H2020 PALE-Blu Project: Understanding pathogen-livestock-environment interactions involving bluetongue virus
- Type Project
- Status Filled
- Execution 2017 -2021
- Assigned Budget 6.039.301,5 €
- Scope Europeo
- Main source of financing Horizon 2020
- Project website Proyecto PALE-Blu
Bluetongue virus (BTV) infects wild and domestic ruminants, such as sheep, goats, and cattle. Most strains are transmitted by mosquitoes. Depending on the BTV strain, the impact of the disease on livestock varies, but it can be fatal. Vaccination is the most effective and practical measure to minimize economic losses resulting from the disease.
The EU-funded PALE-Blu project brings together European institutes and partners in endemic regions to study BTV strains. Through whole genome sequence analysis, researchers will map the distribution of different BTV strains, identify their spread mechanisms, and develop prevention strategies.
The project will also study the distribution and population dynamics of insect vectors and explore vaccines, antiviral agents, and improved diagnostic systems. The project's results will improve preparedness for future outbreaks and control strategies.
BTV sequences have been collected, annotated, and curated and entered into the BTV-GLUE website. The beta version of the BTV-GLUE dataset is available on a public web server (http://btv.glue.cvr.ac.uk), which includes an automated genotyping tool for all segments. A comprehensive Culicoides vector abundance database, covering most of Europe and neighboring countries, has been generated to define epizones with different insect vector populations. Updated livestock maps (cattle, sheep, and goats) have helped to define epizones based on ecoclimatic data.
Diagnostic tools for new BTV serotypes, as well as multiplexed assay systems, have been developed and evaluated. Continuous cell lines for an additional Culicoides species have been developed, maintained, and made available to the scientific community. Rescued monoreassortant BTV strains were generated to explore the molecular basis of contact transmission and insect vector transmission, as well as other viral properties, including interactions with the innate immune response and interferon inhibition. The antiviral activity of statin derivatives and calcium channel inhibitors was further explored. Project results and data have been and will continue to be disseminated through one or more of the four websites that have been established or associated with the project: http://www.paleblu.eu, the general project website, which provides project details, presentations, publications, and deliverables.
This includes the project kick-off meeting in Glasgow 2017: http://www.paleblu.eu/system/files/2019-01/2017-09-06-MeetingReportFor1stPALE-BluMeetingCVRGlasgow-LR%20update.pdf and the second nsed meeting in Rabat 2018: http://www.paleblu.eu/system/files/2019-01/2018-09-19-20-2ndPALE-BluMeetingMorocco.pdf See WP1 above. https://www.edenextdata.com/ – the project spatial data archive, see also WP3 above. http://mapserver.izs.it/gis_oiemaps/ – a site showing the global distribution of bluetongue virus (BTV). A newly developed haploid embryonic stem cell library was used to characterize genes and cellular pathways essential for productive bluetongue virus (BTV-8) infection.
Bluetongue is an economically important disease that has invaded Europe, particularly southern and central Europe, since 1998. These changes, linked to climate change, seem unlikely to be reversed. The disease causes significant economic losses due to livestock deaths (more than 25% in sheep), loss of reproductive performance and milk and meat production, restrictions on animal movement and trade, and the costs of control measures.
The PALE-Blu Project brings together 19 different partner organizations in 15 countries to generate data on the distribution and interaction of BTV genetic variants with insect vector and host populations to inform control and prevention strategies. The project analyzed interactions between different virus strains, insect vectors, and vertebrate hosts at the population, individual, and molecular levels. Transmission mechanisms were analyzed to help inform risk assessment, modeling, and mitigation. In particular, the project identifies and maps different virus and vector populations, and the environmental factors that determine their incidence and distribution, to understand how genetic variations may determine the transmission of different BTV serotypes/strains in different regions. Databases were created to facilitate the global identification of different BTV variants through sequence analysis. The project developed diagnostic assays to maintain and enhance current diagnostic and surveillance capabilities.
These include, in particular, the recently identified "novel" serotypes (BTV-25 and higher) to ensure their rapid and accurate detection. The project has sought to generate additional cell lines from European and African Culicoides species for further studies on transmission mechanisms and differences between different vector populations/species. Cross-reactive antigens and epitopes for different BTV serotypes were identified in order to develop safe, multivalent, or cross-reactive vaccine candidates against different BTV serotypes. The project has developed and maintained project communication and management through websites, regular meetings, and publications/presentations aimed at both scientific and general audiences.
Every year since 1998, new outbreaks of bluetongue virus (BTV) have occurred in European livestock. These events, which have been linked to climate change, resulted in massive losses due to deaths, reduced productivity, reproductive failure, restricted animal movement and trade, and reduced surveillance and vaccination costs. PALE-Blu brings together European institutes with expertise in BTV research and diagnostics, with partners in endemic regions (Africa, the Middle East, and Turkey) that act as sources for BTV strains emerging in Europe.
Whole-genome sequence analyses will increase the accuracy of distribution maps of BTV strains, identifying pathways and mechanisms of spread to and within Europe, as well as appropriate prevention strategies. PALE-Blu will analyze the genetic connectivity of Culicoides vector populations in different regions, as well as the movement of individual BTV lineages and genes. Combined with reverse genetics technologies and infection/replication studies in novel Culicoides cell lines, or adults of different Culicoides species, this will elucidate the genetic basis for the geographic location/movement of BTV strains and serotypes.
We will analyze the differences in salivary proteins of Culicoides species, their ability to modify BTV surface proteins (proteases), and the effects on transmission efficiency (in both directions) between host vertebrae and vector insects. These studies will provide a better understanding of the risks of incursion of different strains of bluetongue virus, supporting effective control strategies. PALE-BLU will explore more effective cross-serotype subunit vaccines that are compatible with the DIVA assay and generate a stronger immune response from a single inoculation. We will also explore the potential for using antiviral agents to induce immediate protection after vaccination. More efficient diagnostic systems will also be developed to better detect mixed infections through multiplexing of new or existing diagnostic assay systems.
