to LN. We show that viral envelope N-linked glycosylation is a key determinant of skin immune responses and disease severity. RRV grown in mammalian cells elicited robust early antiviral responses in the skin, while RRV grown in mosquito cells stimulated poorer early antiviral responses. We used glycan mass spectrometry to characterize the glycan profile of mosquito and mammalian cell-derived RRV, showing deglycosylation of the RRV E2 glycoprotein is associated with curtailed skin immune responses and reduced disease following intradermal infection. Altogether, our findings demonstrate skin infection with an arthritogenic alphavirus leads to musculoskeletal disease and envelope glycoprotein glycosylation shapes disease outcome. IMPORTANCE Arthritogenic alphaviruses are transmitted via mosquito bites through the skin, potentially causing debilitating diseases. Our understanding of how viral infection starts in the skin and how virus systemically disseminates to cause disease remains limited. Intradermal arbovirus infection described herein results in musculoskeletal pathology, which is dependent on viral envelope N-linked glycosylation. As such, intradermal infection route provides new insights into how arboviruses cause disease and could be extended to future investigations of skin immune responses following infection with other re-emerging arboviruses.

Objective: This research seeks to identify climate‐sensitive infectious diseases of concern with a present and future likelihood of increased occurrence in the geographically vulnerable Torres Strait Islands, Australia. The objective is to contribute evidence to the need for adequate climate change responses. Methods: Case data of infectious diseases with proven, potential and speculative climate sensitivity were compiled. Results: Five climate‐sensitive diseases in the Torres Strait and Cape York region were identified as of concern: tuberculosis, dengue, Ross River virus, melioidosis and nontuberculous mycobacterial infection. The region constitutes 0.52% of Queensland's population but has a disproportionately high proportion of the state's cases: 20.4% of melioidosis, 2.4% of tuberculosis and 2.1% of dengue. Conclusions: The Indigenous Torres Strait Islander peoples intend to remain living on their traditional country long‐term, yet climate change brings risks of both direct and indirect human health impacts. Implications for public health: Climate‐sensitive infections pose a disproportionate burden and ongoing risk to Torres Strait Islander peoples. Addressing the causes of climate change is the responsibility of various agencies in parallel with direct action to minimise or prevent infections. All efforts should privilege Torres Strait Islander peoples’ voices to self‐determine response actions.

Background Ross River virus (RRV) disease is Australia's most widespread vector-borne disease causing significant public health concern. The aim of this study was to identify the ecological covariates of RRV risk and to develop epidemic forecasting models in a disease hotspot region of South Australia. Methods Seasonal autoregressive integrated moving average models were used to predict the incidence of RRV disease in the Riverland region of South Australia, an area known to have a high incidence of the disease. The model was developed using data from January 2000 to December 2012 then validated using disease notification data on reported cases for the following year. Results Monthly numbers of the mosquito Culex annulirostris (β=0.033, p Conclusions A predictive model has been shown to be useful in forecasting the occurrence of RRV disease, with increased vector populations and rainfall being important factors associated with transmission. This approach may be useful in a public health context by providing early warning of vector-borne diseases in other settings.

Ross River virus (RRV) is a mosquito-borne zoonotic arbovirus associated with high public health and economic burdens across Australia, but particularly in South East Queensland (SEQ). Despite this high burden, humans are considered incidental hosts. Transmission of RRV is maintained among mosquitoes and many nonhuman vertebrate reservoir hosts, although the relative contributions of each of these hosts are unclear. To clarify the importance of a range of vertebrates in RRV transmission in SEQ, a total of 595 serum samples from 31 species were examined for RRV exposure using a gold-standard plaque reduction neutralization test. Data were analyzed statistically using generalized linear models and a coefficient inference tree, and spatially. RRV exposure was highly variable between and within species groups. Critically, species group ("placental mammal," "marsupial," and "bird"), which has previously been used as a proxy for reservoir hosts, was a poor correlate for exposure. Instead, we found that generalized "diet" and greater "body mass" were most strongly correlated with seropositivity. We also identified significant differences in seropositivity between the two major possum species (ringtail possums and brushtail possums), which are ecologically and taxonomically different. Finally, we identified distinct hotspots and coldspots of seropositivity in nonhuman vertebrates, which correlated with human notification data. This is the largest diversity of species tested for RRV in a single study to date. The analysis methods within this study provide a framework for analyzing serological data in combination with species traits for other zoonotic disease, but more specifically for RRV highlight areas to target further public health research and surveillance effort.

To examine the sequence of environmental and entomological events prior to a substantial increase in Ross River virus (RRV) and Barmah Forest virus (BFV) notifications with a view to informing future public health response.Rainfall, tidal, mosquito and human arboviral notification data were analysed to determine the temporality of events.Following two extremely dry years, there was a substantial increase in the abundance of mosquitoes along coastal New South Wales (NSW) two weeks after a significant rainfall event and high tides in February 2020. Subsequently, RRV and BFV notifications in north east NSW began to increase eight and nine weeks respectively after the high rainfall, with RRV notifications peaking 12 weeks after the high rainfall.Mosquito bite avoidance messaging should be instigated within two weeks of high summer rainfall, especially after an extended dry period.Intense summertime rain events, which are expected to increase in frequency in south-east Australia with climate change, can lead to significant increases in arboviral disease. These events need to be recognised by public health practitioners to facilitate timely public health response. This has taken on added importance since the emergence of Japanese encephalitis virus in southeastern Australia in 2022.

Transmission of vector-borne pathogens can vary in complexity from single-vector, single-host systems through to multivector, multihost vertebrate systems. Understanding the dynamics of transmission is important for disease prevention efforts, but is dependent on disentangling complex interactions within coupled natural systems. Ross River virus (RRV) is a multivector multihost pathogen responsible for the greatest number of notified vector-borne pathogen infections in humans in Australia. Current evidence suggests that nonhuman vertebrates are critical for the maintenance and spillover of RRV into mosquito populations. Yet, there is a limited knowledge of which mosquito vector species and amplifying vertebrate host species are most important for transmission of RRV to humans. We conducted field surveys of nonhuman vertebrates and mosquitoes in the RRV endemic city of Brisbane, Australia, to assess the effect of vector and host community structure on human RRV notifications. Six suburbs were selected across a gradient of human disease notification rates. Differences in vertebrate and mosquito compositions were observed across all suburbs. Suburbs with higher RRV notification rates contained greater vertebrate biomass (dominated by the presence of horses) and higher mosquito abundances. This study suggests that horse-mosquito interactions should be considered in more detail and that vertebrate biomass and mosquito abundance be incorporated into future RRV modeling studies and considered in public health strategies for RRV management.

More than 75 arboviruses (arthropod-borne viruses) have been identified in Australia. While Alfuy virus (ALFV), Barmah Forest virus (BFV), Edge Hill virus (EHV), Kokobera virus (KOKV), Murray Valley encephalitis virus (MVEV), Sindbis virus (SINV), Ross River virus (RRV), Stratford virus (STRV), and West Nile virus strain Kunjin (KUNV) have been associated with human infection, there remains a paucity of data regarding their respective transmission cycles and any potential nonhuman vertebrate hosts. It is likely that these viruses are maintained in zoonotic cycles involving native animals rather than solely by human-to-human transmission. A serosurvey (n = 100) was undertaken to determine the prevalence of neutralizing antibodies against a panel of Australian arboviruses in western gray kangaroos (Macropus fuliginosus) obtained from 11 locations in the midwest to southwest of Western Australia. Neutralizing antibodies against RRV were detected in 25%, against BFV in 14%, and antibodies to both viruses in 34% of serum samples. The prevalence of antibodies against these two viruses was the same in males and females, but higher in adult than in subadult kangaroos (p

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.

Arthritogenic alphaviruses are mosquito-borne viruses that are a major cause of infectious arthropathies worldwide, and recent outbreaks of chikungunya virus and Ross River virus (RRV) infections highlight the need for robust intervention strategies. Alphaviral arthritis can persist for months after the initial acute disease, and is mediated by cellular immune responses. A common strategy to limit inflammation and pathology is to dampen the overwhelming inflammatory responses by modulating proinflammatory cytokine pathways. Here, we investigate the contribution of interleukin-17 (IL-17), a cytokine involved in arthropathies such as rheumatoid arthritis, in the development RRV-induced arthritis and myositis. IL-17 was quantified in serum from RRV-infected patients, and mice were infected with RRV and joints and muscle tissues collected to analyse cellular infiltrates, tissue mRNA, cytokine expression, and joint and muscle histopathology. IL-17 expression was increased in musculoskeletal tissues and serum of RRV-infected mice and humans, respectively. IL-17–producing T cells and neutrophils contributed to the cellular infiltrate in the joint and muscle tissue during acute RRV disease in mice. Blockade of IL-17A/F using a monoclonal antibody (mAb) reduced disease severity in RRV-infected mice and led to decreased proinflammatory proteins, cellular infiltration in synovial tissues and cartilage damage, without affecting viral titers in inflamed tissues. IL-17A/F blockade triggered a shift in transcriptional profile of both leukocyte infiltrates and musculoskeletal stromal cells by downregulating proinflammatory genes. This study highlights a previously uncharacterized role for an effector cytokine in alphaviral pathology and points towards potential therapeutic benefit in targeting IL-17 to treat patients presenting with RRV-induced arthropathy.

We collected 5,500 mosquitoes belonging to six species in three locations in China. Their viromes were tested using metagenomic sequencing and bioinformatic analysis. The affluent viral sequences that were detected and annotated belong to 22 viral taxonomic families. Then, PCR was performed to confirm the results, followed by phylogenetic analysis. Herein, part of mosquito virome was identified, including chikungunya virus (CHIKV), Getah virus (GETV), and Ross river virus (RRV). After metagenomic analysis, seven CHIKV sequences were verified by PCR amplification, among which CHIKV-China/YN2018-1 had the highest homology with the CHIKV isolated in Senegal, 1983, with a nucleotide (nt) identity of at least 81%, belonging to genotype West Africa viral genes. Five GETV sequences were identified, which had a high homology with the GETV sequences isolated from

Alphaviruses such as Ross River virus (RRV), chikungunya virus and Venezuelan equine encephalitis virus are mosquito-borne pathogens that can cause arthritis or encephalitis diseases. Nonstructural protein 4 (nsP4) of alphaviruses possesses RNA-dependent RNA polymerase (RdRp) activity essential for viral RNA replication. No 3D structure has been available for nsP4 of any alphaviruses despite its importance for understanding alphaviral RNA replication and for the design of antiviral drugs. Here, we report a crystal structure of the RdRp domain of nsP4 from RRV determined at a resolution of 2.6 A. The structure of the alphavirus RdRp domain appears most closely related to RdRps from pestiviruses, noroviruses and picornaviruses. Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and nuclear magnetic resonance (NMR) methods, we showed that in-solution nsP4 is highly dynamic with an intrinsically disordered N-terminal domain. Both full-length nsP4 and the RdRp domain were able to catalyze in vitro RNA polymerization. Structure-guided mutagenesis using a trans-replicase system identified nsP4 regions critical for viral RNA replication. Significance Statement Alphaviruses are a group of viruses that comprise several important pathogens that provoke encephalitis or arthritis in humans. Through its RdRp activity, nsP4 of alphaviruses plays a crucial role in viral RNA replication. We determined the crystal structure of nsP4, disclosing a dynamic structure resembling the core catalytic domain of RNA polymerases from pestiviruses, picornaviruses, and noroviruses. These findings expand our knowledge of the molecular basis for alphavirus RNA replication and should accelerate the design of specific antiviral compounds targeting RNA polymerase activity.

Over the past few decades, there have been resurgences in vector-borne diseases that may have been driven by factors such as climate change, drug resistance, and urbanization. To predict these changes, forecasting methods and simulation models have been developed, but they are difficult to apply to vector-borne diseases due to limited case data available and the complex dynamics of arthropod vectors. Having the ability to predict imminent outbreaks before cases increase is imperative to mitigate the consequences of early exponential growth. One promising approach applies the theory of critical slowing down, which predicts that as a system approaches a critical transition (for example, from disease elimination to resurgence), its ability to return to stability following minor disturbances diminishes. This phenomenon results in particular patterns in disease incidence that are detectable as characteristic changes in summary statistics prior to the critical transition. Additionally, temperature strongly influences mosquito traits and life cycles, which in turn affect disease transmission. Detection of thermal thresholds, temperature moving from an inhibitory range to a suitable range for transmission, can allow us to take timely preventative actions prior to a potential outbreak. We tested for early warning signals of critical slowing down of Ross River virus in Queensland, Australia, by calculating nine summary statistics across a rolling window. The summary statistics were then compared to the temperature suitability for transmission (defined as relative R0(T) from a previous model) to determine whether the system crossed a thermal threshold. Five of the 15 HHS regions exhibited critical slowing down, primarily in variance, skewness, kurtosis, autocorrelation, and index of dispersion. Gold Coast exhibited the strongest evidence for critical slowing down occurring when temperatures crossed a threshold between 18.2-18.3 degrees Celsius. This shows that early warning signal detection can aid in predicting disease outbreaks and determining possible influential variables such as temperature.

Ross River virus (RRV) is mosquito-borne arboviral infection that causes fever, polyarthritis, and rash. First described in northern Australia and then, widely throughout Australia and many western South Pacific islands. It is common in the tropical coastal regions of northern Australia. RRV can be transmitted by, Aedes aegypti, Ae. camptorhynchus, Ae. vigilax, and Culex annulirostris. Kangaroos, wallabies and horses are principal vertebrate hosts. Symptoms frequently occur together but may occur in single. Arthritis in wrists, knees, ankles, and finger joints is common and frequently symmetric. Rash is usually maculopapular involving limbs and trunk. Arthralgia may persist for up to 3 months. Fatigue is the commonest symptom. Diagnosis is by hemagglutination inhibition (HI) antibody and ELISA. A fourfold rise in HI titer is diagnostic; ≥1:1280 levels is recent infection. RRV-specific IgM persists for months after acute infection. Treatment is supportive care, analgesics, and non-steroidal anti-inflammatory drugs. Feasible preventive measure is avoidance of mosquito bites. Helpful interventions include use of window and door screens, mosquito repellants, and light colored clothing. Over the long-term, drainage of mosquito breeding areas in endemic areas may be helpful to control infection.

Australia experienced its largest recorded outbreak of Ross River virus (RRV) during the 2014–15 reporting year, comprising >10,000 reported cases. We investigated epidemiologic, entomologic, and virologic factors that potentially contributed to the scale of the outbreak in Queensland, the state with the highest number of notifications (6,371). Spatial analysis of human cases showed that notifications were geographically widespread. In Brisbane, human case notifications and virus detections in mosquitoes occurred across inland and coastal locations. Viral sequence data demonstrated 2 RRV lineages (northeastern genotypes I and II) were circulating, and a new strain containing 3 unique amino acid changes in the envelope 2 protein was identified. Longitudinal mosquito collections demonstrated unusually high relative abundance of Culex annulirostris and Aedes procax mosquitoes, attributable to extensive freshwater larval habitats caused by early and persistent rainfall during the reporting year. Increased prevalence of these mosquitoes probably contributed to the scale of this outbreak.

Ross 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 in 1979 to 1980.

The Australian backyard mosquito, Aedes notoscriptus, is a highly urbanised pest species that has invaded New Zealand and the USA. Importantly, Ae. notoscriptus has been implicated as a vector of Ross River virus, a common and arthritogenic arbovirus in Australia, and is a laboratory vector of numerous other pathogenic viruses, including West Nile, yellow fever, and Zika viruses. To further explore live viruses harboured by field populations of Ae. notoscriptus and, more specifically, assess the genetic diversity of its virome, we processed 495 pools, comprising a total of 6,674 female Ae. notoscriptus collected across fifteen suburbs in Brisbane, Australia, between January 2018 and May 2019. Nine virus isolates were recovered and characterised by metagenomic sequencing and phylogenetics. The principal viral family represented was Flaviviridae. Known viruses belonging to the genera Flavivirus, Orbivirus, Mesonivirus, and Nelorpivirus were identified together with two novel virus species, including a divergent Thogoto-like orthomyxovirus and an insect-specific flavivirus. Among these, we recovered three Stratford virus (STRV) isolates and an isolate of Wongorr virus (WGRV), which for these viral species is unprecedented for the geographical area of Brisbane. Thus, the documented geographical distribution of STRV and WGRV, both known for their respective medical and veterinary importance, has now been expanded to include this major urban centre. Phylogenies of the remaining five viruses, namely, Casuarina, Ngewotan, the novel Thogoto-like virus, and two new flavivirus species, suggested they are insect-specific viruses. None of these viruses have been previously associated with Ae. notoscriptus or been reported in Brisbane. These findings exemplify the rich genetic diversity and viral abundance within the Ae. notoscriptus virome and further highlight this species as a vector of concern with the potential to transmit viruses impacting human or animal health. Considering it is a common pest and vector in residential areas and is expanding its global distribution, ongoing surveillance, and ecological study of Ae. notoscriptus, together with mapping of its virome and phenotypic characterisation of isolated viruses, is clearly warranted. Immanently, these initiatives are essential for future understanding of both the mosquito virome and the evolution of individual viral species.

Across the Pacific, and including in the Solomon Islands, outbreaks of arboviruses such as dengue, chikungunya, and Zika are increasing in frequency, scale and impact. Outbreaks of mosquito-borne disease have the potential to overwhelm the health systems of small island nations. This study mapped the seroprevalence of dengue, Zika, chikungunya and Ross River viruses in 5 study sites in the Solomon Islands. Serum samples from 1,021 participants were analysed by ELISA. Overall, 56% of participants were flavivirus-seropositive for dengue (28%), Zika (1%) or both flaviviruses (27%); and 53% of participants were alphavirus-seropositive for chikungunya (3%), Ross River virus (31%) or both alphaviruses (18%). Seroprevalence for both flaviviruses and alphaviruses varied by village and age of the participant. The most prevalent arboviruses in the Solomon Islands were dengue and Ross River virus. The high seroprevalence of dengue suggests that herd immunity may be a driver of dengue outbreak dynamics in the Solomon Islands. Despite being undetected prior to this survey, serology results suggest that Ross River virus transmission is endemic. There is a real need to increase the diagnostic capacities for each of the arboviruses to support effective case management and to provide timely information to inform vector control efforts and other outbreak mitigation interventions.

In PNAS, Malonis et al. (1) isolate and characterize several human monoclonal antibodies (MoAbs) that neutralize infection with arthritogenic alphaviruses. Alphaviruses represent a large group of positive-strand RNA viruses, some of which cause infections in humans. They are widely distributed, are transmitted by mosquitoes, and have been clinically classified as encephalitic and arthritogenic, according to the most prevalent symptoms in human and animal infections. Among alphaviruses, Chikungunya virus (CHIKV) is a frequent cause of outbreaks in different geographic locations and is characterized by fever and joint inflammation, often accompanied by persistent joint pain and arthralgia for several months after initial infection that can lead to joint immobilization (2). CHIKV is transmitted by Aedes mosquitoes, and, although most infections take place in the tropical and subtropical regions, outbreaks and local transmission of CHIKV have been known to occur in Europe and the United States too. The expansion of the geographical distribution of the Aedes vector has been a major contributor to the increases in CHIKV infections during the last decades (3). Other arthritogenic alphaviruses known to infect humans are Mayaro virus (MAYV), Ross River virus (RRV), and O’nyong-nyong virus (ONNV), present in South America, the South Pacific, and Africa, respectively. Currently, despite their burden on human health, there are no available specific treatments or vaccines against any alphaviruses. The use of pathogen-specific … [↵][1]1 Email: adolfo.garcia-sastre{at}mssm.edu. [1]: #xref-corresp-1-1

Ross River virus (RRV), the most common human arbovirus infection in Australia, causes significant morbidity and substantial medical costs. About half of Australian cases occur in Queensland. We describe the spatial and temporal patterns of RRV disease in Queensland over the past two decades. RRV notifications, human population data, and weather data from 2001 to 2020 were analysed by the Statistical Area Level 2 (SA2) area. Spatial interpolation or linear extrapolation were used for missing weather values and the estimated population in 2020, respectively. Notifications and incidence rates were analysed through space and time. During the study period, there were 43,699 notifications in Queensland. The highest annual number of notifications was recorded in 2015 (6182), followed by 2020 (3160). The average annual incidence rate was 5 per 10,000 people and the peak period for RRV notifications was March to May. Generally, SA2 areas in northern Queensland had higher numbers of notifications and higher incidence rates than SA2 areas in southern Queensland. The SA2 areas with high incidence rates were in east coastal areas and western Queensland. The timely prediction may aid disease prevention and routine vector control programs, and RRV management plans are important for these areas.