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Climate change is expected to threaten human health and well-being via its effects on climate-sensitive infectious diseases, potentially changing their spatial distributions, affecting annual/seasonal cycles, or altering disease incidence and severity. Climate sensitivity of pathogens is a key indicator that diseases might respond to climate change, but the proportion of pathogens that is climate-sensitive, and their characteristics, are not known. The climate sensitivity of European human and domestic animal infectious pathogens, and the characteristics associated with sensitivity, were assessed systematically in terms of selection of pathogens and choice of literature reviewed. Sixty-three percent (N = 157) of pathogens were climate sensitive; 82% to primary drivers such as rainfall and temperature. Protozoa and helminths, vector-borne, foodborne, soilborne and waterborne transmission routes were associated with larger numbers of climate drivers. Zoonotic pathogens were more climate sensitive than human-or animal-only pathogens. Thirty-seven percent of disability-adjusted-life-years arise from human infectious diseases that are sensitive to primary climate drivers. These results help prioritize surveillance for pathogens that may respond to climate change. Although this study identifies a high degree of climate sensitivity among important pathogens, their response to climate change will be dependent on the nature of their association with climate drivers and impacts of other drivers.

Interactions between species, particularly where one is likely to be a pathogen of the other, as well as the geographical distribution of species, have been systematically extracted from various web-based, free-access sources, and assembled with the accompanying evidence into a single database. The database attempts to answer questions such as what are all the pathogens of a host, and what are all the hosts of a pathogen, what are all the countries where a pathogen was found, and what are all the pathogens found in a country. Two datasets were extracted from the database, focussing on species interactions and species distribution, based on evidence published between 1950–2012. The quality of their evidence was checked and verified against well-known, alternative, datasets of pathogens infecting humans, domestic animals and wild mammals. The presented datasets provide a valuable resource for researchers of infectious diseases of humans and animals, including zoonoses.

Background Plague, a zoonosis caused by Yersinia pestis, is found in Asia and the Americas, but predominantly in Africa, with the island of Madagascar reporting almost one third of human cases worldwide. Plague's occurrence is affected by local climate factors which in turn are influenced by large-scale climate phenomena such as the El Niño Southern Oscillation (ENSO). The effects of ENSO on regional climate are often enhanced or reduced by a second large-scale climate phenomenon, the Indian Ocean Dipole (IOD). It is known that ENSO and the IOD interact as drivers of disease. Yet the impacts of these phenomena in driving plague dynamics via their effect on regional climate, and specifically contributing to the foci of transmission on Madagascar, are unknown. Here we present the first analysis of the effects of ENSO and IOD on plague in Madagascar. Methodology/principal findings We use a forty-eight year monthly time-series of reported human plague cases from 1960 to 2008. Using wavelet analysis, we show that over the last fifty years there have been complex non-stationary associations between ENSO/IOD and the dynamics of plague in Madagascar. We demonstrate that ENSO and IOD influence temperature in Madagascar and that temperature and plague cycles are associated. The effects on plague appear to be mediated more by temperature, but precipitation also undoubtedly influences plague in Madagascar. Our results confirm a relationship between plague anomalies and an increase in the intensity of ENSO events and precipitation. Conclusions/significance This work widens the understanding of how climate factors acting over different temporal scales can combine to drive local disease dynamics. Given the association of increasing ENSO strength and plague anomalies in Madagascar it may in future be possible to forecast plague outbreaks in Madagascar. The study gives insight into the complex and changing relationship between climate factors and plague in Madagascar., Author Summary Plague is a vector-borne bacterial infection with rodents and their fleas as its principal hosts. Transmission to humans occurs via the bite of an infected flea. In the highlands of Madagascar, plague is endemic and more than one hundred human cases are reported every year. Global climate is known to affect many infectious diseases and has been shown to affect plague incidence in other areas of the world. The ENSO and the IOD are global climate drivers affecting rainfall and temperature in Madagascar. Our study investigates the effect of global climate drivers on human plague incidence on the island. We found a link between ENSO, IOD, temperature and precipitation and plague incidence throughout the 48-year time-series although it was not constant over time. The correlation between ENSO and plague turned from weakly positive to strongly negative and then to positive, and the association with the IOD became stronger with time. We demonstrate that during periods of high ENSO intensity, plague incidence is likely to increase via ENSO's impact on temperature and precipitation. This shows that climate indices can be a tool to help predict human plague incidence.

BACKGROUND: Prions are known to cause transmissible spongiform encephalopathies (TSE) after accumulation in the central nervous system. There is increasing evidence that prions are also present in body fluids and that prion infection by blood transmission is possible. The low concentration of the proteinaceous agent in body fluids and its long incubation time complicate epidemiologic analysis and estimation of spreading and thus the risk of human infection. This situation is particularly unsatisfactory for food and pharmaceutical industries, given the lack of sensitive tools for monitoring the infectious agent. METHODOLOGY/PRINCIPAL FINDINGS: We have developed an adsorption matrix, Alicon PrioTrap, which binds with high affinity and specificity to prion proteins. Thus we were able to identify prion protein (PrP(C))--the precursor of prions (PrP(Sc))--in milk from humans, cows, sheep, and goats. The absolute amount of PrP(C) differs between the species (from microg/l range in sheep to ng/l range in human milk). PrP(C) is also found in homogenised and pasteurised off-the-shelf milk, and even ultrahigh temperature treatment only partially diminishes endogenous PrP(C) concentration. CONCLUSIONS/SIGNIFICANCE: In view of a recent study showing evidence of prion replication occurring in the mammary gland of scrapie infected sheep suffering from mastitis, the appearance of PrP(C) in milk implies the possibility that milk of TSE-infected animals serves as source for PrP(Sc).

Between 2006 and 2011 two Culicoides-borne diseases of ruminants emerged in Europe: bluetongue virus serotype-8 (BTV-8) and Schmallenberg virus (SBV). This thesis sought to answer questions arising from this developing disease landscape, to better inform policymakers, stakeholder groups and disease modellers. SBV spread rapidly through Europe, reaching the UK in January 2012. However, in 2014 no cases were reported. It was unknown if this was a lack of circulation, or a lack of reporting. A freedom from disease study was designed. 1444 sheep, born between October 2014 and April 2015, were sampled from 131 farms from Cornwall to Kent. Samples were tested by ELISA for antibodies against SBV, 5 positive samples were confirmed negative by VNT. Circulation of SBV in 2015 in the south of England was concluded to have been unlikely. Like SBV, BTV-8 had circulated throughout Europe, only to be controlled by movement restrictions and vaccination. Subsequently, Europe was declared BTV-8 free in 2010 and vaccination production halted. In 2015 BTV-8 re-emerged in Europe. An online questionnaire determined that respondents from smaller farms, those that had previously vaccinated against BTV-8 and those who were deemed to be ‘risk adverse’ were all more likely to want to vaccinate, and more willing to pay more to vaccinate. Voluntary vaccination only achieved an 80% uptake if vaccination was free and after BTV-8 cases were reported in the UK despite 90% of farmer respondents stating they believed it important to keep BTV-8 out of the UK. Not all farmers vaccinated all of their flock/herd previously. This survey highlights the complex issues surrounding voluntary vaccination at the farm perceived risk versus cost level. The mechanisms for how either virus successfully overwintered are still poorly understood. A cross-sectional study demonstrated that Culicoides vectors are active during peak lambing periods inside lambing sheds. A longitudinal study the following lambing season demonstrated that Culicoides were more abundant indoors than outdoors, and demonstrated activity of gravid and parous Culicoides over the winter. This demonstrates a possible mechanism for overwintering of BTV-8 and SBV in the south of England. SBV re-emerged in 2016. A questionnaire was designed to determine the impact of SBV on the 2016/2017 lambing period. The impact was found to be highly comparable to a previous study of the 2012/2013 outbreak. Additionally SBV confirmed and suspected farms were more likely to have mated earlier in the season. If SBV continues to re-emerge cyclically then the impact of disease will continue to be significant unless intervention is taken. These studies have added to our understanding of, and farmer response to, the SBV and BTV-8 outbreaks, and added to policymakers, stakeholders groups and disease modellers knowledge.

Louping ill virus (LIV), a member of the tick-borne encephalitis virus (TBEV) serocomplex, had been the only known zoonotic tick-borne flavivirus endemic to the UK. LIV is closely related to and serologically reacts with TBEV, which is much more pathogenic to humans; causing around 3,000 cases in the European region annually. TBEV is endemic across much of Europe, where it is increasing in range, but was thought to be absent from the UK. It is important to understand the potential for TBEV to be emerging in the UK undetected. A large-scale sentinel deer serosurveillance study was conducted to identify regions of exposure to TBEV-serocomplex pathogens. Serum samples were tested for specific antibodies to TBEV as a measure to indicate exposure. In addition, submitted tick samples removed from deer, close to an ELISA positive sample, were tested for TBEV and LIV RNA by RT-PCR. Overall, 4% of samples were ELISA-positive for the TBEV serocomplex. The Thetford Forest area in England had both the highest proportion (47.7%) of seropositive samples, and importantly no previous reports of LIV infection in livestock which could cross-react with the TBEV serology assays. Of 2,041 tested ticks from areas near seropositive deer, five were positive by TBEV/LIV RT-PCR, all within the Thetford Forest area. From 1 tick, a full-length genomic sequence of TBEV-Eu was identified. A two-year extensive ecological study collecting questing ticks was conducted in sites associated with high rates of exposure to TBEV-serocomplex virus. A total of 7,085 questing ticks were collected in Thetford Forest, with TBEV being detected in 6 sites out of 24 sites surveyed over 2018 and 2019. In addition, 3,205 questing ticks were collected and tested from 7 sites in the New Forest and bordering areas, resulting in the detection of TBEV in one site on the Hampshire/Dorset border. These results demonstrate that TBEV has been detected in the UK for the first time - in two geographically distinct locations 200 miles apart. High seropositivity and presence in questing ticks suggests it is being maintained in enzootic cycles in these areas. This finding is of public health significance and requires rapid dissemination of findings to health professionals in the UK.

Culicoides biting midges (Diptera: Ceratopogonidae) are biological vectors of economically important arboviruses of livestock. Two such arboviruses, bluetongue virus (BTV) and Schmallenberg virus (SBV) have recently emerged in northern Europe inflicting unprecedented outbreaks of disease in this region. The aim of the current investigation was to explore both host seeking behaviour and surveillance methods for livestock-associated Culicoides species in the UK. To achieve this aim, a series of field-based, manipulative experiments were conducted using three farm sites in southern England. These studies demonstrated that host preference had a significant impact upon several parameters important in determining arbovirus transmission. Culicoides were found to be differentially attracted to different breeds of sheep (p

Bluetongue (BT) is a seasonal vector-borne, viral, disease that causes significant economic and welfare problems in ruminants. It is transmitted by species of Culicoides midges (Diptera: Ceratopogonidae), and as such, the distribution of the disease is restricted to regions where the vectors are present. Once restricted to tropical and subtropical regions of the world, serotypes of BT have been causing outbreaks in southern Europe, following its introduction in 1998, and in 2006, BT serotype-8 emerged in northern Europe, causing devastating economic, welfare and production consequences. The northwards expansion of BT has been attributed to a shift in the geographic limit of the Culicoides imicola Meigen vector, and the involvement of the newly implicated Palaearctic vectors, the Obsoletus and Pulicaris Groups. Little is known about the ecological characteristics of the newly implicated vectors, or indeed those believed to be non-vectors, including their distribution and abundance, making disease risk assessment and management difficult. Within this thesis, a series of field experiments were initiated on a group of farms to gain insight into the distribution and abundance of Culicoides species. The results highlighted that a very high level of variation is seen when trapping Culicoides at the local-scale, yet it is possible to build a strong model explaining this variation using a mixture of host and environmental variables, with satellite-derived ecological correlates. This high level of variation in midge catches present between farms undermines attempts to record their nationwide distribution in larger scale models. The results uniquely model Obsoletus Group abundance, and highlight a difference in host involvement between vector and non-vector models. Further field studies which showed a lack of significant variation both between years and at the within-farm level highlight the robustness of this model in predicting the distribution of the BT vectors species, such that it could prove useful for exploring targeted surveillance and control methods. Culicoides distributions do not remain static, therefore an understanding of their flight behaviour is critical to determining the distance over which an insect may transmit a disease agent and the size of the area over which control should be applied. Laboratory studies were undertaken to validate the use of commercial fluorescent dusts as a quick and effective method of marking Culicoides for both field and laboratory studies, and a ‘self-marking’ technique was conceived. Dispersal studies, using the dusts, determined the distances that Obsoletus Group females and males, as well as C. pulicaris females, are able to disperse over a set period of time. This knowledge of flight speed and distance is of utmost value as a critical component in the modelling of BT disease and other Culicoides-borne diseases. The Obsoletus Group contains four members (C. obsoletus, C. scoticus, C. chiopterus and C. dewulfi¬) which are difficult to differentiate down a microscope. Using morphometric analyses, female C. obsoletus and C. scoticus individuals could be separated under a stereomicroscope based on abdominal measurements. Studies such as those contained in this thesis, therefore, are of utmost value in providing information on critical components in the modelling of BT disease and other Culicoides-borne diseases.