Research on bluetongue virus, which affects livestock, has led to new ways of monitoring and controlling the disease. Bluetongue (BTV) is a viral disease that affects livestock worldwide, including sheep, cattle, camels, deer, and goats. Caused by the bluetongue virus (BTV) and spread by biting mosquitoes, if BTV doesn't kill an animal, it can still reduce meat, milk, and offspring production.
This, coupled with the trade restrictions that follow an LB outbreak and the costs of surveillance, vaccines, and testing to demonstrate disease eradication, results in significant economic losses for the agricultural industry. One thing that makes the disease particularly complex is the BTV genome. The genome is composed of 10 double-stranded RNA segments, each of which encodes one or more of the viral proteins. "This segmentation allows the virus to easily swap genome segments between strains during coinfections, rapidly creating new variants with novel disease risks," says Peter Mertens, a virologist at the University of Nottingham.
More than 30 distinct serotypes of bluetongue virus (BTV) have been identified, several of which may co-circulate in endemic and outbreak regions. With support from the EU-funded PALE-Blu project, Mertens is leading a major effort to better understand the underlying disease and improve techniques for rapid and accurate monitoring and control of the virus. “This is a large project bringing together partners from across Europe, the Mediterranean, and Africa,” explains Mertens. “Together, we set out to provide new datasets, reagents, and resources on BTV itself and its interactions with mammalian hosts and insect vector species.” Understanding replication, transmission, and epidemiology According to Mertens, the culmination of the project’s work is a greater understanding of BTV replication, transmission, and epidemiology. “Not only do we better understand the risks of further BTV outbreaks and spread, but, perhaps more importantly, we have new methods and tools to control them,” she adds. Two important developments are the rapid sequencing technologies of the BTV genome and the BTV-Glue website.
Together, these support the detection, rapid identification, and further characterization of different BTV strains. "This helps us determine the ancestry, origins, and movement of individual BTV strains causing different outbreaks," Mertens notes. Furthermore, the project has produced significant new insights into the disease. For example, by analyzing the evolution rates of BTV strains that caused recent outbreaks in France, the project showed that the virus's evolution was 'frozen' between outbreak periods. "It has been suggested that BTV could have re-emerged as a result of artificial insemination with frozen semen," Mertens says. Researchers found several previously unknown strains of bluetongue virus in Mongolia, the Middle East, and the Mediterranean. "Although most exhibit low virulence, several of these viruses might not require insect vectors and could instead be transmitted directly between mammalian hosts," Mertens notes. "This could have a significant impact on how the disease spreads, allowing outbreaks to occur even during times of the year when insect vectors are absent."
The project also made progress in mitigating the risk of an outbreak. For example, an improved diagnostic array was developed to optimize the detection and identification of virus strains. Researchers also discovered a component of the insect vector's saliva that could stimulate the immune response in infected animals. "The project has developed new vaccine candidates and identified individual proteins of bluetongue virus that generate cross-protection between serotypes, which represents an important first step toward a cross-serotype vaccine that would better protect livestock and agricultural industries from the effects of La La disease," Mertens concludes.
BTV-GLUE has helped the bluetongue virus community study the biology, evolution, and outbreaks of the virus to distinguish the properties of strains circulating worldwide. Incorporating Culicoides distribution data into previously developed epizonal maps has helped identify areas at risk for virus transmission.
A model of wind-borne Culicoides movements also helps characterize natural barriers to vector dispersal. Together, these models help us understand and identify pathways and risk factors for BTV incursions and their epidemiology. Work is underway to maintain a comprehensive suite of diagnostic assays to detect current and known BTV serotypes that pose outbreak risks. Work toward assay multiplexing using novel platforms such as MagPlex has helped automate throughput. Recent advances in sequencing technologies provide opportunities to identify viral pathogens using a metagenomic approach.
The development of cell lines from other mosquito species has helped support studies that improve our understanding of the molecular characteristics that determine whether a particular mosquito species is a competent vector for a specific BTV strain. Investigations into viral genetic control of infection, replication, and vector competence in European Culicoides species have improved our understanding of the viral, insect, and host factors that enable insect-mediated transmission of BTV. This could help us predict the vectorial transmissibility of BTV strains directly through viral genome research. Identifying viral genetic control of horizontal transmission (HT) in the ruminant host could allow us to predict the non-vectorial transmissibility of BTV strains through viral genome research. The data obtained will improve control measures and advise policymakers on the risks posed by new BTV strains.
The development of a library of BTV-specific monoclonal antibodies was designed to support the identification of VP2 regions/epitopes involved in the protective response. It would also facilitate the development of serotype-specific serological assays (e.g., ELISA). However, these studies were unsuccessful in sheep, so they were transferred to a bovine system. Delays caused by the COVID-19 outbreak delayed many aspects of the PALE-Blu studies, and work on monoclonal antibodies continues to progress.
The generation and validation of new vaccines, vaccination strategies, and antivirals compatible with existing surveillance methods/assays, and potentially cross-serotype compatible, has the potential to improve our rapid response capacity to disease emergence. The development of effective, broad-spectrum antiviral strategies for dsRNA viruses using orbiviruses could be a step toward controlling the replication of these viruses in infected animals, potentially including humans. The PALE-Blu websites provide project-related data to its members. Their combined visit rate exceeds 3,000 per month. The project has also generated fact sheets, regular e-newsletters, and a short video series describing the project's results and impact. Like the websites, these are intended for a broad audience, not just practitioners and planners.
- THE UNIVERSITY OF NOTTINGHAM
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