http://www.dspace.cam.ac.uk:80/handle/1810/221770 Sat, 25 May 2013 18:14:28 GMT 2013-05-25T18:14:28Z http://www.dspace.cam.ac.uk:80/handle/1810/244571 Title: The epidemiology of Lagos bat virus and henipaviruses in straw-coloured fruit bats (Eidolon helvum), using population genetics to infer population connectivity Authors: Peel, Alison Jane Abstract: The straw-coloured fruit bat, Eidolon helvum, has been identified as a reservoir for potentially-zoonotic henipaviruses and Lagos bat virus (LBV) in continental Africa. Longitudinal studies at a large urban colony in Accra, Ghana aim to better understand E. helvum and viral ecology, as well as the nature of human-bat interactions. To assess whether the findings from these studies can be extrapolated across the species’ continental range, more information on the movement ecology of the species and connectivity of populations across its range was required. A multifaceted approach, using techniques from the field of genetics, population ecology, and virology, was used to understand the ways in which the structure and dynamics of fruit bat populations across Africa may affect the viral transmission dynamics within them. Given recent difficulties in using electronic positioning systems on E. helvum to track movement, genetic methods were proposed as the most appropriate way to assess connectivity between populations across such a vast range. Henipavirus and LBV serological analyses were undertaken on samples from 12 populations of E. helvum bats across its continental and offshore-island range. A combination of mitochondrial DNA and microsatellite markers were used to describe the genetic metapopulation structure of E. helvum and data were obtained in each location on population sizes, demographic structure, reproductive and migratory seasonality, as well as bat-human interactions. Consistent with expectations for a vagile migratory species, a panmictic continental population structure was detected across its continental range, although the extent of this panmixia was greater than previously detected in any other mammal or bird. Antibodies to henipaviruses and LBV were detected in all continental populations. Isolated island populations in the Gulf of Guinea were genetically distinct from each other and the continental population. Given the isolation of these island fruit bats and the lack of connectivity with other populations, it was expected that populations would be too small to allow persistence of any viruses that cause acute, immunising infections. Contrary to expectations, island individuals displayed evidence for exposure to both viruses. E. helvum is known to roost close in proximity to human populations across continental Africa, and these results could therefore have important public health implications. Further longitudinal studies across multiple locations and information on social structure, daily and seasonal movements are needed to make inferences about virus transmission dynamics and zoonotic risks within the complex population structure. Description: Access to this thesis is restricted until at least May 2015 for publication reasons Mon, 09 Apr 2012 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244571 2012-04-09T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244244 Title: Characterisation and therapeutic modulation of toll-like receptor signalling in response to the intracellular pathogen F. tularensis Authors: Saint, Richard Abstract: The induction of an innate immune response upon infection is dependent on the detection of the invading organism and the generation of a signalling cascade leading to the production of inflammatory mediators. Toll-like receptors are expressed on multiple cell types and induce the activation of a complex network of signalling pathways containing numerous branches with multiple interactions and cross-talk between the different branches. The TLR system is integral to the generation of a protective immune response and as such is an important target for pathogen-associated modulation. Many bacterial and viral pathogens employ strategies for interrupting or modulating TLR signalling to evade the host immune response. The obligate intracellular bacterial pathogen, F. tularensis, successfully invades and replicates within immune and epithelial cells. However, despite significant research the exact mechanisms used by this pathogen to successfully evade the host immune response remain elusive. To establish the exact signalling events that occur within a host upon infection with F. tularensis, the activation of specific signalling proteins was characterised using in vitro and in vivo models. The MAPKs, ERK and p38, were identified as critical in generating the host response. Furthermore, the temporal regulation of these signalling proteins was found to be bi-phasic with an early transient activation of both ERK and p38 followed by a sustained activation of ERK and a suppression of p38 activation at later time points. The role of ERK was investigated further using a specific inhibitor (PD0325901). Although there was no decrease in bacterial burdens in vitro and no increase in survival in mice treated with PD0325901, the inhibition of ERK activation reduced the secretion of TNF and IL-6 and reduced systemic bacterial proliferation in vivo. The induction of immune signalling cascades requires the activation of one or more receptors. The contribution of TLR2, TLR4 and TLR9 to the immune response to F. tularensis infection was examined using KO cell lines and specific antagonists. TLR2 was confirmed as a receptor for F. tularensis and was observed to play a role in the translational regulation of TNF. A role for TLR4 was also identified and further characterisation identified a potential priming relationship with TLR9. Sub-stimulation of 13 TLR4 by LPS enhanced the response induced by a subsequent stimulation of TLR9 by purified F. tularensis DNA. Overall, this study has provided evidence that, during infection, F. tularensis interacts with innate immune signalling pathways. By simultaneously suppressing p38 activation and prolonging ERK activation F. tularensis is able to regulate cytokine secretion and the induction of host-cell death mechanisms. Furthermore, this work has demonstrated that the activation of TLR9 by F. tularensis genomic DNA can be primed by a prior sub-stimulation of TLR4, although more research is required to fully understand the contribution of this interaction to the pathogenesis of F. tularensis. Tue, 08 Jan 2013 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244244 2013-01-08T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/240640 Title: Social network analysis of behavioural interactions influencing the development of fin damage in Atlantic salmon (Salmo salar) Authors: Cañon Jones, Hernán Alberto Abstract: The development of fin damage in Atlantic salmon parr was investigated using social network analysis of behavioural interactions occurring under different feeding and stocking conditions. Four separate experiments were carried out in which groups of fish were subjected to a long food restriction period (30 days) described in Chapter 2, high (30 kg/m3) or low (8 kg/m3) fish stocking densities (Chapter 3), predictable or unpredictable food delivery regime (Chapter 4) or a short food restriction period (10 days) described in Chapter 5. Dorsal fin damage (erosion, splits and fin index) was significantly higher in groups of fish subjected to food restriction periods (short and long), held at high stocking density (30 kg/m3) or with an unpredictable food delivery regime. No other fins were found to be affected by fin damage irrespective of the treatment. The social networks based on aggressive interactions showed higher centrality, clustering coefficients, in-degree centrality, out-degree centrality and less dense networks in groups subjected to food restriction (short and long), low stocking densities 8 kg/m3), and unpredictable food delivery. The high centralities and clustering coefficients indicated separation of fish within the groups into initiators of aggression and receivers of aggression. This separation of roles was seen only in the food restricted group, high density groups and unpredictable food delivery groups. Initiators had higher out-degree centrality while receivers showed high in-degree centrality. Also, initiators of aggressive interactions had less fin erosion, higher final weights and higher body lengths than receivers of aggression. The severity of fin damage was significantly higher when this role differentiation occurred, and it was highly correlated with fin biting events. Additionally, overall aggression was higher in food restricted groups, low density groups and unpredictable groups. The dynamic analyses of networks over time (Chapter 6) showed that fish classified as initiators of aggression did not change this behaviour after normal/control environmental conditions were restored (i.e. ad libitum food delivery, low stocking density or predictable food delivery). The latter result indicates that individual fish maintained their behaviour irrespective of their social context, which is consistent with the definition of behavioural syndromes, personalities or temperament defined for other non-human animals. Overall these studies demonstrated the importance of using social network analysis to clearly identify and quantify roles that individual fish assume within their network group and through time based on their behavioural interactions leading to dorsal fin damage and differential physical characteristics. The results are potentially applicable within the commercial aquaculture industry as a valuable technique to evaluate and improve the welfare of farmed fish. Mon, 10 Oct 2011 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/240640 2011-10-10T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/240490 Title: Spatial spread of farm animal diseases Authors: Vernon, Matthew Christopher Abstract: Data on cattle movements within the United Kingdom have recently become available. As part of the conditions for lifting an export ban on British beef following the bovine spongiform encephalopathy epidemic, the European Union required that the UK should have "An effective animal identification and movement recording system". The Cattle Tracing System (CTS) was introduced in September 1998, and the scheme was extended to include all cattle by the beginning of 2001. Contact networks have proved valuable in studying the epidemiology of diseases in man, such as human immunodeficiency virus; the availability of CTS cattle movement data has enabled contact network analysis to be applied to diseases of farm livestock. The CTS data may be represented as a large network; cattle holdings are represented as nodes, with a movement of cattle between holdings being an edge. To address concerns about the quality of this cattle movement data, a field study was conducted on Lewis, one of the Western Isles of Scotland. Farmers were recruited with the assistance of the local veterinary surgeon, and asked to record a range of potential risk behaviours relating to the transmission of infectious diseases (moving livestock, sharing pasture, etc.) for a one-month period. For the study area in question, movements of cattle not reported to CTS (especially to or from common grazing land) were a substantial contribution to the contact network during the study period. A wide range of measures of network structure exist, but their relevance to the dynamics of infectious diseases on networks is unclear. To address this, a discrete-time stochastic SIR simulation model of disease on a network was designed and implemented in software. Using this simulation model, a network model with the key structural features of the CTS contact network was constructed, by considering a range of measures of network structure, and testing resulting model networks against CTS-derived networks. The resulting model was shown to predict the dynamics of a simulated disease model on that contact network more closely than existing models of global network structure. Much work on the contact structure of the UK cattle herd has relied on relatively simple static network representations of movement data. By using simulated diseases, the serious shortcomings of static network representations compared to more complex dynamic network representations were demonstrated. A substantial library of software for the generation and analysis of large networks, and the simulation of disease thereupon, has been produced, and has been made generally available. The design and implementation of this software is discussed, including the algorithms and data structures deployed, as well as validation of the software, and its portability to different computing platforms. Thu, 30 Sep 2010 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/240490 2010-09-30T23:00:00Z