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Background Culicoides biting midges are biological vectors of arboviruses including bluetongue virus (BTV), Schmallenberg virus (SBV) and African horse sickness virus (AHSV). Zoos are home to a wide range of ‘at risk’ exotic and native species of animals. These animals have a high value both in monetary terms, conservation significance and breeding potential. To understand the risk these viruses pose to zoo animals, it is necessary to characterise the Culicoides fauna at zoos and determine which potential vector species are feeding on which hosts. Methods Light-suction traps were used at two UK zoos: the Zoological Society of London (ZSL) London Zoo (LZ) and ZSL Whipsnade Zoo (WZ). Traps were run one night each week from June 2014 to June 2015. Culicoides were morphologically identified to the species level and any blood-fed Culicoides were processed for blood-meal analysis. DNA from blood meals was extracted and amplified using previously published primers. Sequencing was then carried out to determine the host species. Results A total of 11,648 Culicoides were trapped and identified ( n  = 5880 from ZSL WZ; n  = 5768 from ZSL LZ), constituting 25 different species. The six putative vectors of BTV, SBV and AHSV in northern Europe were found at both zoos and made up the majority of the total catch ( n  = 10,701). A total of 31 host sequences were obtained from blood-fed Culicoides. Culicoides obsoletus / C. scoticus , Culicoides dewulfi , Culicoides parroti and Culicoides punctatus were found to be biting a wide range of mammals including Bactrian camels, Indian rhinoceros, Asian elephants and humans, with Culicoides obsoletus/C. scoticus also biting Darwin’s rhea. The bird-biting species, Culicoides achrayi , was found to be feeding on blackbirds, blue tits, magpies and carrion crows. Conclusions To our knowledge, this is the first study to directly confirm blood-feeding of Culicoides on exotic zoo animals in the UK and shows that they are able to utilise a wide range of exotic as well as native host species. Due to the susceptibility of some zoo animals to Culicoides -borne arboviruses, this study demonstrates that in the event of an outbreak of one of these viruses in the UK, preventative and mitigating measures would need to be taken.

Background Culicoides biting midges (Diptera: Ceratopogonidae) are biological vectors of internationally important arboviruses and inflict biting nuisance on humans, companion animals and livestock. In temperate regions, transmission of arboviruses is limited by temperature thresholds, in both replication and dissemination of arboviruses within the vector and in the flight activity of adult Culicoides . This study aims to determine the cold-temperature thresholds for flight activity of Culicoides from the UK under laboratory conditions. Methods Over 18,000 Culicoides adults were collected from the field using 4 W down-draught miniature ultraviolet Centers for Disease Control traps. Populations of Culicoides were sampled at three different geographical locations within the UK during the summer months and again in the autumn at one geographical location. Activity at constant temperatures was assessed using a bioassay that detected movement of adult Culicoides towards an ultraviolet light source over a 24-h period. Results The proportion of active adult Culicoides increased with temperature but cold temperature thresholds for activity varied significantly according to collection season and location. Populations dominated by the subgenus Avaritia collected in South East England had a lower activity threshold temperature in the autumn (4 °C) compared with populations collected in the summer (10 °C). Within the subgenus Avaritia , Culicoides scoticus was significantly more active across all temperatures tested than Culicoides obsoletus within the experimental setup. Populations of Culicoides impunctatus collected in the North East of England were only active once temperatures reached 14 °C. Preliminary data suggested flight activity of the subgenus Avaritia does not differ between populations in South East England and those in the Scottish Borders. Conclusions These findings demonstrate seasonal changes in temperature thresholds for flight and across different populations of Culicoides. These data, alongside that defining thresholds for virus replication within Culicoides, provide a primary tool for risk assessment of arbovirus transmission in temperate regions. In addition, the study also provides a comparison with thermal limits derived directly from light-suction trapping data, which is currently used as the main method to define adult Culicoides activity during surveillance. Graphical Abstract

Background Understanding seasonal patterns of abundance of insect vectors is important for optimisation of control strategies of vector-borne diseases. Environmental drivers such as temperature, humidity and photoperiod influence vector abundance, but it is not generally known how these drivers combine to affect seasonal population dynamics. Methods In this paper, we derive and analyse a novel mechanistic stage-structured simulation model for Culicoides biting midges-the principle vectors of bluetongue and Schmallenberg viruses which cause mortality and morbidity in livestock and impact trade. We model variable life-history traits as functional forms that are dependent on environmental drivers, including air temperature, soil temperature and photoperiod. The model is fitted to Obsoletus group adult suction-trap data sampled daily at five locations throughout the UK for 2008. Results The model predicts population dynamics that closely resemble UK field observations, including the characteristic biannual peaks of adult abundance. Using the model, we then investigate the effects of insecticide control, showing that control strategies focussing on the autumn peak of adult midge abundance have the highest impact in terms of population reduction in the autumn and averaged over the year. Conversely, control during the spring peak of adult abundance leads to adverse increases in adult abundance in the autumn peak. Conclusions The mechanisms of the biannual peaks of adult abundance, which are important features of midge seasonality in northern Europe and are key determinants of the risk of establishment and spread of midge-borne diseases, have been hypothesised over for many years. Our model suggests that the peaks correspond to two generations per year (bivoltine) are largely determined by pre-adult development. Furthermore, control strategies should focus on reducing the autumn peak since the immature stages are released from density-dependence regulation. We conclude that more extensive modelling of Culicoides biting midge populations in different geographical contexts will help to optimise control strategies and predictions of disease outbreaks.

Background Arthropods transmit a wide range of pathogens of importance for the global health of humans, animals, and plants. One group of these arthropod vectors, Culicoides biting midges (Diptera: Ceratopogonidae), is the biological vector of several human and animal pathogens, including economically important livestock viruses like bluetongue virus (BTV). Like other arthropod-borne viruses (arboviruses), Culicoides -borne viruses must reach and replicate in the salivary apparatus, from where they can be transmitted to susceptible hosts through the saliva during subsequent blood feeding. Despite the importance of the salivary gland apparatus for pathogen transmission to susceptible animals from the bite of infected Culicoides , these structures have received relatively little attention, perhaps due to the small size and fragility of these vectors. Results In this study, we developed techniques to visualize the infection of the salivary glands and other soft tissues with BTV, in some of the smallest known arbovirus vectors, Culicoides biting midges, using three-dimensional immunofluorescence confocal microscopy. We showed BTV infection of specific structures of the salivary gland apparatus of female Culicoides vectors following oral virus uptake, related visualisation of viral infection in the salivary apparatus to high viral RNA copies in the body, and demonstrated for the first time, that the accessory glands are a primary site for BTV replication within the salivary apparatus. Conclusions Our work has revealed a novel site of virus-vector interactions, and a novel role of the accessory glands of Culicoides in arbovirus amplification and transmission. Our approach would also be applicable to a wide range of arbovirus vector groups including sand flies (Diptera: Psychodidae), as well as provide a powerful tool to investigate arbovirus infection and dissemination, particularly where there are practical challenges in the visualization of small size and delicate tissues of arthropods.

Surveillance of adult Culicoides biting midge flight activity is used as an applied ecological method to guide the management of arbovirus incursions on livestock production in Europe and Australia. To date the impact of changes in the phenology of adult vector activity on arbovirus transmission has not been defined. We investigated this at two sites in the UK, identifying 150,000 Culicoides biting midges taken from 2867 collections over a nearly 40 year timescale. Whilst we recorded no change in seasonal activity at one site, shifts in first adult appearance and last adult appearance increased the seasonal activity period of Culicoides species at the other site by 40 days over the time period. Lengthening of the adult activity season was driven by an increase in abundance of Culicoides and correlated with local increases in temperature and precipitation. This diversity in responses poses significant challenges for predicting future transmission and overwintering risk. Policy implications. Our analysis not only shows a dramatic and consistent increase in the adult active period of Culicoides biting midges, but also that this varies significantly between sites. This suggests broad‐scale analyses alone are insufficient to understand the potential impacts of changes in climate on arbovirus vector populations. Understanding the impact of climate change on adult Culicoides seasonality and transmission of arboviruses requires the context of changes in a range of other local ecological drivers.

1. Culicoides biting midges (Diptera, Ceratopogonidae) are vectors of arboviruses that cause significant economic and welfare impact. Local-scale spread of Culicoides-home arboviruses is largely determined by the between-farm movement of infected Culicoides. 2. Study of the dispersal behaviour of Culicoides by capture-mark-recapture (CMR) is problematic due to the likelihood of mortality and changes in behaviour upon capture caused by the small size and fragility of these insects, evidenced by low recapture rates. To counter the problem of using CMR with Culicoides, this study utilised an ovalbumin immunomarking technique to quantify the within- and between-farm dispersal of Culicoides in southern England. 3. Both within- and between-farm dispersal of Culicoides was observed. Of the 9058 Culicoides collected over 22 nights of trapping, 600 ovalbumin-positive Culicoides, of 12 species including those implicated as arbovirus vectors, were collected with a maximum dispersal distance of 3125 m. 4. This study provides the first species-level data on the between-farm dispersal of potential bluetongue, Schmallenberg and African horse sickness virus vectors in northern Europe. High-resolution meteorological data determined upwind and downwind flight by Culicoides had occurred. Cumulative collection and meteorological data suggest 15-6% of flights over 1 km were upwind of the treatment area and 844% downwind. 5. Synthesis and applications. The use of immunomarking eliminates the potential adverse effects on survival and behaviour of insect collection prior to marking, substantially improving the resolution and accuracy of estimates of the dispersal potential of small and delicate vector species such as Culicoides. Using this technique, quantification of the range of Culicoides dispersal with regard to meteorological conditions including wind direction will enable improved, data-driven modelling of the spread of Culicoidesarboviruses and will inform policy response to incursions and outbreaks.

1. Culicoides biting midges are vectors of internationally important arboviruses including bluetongue virus (BTV). The ecological constraints imposed by the small body size of these insects strongly influence the epidemiology of the diseases they can carry. Bluetongue virus recently emerged in northern Europe, and atmospheric dispersion models have subsequently been employed to simulate vector movement (and hence likely spread of BTV). The data underlying such models, however, have hitherto either been obtained from small-scale studies or from outside the northwestern Palaearctic. 2. The effects of seasonality and local meteorological conditions upon the daily presence and abundance of Culicoides vectors were examined using 2760 samples collected across a network of 12 different habitat types in England during 2008. Over 50 000 individuals were estimated to be in the samples with males constituting 62% of the total collection, allowing straightforward comparison between potential vector species in terms of their activity rates and seasonality. Culicoides abundance was linked to livestock density and land use. Farm-associated Culicoides species were recorded at all sites including species thought to be restricted to this ecosystem by larval habitat, suggesting a greater potential for dispersal over land than previously thought. 3. Synthesis and applications. The model developed has already been applied in a functional dispersion model to predict disease risk from wind-borne infected Culicoides incursion into the UK and elsewhere. The study has expounded the long-distance dispersal potential of Culicoides, essential for future prediction of the incursion and spread of Culicoides-borne pathogens. It has additionally contributed to the understanding of the ecology of highly dispersive insect vectors.

Lumpy skin disease virus (LSDV) is a poxvirus that can cause severe, systemic disease in cattle. By far the most important route of transmission of LSDV is mechanical transmission via haematophagous arthropod vectors. However we lack detailed information on this process including the likelihood of transmission by different vector species. This study used an experimental bovine model of LSDV transmission to quantify the transmission of LSDV from an infected donor to a naïve recipient calf. Three species of Diptera representing different vector groups were included (Stomoxys calcitrans, Aedes aegypti and Culicoides nubeculosus, respectively a large biting fly, a mosquito and a midge), and the clinical, virological and immunological outcomes in the recipient calves studied. The ability of Ae. aegypti to mechanically transmit LSDV following feeding on an artificial membrane feeding system was also examined. Both Ae. aegypti and S. calcitrans were able to transmit LSDV, resulting in disease in recipient calves. Bites from virus-positive C. nubeculosus did not result in disease in recipient calves, though the presence of neutralising antibodies in these recipients indicated exposure to virus or virus components. Ae. aegypti successfully transmitted LSDV following feeding on LSDV-spiked blood through an artificial membrane feeding system, validating this laboratory model as a future replacement for donor cattle. Mathematical models of the data were generated and predicted S. calcitrans to be the most efficient vector of LSDV of the insects tested with a reproduction number (R0) of 5.8. Lumpy skin disease virus (LSDV) is a neglected, rapidly emerging pathogen of cattle that has spread into Europe and throughout the Middle East and Asia over the past ten years. Lack of understanding of the mechanism of transmission of LSDV has hampered efforts to control its rapid spread. This study compares the ability of three model species of Diptera (Stomoxys calcitrans, Aedes aegypti and Culicoides nubeculosus) to mechanically transmit the virus to cattle, generating high quality quantitative data to facilitate mathematical modelling of virus transmission. S. calcitrans was identified as a potential driver of LSDV transmission with a R0 of 5.8. This work provides new insights into the vector transmission of LSDV that can be used to design more targeted and effective disease control programmes.

