No description available.

The global disease scape is constantly shifting, influenced by demographic transitions, altering the balance of the burden of infectious and non‐communicable diseases. The epidemiological transitions can be divided into three stages: the first, an increase in infectious disease burden as populations settled, then grew into towns and cities providing conditions for infectious agents to maintain spread; the second transition follows industrialisation, changes in lifestyle, diet and improved sanitation whereby infectious diseases are reduced and non‐communicable disease (NCD) prevalence increases; the third transition describes the re‐emergence of infectious diseases as the AIDS epidemic and other emerging and re‐emerging disease outbreaks lead to an increasing burden of infectious diseases, particularly in developing countries. Analysis of the disease‐scape has been carried out using WHO Global Burden of Disease data and correlation to demographic factors calculated using World Bank Development Indicators. The balance of chronic NCDs and infectious diseases can be represented numerically as the unit rate of infectious to non‐communicable diseases. The rate, which indicates at which end the continuum lies can then be correlated to these demographic development indicators to assess the factors which are influential to the continuum. As the balance of infectious and non‐communicable diseases around the world alters, the focus of the advocacy at the global health level has been examined to assess if the trends follow that of the shifting continuum. This has been carried out through an assessment of the WHO World Health Assembly (WHA) resolutions adopted annually between 1948 and 2013 on the subject of infectious and/or non-communicable diseases. The principle of International health stemmed from the need to contain the international spread of communicable diseases, so it is not surprising that in the first decade of the WHO, 88% of the resolutions adopted for infectious and non‐communicable disease were adopted for infectious diseases. In the latest ten years of the WHO, 72% of the Assembly resolutions for infectious and non‐communicable diseases were focused on infectious diseases; this indicates that while there has been a shift in the balance, the adopted resolutions still focus heavily on infectious diseases. An example of how advocacy can elevate diseases to a higher position on the global health agenda is that of the Neglected Tropical Diseases. Following the Millennium Development Goals, this group of seventeen diseases has been highlighted as being “neglected” in terms of funding, research and political will. A review of the campaign to highlight this shows how global health advocacy can elevate diseases to a prominent position on the global health agenda. With this in mind, the advocacy for a sub‐group of Neglected Zoonotic Diseases has been examined at the WHA level. The results highlight the sporadic nature of support to control these diseases, and that activism for control of some of the major zoonotic diseases remains lacking. Rabies is explored as an example of a disease for which there are recommendations and support at the global level for the control and elimination of the disease, but for which barriers to control exist locally in endemic countries. The advocacy for diseases at the global health level has the possibility to impact the priorities of health care within individual nations. However the advocacy at this level may take time to reflect the changes within the disease‐scape. The impact of such advocacy is also limited by local political will, availability of resources and local cultural implications. Therefore there is a need to ensure that efforts to control diseases are tailored to specific populations and that resources are made available to support the advocacy.

Amphibians are declining at alarming rates globally. Multiple factors contribute to these declines, including chemical contaminants and emergent diseases. In recent years, agrochemical use, especially fungicide applications, has increased considerably. Previous studies have demonstrated that these agrochemicals leave application sites and enter wetlands via runoff and have detrimental effects on non-target organisms. For example, exposure to contaminants can have multifarious effects on amphibians, such as reducing their ability to deal with a secondary stressor, such as disease. A pathogen that is found concomitant with chemical contaminants in aquatic systems is Batrachochytrium dendrobatidis (Bd). Bd has decimated amphibian populations worldwide. Susceptibility to this pathogen varies across amphibian life stages, and is greater in adults than larvae. Consequently, it is important to examine the effects of simultaneous and serial Bd and agrochemical exposure throughout amphibian development. I assessed the combined effects of 3 different fungicides and Bd on two amphibian species: Cuban tree frogs (Osteopilus septentrionalis) and grey tree frogs (Hyla versicolor), both simultaneously and across life stages. To elucidate the complexities of these interactions, I conducted two experiments, one in the laboratory and another in outdoor mesocosms. Frogs were exposed to most of the possible combinations of fungicides and Bd as tadpoles and metamorphs. The presence of fungicides during the tadpole stage caused no difference in timing to metamorphosis and therefore no extension of time animals were exposed to the pathogen. Fungicides did not reduce fungal growth; in fact, tadpoles exposed simultaneously to a fungicide and Bd, regardless of the specific fungicide, had increased fungal loads compared to acetone controls. Additionally, animals exposed to both stressors simultaneously had higher mortality compared to controls or any of the stressors singly. Lastly, the fungicide had persistent effects on amphibian health by affecting susceptibility to Bd later in ontogeny. Frogs exposed to any of the three fungicides as a tadpole had higher Bd prevalence, Bd abundance, and Bd-induced mortality when challenged with Bd after metamorphosis, an average of 71 days after their last fungicide exposure. In conclusion, I found no benefits of fungicides for amphibians. In fact, results indicate both immediate and delayed negative effects of exposure to fungicides and Bd. These findings highlight the importance of studying multiple potential contributors to amphibian declines, simultaneously and sequentially, to understand net effects of stressors on amphibian performance.

Alors que l’épidémiologie de la dengue dans le sud du Vietnam est caractérisée par un régime d’hyper-endémicité, la maladie est en train d’émerger dans le nord du pays depuis une quinzaine d’années. Les incidences annuelles augmentent de façon constante d’année en année et la maladie diffuse à partir de Hanoi vers les zones rurales environnantes. Le travail de recherche effectué durant cette thèse s’intéresse aux déterminants spatiaux et temporels de la transmission de la dengue dans un contexte d’émergence. Les résultats sont organisés en 3 parties. La première se concentre sur l’étude d’une épidémie qui frappa à l’automne 2013 l’île de Cat Ba, au large du Vietnam dans la baie d’Halong. Cette île est caractérisée par une population de petite taille vivant essentiellement de l’exploitation des produits de la mer ainsi que du tourisme. Une grande proportion de cette population vit sur des villages flottant au large de l’île. Nous avons comparé l’épidémiologie de la dengue sur les villages flottants et sur l’île. Pour cela nous avons testé l’agrégation spatio-temporelle des cas de dengue. Nos résultats montrent une incidence de dengue sur les villages flottant plus forte que sur l’île, malgré des densités de moustiques plus faibles. Les cas de dengue étaient également extrêmement agrégés dans le temps et l’espace, suggérant une importation de moustiques infectés plutôt qu’un cycle de transmission local complet.La seconde partie de cette thèse s’est intéressée aux déterminants environnementaux de la transmission de la dengue dans la province de Hanoi. Cette étude est basée sur l’analyse de 31906 cas de dengue géospatialisés de 2008 à 2013 et utilise des méthodes de SIG couplées avec des techniques modernes d’apprentissage automatique dans le but de quantifier en détail les influences de chaque covariable environnementale sur le risque de dengue. Nos résultats montrent une forte influence de la densité de population sur l’incidence de la dengue, comme précédemment documenté dans d’autres régions du monde. L’incidence de la dengue augmente avec la couverture végétale pour de faibles niveaux de couverture végétale et atteint de très faibles niveaux lorsque la couverture végétale est au-dessus d’un certain seuil. Une telle relation est cohérente avec ce qui est actuellement connu sur l’écologie des vecteurs de dengue. Finalement, nos résultats ont montré une forte association entre les incidences de dengue et les zones résidentielles universitaires. Ces zones sont peuplées d’étudiants venant des régions autour de Hanoi où l’incidence est faible. La susceptibilité à la dengue de cette population estudiantine est donc plus forte que dans le reste de la population de Hanoi.La dernière partie de cette thèse s’est intéressée aux relations entre les épidémies successives de dengue à Hanoi de 2011 à 2014. L’épidémiologie de la dengue à Hanoi est très saisonnière avec de très faibles incidences en hiver. Une question majeure dans une telle situation est de savoir si les virus de dengue persistent localement entre chaque épidémie. Si non, alors les cas de dengue observés en hiver correspondraient à des cas d’importation qui pourraient démarrer une nouvelle épidémie chaque été lorsque les conditions climatiques locales deviennent à nouveau favorables pour la transmission de la dengue. Nous avons utilisé une approche de phylogénie moléculaire de virus échantillonnés à Hanoi ainsi que dans d’autres localités en Asie du sud-est d’où les virus de dengue pourraient migrer. L’idée d’une telle approche consiste à comparer les distances phylogénétiques entre des virus circulants dans une localité une année donnée et des virus circulants soit la même année dans d’autres localités, soit durant les années précédentes dans la même localité. Nos résultats suggèrent que, chaque année, les épidémies de dengue à Hanoi démarrent à partir des virus de dengue importés depuis Ho Chi Minh ville. Ce schéma semble être le cas pour les 4 sérotypes de dengue. / While high dengue transmission has been documented in the southern part of Vietnam since the late seventies, the disease started to emerge in the northern part of the country 15 years ago only. In northern Vietnam, annual incidences are consistently increasing from year to year and progressively spreading from Hanoi to the surrounding rural areas. Very little is known on the causes of this recent emergence.The research carried out in this PhD revolves around the spatial and temporal determinants of dengue epidemiological transmission in a context of emergence and the results are organized in 3 parts. The first one focuses on a single epidemic of dengue that occurred during the autumn of 2013 on the small island of Cat Ba, off the coast of Vietnam in Ha Long bay. