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Nature May 2018Arthritogenic alphaviruses comprise a group of enveloped RNA viruses that are transmitted to humans by mosquitoes and cause debilitating acute and chronic...
Arthritogenic alphaviruses comprise a group of enveloped RNA viruses that are transmitted to humans by mosquitoes and cause debilitating acute and chronic musculoskeletal disease . The host factors required for alphavirus entry remain poorly characterized . Here we use a genome-wide CRISPR-Cas9-based screen to identify the cell adhesion molecule Mxra8 as an entry mediator for multiple emerging arthritogenic alphaviruses, including chikungunya, Ross River, Mayaro and O'nyong nyong viruses. Gene editing of mouse Mxra8 or human MXRA8 resulted in reduced levels of viral infection of cells and, reciprocally, ectopic expression of these genes resulted in increased infection. Mxra8 bound directly to chikungunya virus particles and enhanced virus attachment and internalization into cells. Consistent with these findings, Mxra8-Fc fusion protein or anti-Mxra8 monoclonal antibodies blocked chikungunya virus infection in multiple cell types, including primary human synovial fibroblasts, osteoblasts, chondrocytes and skeletal muscle cells. Mutagenesis experiments suggest that Mxra8 binds to a surface-exposed region across the A and B domains of chikungunya virus E2 protein, which are a speculated site of attachment. Finally, administration of the Mxra8-Fc protein or anti-Mxra8 blocking antibodies to mice reduced chikungunya and O'nyong nyong virus infection as well as associated foot swelling. Pharmacological targeting of Mxra8 could form a strategy for mitigating infection and disease by multiple arthritogenic alphaviruses.
Topics: 3T3 Cells; Animals; Antibodies, Blocking; CRISPR-Cas Systems; Chikungunya virus; Chondrocytes; Fibroblasts; Humans; Immunoglobulins; Male; Membrane Proteins; Mice; Muscle, Skeletal; O'nyong-nyong Virus; Osteoblasts; Receptors, Fc; Receptors, Virus
PubMed: 29769725
DOI: 10.1038/s41586-018-0121-3 -
Microbes and Infection Nov 2017Ross River virus (RRV) is an arthitogenic alphavirus capable of causing outbreaks of debilitating musculoskeletal inflammatory disease in humans. RRV is the most common... (Review)
Review
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.
Topics: Alphavirus Infections; Animals; Disease Models, Animal; Humans; Palliative Care; Ross River virus
PubMed: 28754345
DOI: 10.1016/j.micinf.2017.07.001 -
PLoS Pathogens Feb 2022Arthritogenic alphaviruses are mosquito-borne viruses that are a major cause of infectious arthropathies worldwide, and recent outbreaks of chikungunya virus and Ross...
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.
Topics: Alphavirus Infections; Animals; Arthritis, Rheumatoid; Chlorocebus aethiops; Cytokines; Disease Models, Animal; Female; Humans; Immunity, Cellular; Inflammation; Interleukin-17; Male; Mice; Mice, Inbred C57BL; Myositis; Ross River virus; Vero Cells; Viral Load
PubMed: 35143591
DOI: 10.1371/journal.ppat.1010185 -
Tropical Medicine and Infectious Disease Aug 2021Ross River virus (RRV), the most common human arbovirus infection in Australia, causes significant morbidity and substantial medical costs. About half of Australian...
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.
PubMed: 34449729
DOI: 10.3390/tropicalmed6030145 -
PeerJ 2022Transmission of Ross River virus (RRV) is influenced by climatic, environmental, and socio-economic factors. Accurate and robust predictions based on these factors are...
Transmission of Ross River virus (RRV) is influenced by climatic, environmental, and socio-economic factors. Accurate and robust predictions based on these factors are necessary for disease prevention and control. However, the complicated transmission cycle and the characteristics of RRV notification data present challenges. Studies to compare model performance are lacking. In this study, we used RRV notification data and exposure data from 2001 to 2020 in Queensland, Australia, and compared ten models (including generalised linear models, zero-inflated models, and generalised additive models) to predict RRV incidence in different regions of Queensland. We aimed to compare model performance and to evaluate the effect of statistical over-dispersion and zero-inflation of RRV surveillance data, and non-linearity of predictors on model fit. A variable selection strategy for screening important predictors was developed and was found to be efficient and able to generate consistent and reasonable numbers of predictors across regions and in all training sets. Negative binomial models generally exhibited better model fit than Poisson models, suggesting that over-dispersion in the data is the primary factor driving model fit compared to non-linearity of predictors and excess zeros. All models predicted the peak periods well but were unable to fit and predict the magnitude of peaks, especially when there were high numbers of cases. Adding new variables including historical RRV cases and mosquito abundance may improve model performance. The standard negative binomial generalised linear model is stable, simple, and effective in prediction, and is thus considered the best choice among all models.
Topics: Animals; Humans; Queensland; Ross River virus; Incidence; Alphavirus Infections; Mosquito Vectors; Australia
PubMed: 36389410
DOI: 10.7717/peerj.14213 -
Advances in Virus Research 2020Alphaviruses, members of the enveloped, positive-sense, single-stranded RNA Togaviridae family, represent a reemerging public health threat as mosquito vectors expand...
Alphaviruses, members of the enveloped, positive-sense, single-stranded RNA Togaviridae family, represent a reemerging public health threat as mosquito vectors expand into new geographic territories. The Old World alphaviruses, which include chikungunya virus, Ross River virus, and Sindbis virus, tend to cause a clinical syndrome characterized by fever, rash, and arthritis, whereas the New World alphaviruses, which consist of Venezuelan equine encephalitis virus, eastern equine encephalitis virus, and western equine encephalitis virus, induce encephalomyelitis. Following recovery from the acute phase of infection, many patients are left with debilitating persistent joint and neurological complications that can last for years. Clues from human cases and studies using animal models strongly suggest that much of the disease and pathology induced by alphavirus infection, particularly atypical and chronic manifestations, is mediated by the immune system rather than directly by the virus. This review discusses the current understanding of the immunopathogenesis of the arthritogenic and neurotropic alphaviruses accumulated through both natural infection of humans and experimental infection of animals, particularly mice. As treatment following alphavirus infection is currently limited to supportive care, understanding the contribution of the immune system to the disease process is critical to developing safe and effective therapies.
Topics: Alphavirus; Alphavirus Infections; Animals; Encephalitis Virus, Venezuelan Equine; Horses; Humans; Mice
PubMed: 32711733
DOI: 10.1016/bs.aivir.2020.06.002 -
Veterinary Microbiology Jan 2010This review will cover zoonotic, encephalitic alphaviruses in the family Togaviridae. Encephalitic alphaviruses, i.e. Western- (WEEV), Eastern- (EEEV), Venezuelan equine... (Review)
Review
This review will cover zoonotic, encephalitic alphaviruses in the family Togaviridae. Encephalitic alphaviruses, i.e. Western- (WEEV), Eastern- (EEEV), Venezuelan equine encephalitis virus (VEEV) and, more rarely, Ross River virus, Chikungunya virus and Highlands J virus (HJV), are neuroinvasive and may cause neurological symptoms ranging from mild (e.g., febrile illness) to severe (e.g., encephalitis) in humans and equines. Among the naturally occurring alphaviruses, WEEV, EEEV and VEEV have widespread distributions in North, Central and South America. WEEV has found spanning the U.S. from the mid-West (Michigan and Illinois) to the West coast and extending to Canada with human cases reported in 21 states. EEEV is found along the Gulf (Texas to Florida) and Atlantic Coast (Georgia to New Hampshire), as well as in the mid-West (Wisconsin, Illinois and Michigan) and in Canada, with human cases reported in 19 states. In contrast, transmission of VEEV occurs predominantly in Central and South America. As with their geographical distribution, equine encephalitis viruses differ in their main mosquito vector species and their zoonotic potential.
Topics: Alphavirus; Alphavirus Infections; Americas; Animals; Encephalitis, Viral; Geography; Horse Diseases; Horses; Humans; Zoonoses
PubMed: 19775836
DOI: 10.1016/j.vetmic.2009.08.023 -
Reumatologia Clinica 2018Tropical alphaviruses have special tropism for bone and joint tissue. Patients can develop chronic rheumatic disorders similar to rheumatoid arthritis and ankylosing... (Review)
Review
Tropical alphaviruses have special tropism for bone and joint tissue. Patients can develop chronic rheumatic disorders similar to rheumatoid arthritis and ankylosing spondylitis. The prototype is Chikungunya virus, although other lesser known viruses in our environment such as Sindbis, Ross River, Mayaro, O'nyong nyong and Barmah Forest viruses have the potential to be sped through vectors and cause chronic rheumatic disease. International population movements have increased the numbers of patients diagnosed with these tropical viruses in areas in which they are not endemic. Since they can leave persistent symptoms and affect the quality of life of the patients, it is important that we be aware of them. Changes in ecosystems have favored the expansion of competent mosquitoes, making fears of local transmission in southern Europe a reality. The objective of this review is to provide a clinical approach to the different arthritogenic tropical alphaviruses, especially those in which chronic rheumatic disease is more frequent.
Topics: Alphavirus Infections; Arthritis, Infectious; Global Health; Humans; Rheumatic Diseases
PubMed: 28365217
DOI: 10.1016/j.reuma.2017.01.006 -
Vaccines Aug 2022Alphaviruses such as the human pathogenic chikungunya virus (CHIKV) and Ross River virus (RRV) can cause explosive outbreaks raising public health concerns. However, no...
Alphaviruses such as the human pathogenic chikungunya virus (CHIKV) and Ross River virus (RRV) can cause explosive outbreaks raising public health concerns. However, no vaccine or specific antiviral treatment is yet available. We recently established a CHIKV vaccine candidate based on trans-amplifying RNA (taRNA). This novel system consists of a replicase-encoding mRNA and a trans-replicon (TR) RNA encoding the antigen. The TR-RNA is amplified by the replicase in situ. We were interested in determining whether multiple TR-RNAs can be amplified in parallel and if, thus, a multivalent vaccine candidate can be generated. In vitro, we observed an efficient amplification of two TR-RNAs, encoding for the CHIKV and the RRV envelope proteins, by the replicase, which resulted in a high antigen expression. Vaccination of BALB/c mice with the two TR-RNAs induced CHIKV- and RRV-specific humoral and cellular immune responses. However, antibody titers and neutralization capacity were higher after immunization with a single TR-RNA. In contrast, alphavirus-specific T cell responses were equally potent after the bivalent vaccination. These data show the proof-of-principle that the taRNA system can be used to generate multivalent vaccines; however, further optimizations will be needed for clinical application.
PubMed: 36146452
DOI: 10.3390/vaccines10091374 -
Viruses Jun 2020Alphaviruses are globally distributed and predominately transmitted by mosquitoes. species are common vectors for the clinically important alphaviruses-Chikungunya,...
Alphaviruses are globally distributed and predominately transmitted by mosquitoes. species are common vectors for the clinically important alphaviruses-Chikungunya, Sindbis, and Ross River (RRV) viruses-with also being a vector for the flaviviruses dengue, Yellow Fever, and Zika viruses. was putatively implicated in the large 1979-1980 South Pacific Islands outbreak of RRV-the leading cause of arboviral disease in Australia today. The RNA interference (RNAi) defense response in mosquitoes involves a number of small RNAs, with their kinetics induced by alphaviruses being poorly understood, particularly at the tissue level. We compared the small RNA profiles between RRV-infected and noninfected midgut and fat body tissues at 2, 6, and 12 days post-inoculation (dpi). RRV induced an incremental RNAi response, yielding short interfering and P-element-induced-wimpy-testis (PIWI)-interacting RNAs. Fourteen host microRNAs were differentially expressed due to RRV with the majority in the fat body at 2 dpi. The largely congruent pattern of microRNA regulation with previous reports for alphaviruses and divergence from those for flaviviruses suggests a degree of conservation, whereas patterns of microRNA expression unique to this study provide novel insights into the tissuespecific hostvirus attributes of responses to this previously unexplored oldworld alphavirus.
Topics: Aedes; Animals; Female; Gene Expression Profiling; Host Microbial Interactions; MicroRNAs; Mosquito Vectors; RNA Interference; Ross River virus; Virus Replication
PubMed: 32605094
DOI: 10.3390/v12070695