Background Culicoides biting midges (Diptera: Ceratopogonidae) are biological vectors of internationally important arboviruses and inflict biting nuisance on humans, companion animals and livestock. In temperate regions, transmission of arboviruses is limited by temperature thresholds, both in replication and dissemination of arboviruses within the vector and in the flight activity of adult Culicoides. This study aims to determine the cold-temperature thresholds for flight activity of Culicoides from the United Kingdom under laboratory conditions. Methods Over 18,000 Culicoides adults were collected from the field using 4W down-draught miniature ultraviolet Centers for Disease Control traps. Populations of Culicoides were sampled at three different geographical locations within the United Kingdom during the summer months, and again in the autumn at one geographical location. Activity at constant temperatures was assessed using a bioassay that detected movement of adult Culicoides towards an ultraviolet light source over a 24-hour period. Results The proportion of active adult Culicoides increased with temperature but cold temperature thresholds for activity varied significantly according to collection season and location. Populations dominated by the subgenus Avaritia collected in South East England had a lower activity threshold temperature in the autumn (4°C), when compared with populations collected in the summer (10°C). Within the subgenus Avaritia, Culicoides scoticus was significantly more active across all temperatures tested than Culicoides obsoletus within the experimental setup Populations of Culicoides impunctatus collected in the North East of England, were only active once temperatures reached 14°C. Preliminary data suggested flight activity of the subgenus Avaritia does not differ between populations in South East England and those in the Scottish Borders. Conclusions These findings demonstrate seasonal changes in temperature thresholds for flight and across different populations of Culicoides. This data, alongside that defining thresholds for virus replication within Culicoides, provides a primary tool for risk assessment of arbovirus transmission in temperate regions. In addition, the study also provides a comparison with thermal limits derived directly from light-suction trapping data, which is currently used as the main method to define adult Culicoides activity during surveillance.

The HIV-1 envelope glycoprotein (Env) trimer is located on the surface of the virus and is the target of broadly neutralizing antibodies (bNAbs). Recombinant native-like soluble Env trimer mimetics, such as SOSIP trimers, have taken a central role in HIV-1 vaccine research aimed at inducing bNAbs. We therefore performed a direct and thorough comparison of a full-length unmodified Env trimer containing the transmembrane domain and the cytoplasmic tail, with the sequence matched soluble SOSIP trimer, both based on an early Env sequence (AMC011) from an HIV+ individual that developed bNAbs. The structures of the full-length AMC011 trimer bound to either bNAb PGT145 or PGT151 were very similar to the structures of SOSIP trimers. Antigenically, the full-length and SOSIP trimers were comparable, but in contrast to the full-length trimer, the SOSIP trimer did not bind at all to non-neutralizing antibodies, most likely as a consequence of the intrinsic stabilization of the SOSIP trimer. Furthermore, the glycan composition of full-length and SOSIP trimers was similar overall, but the SOSIP trimer possessed slightly less complex and less extensively processed glycans, which may relate to the intrinsic stabilization as well as the absence of the membrane tether. These data provide insights into how to best use and improve membrane-associated full-length and soluble SOSIP HIV-1 Env trimers as immunogens.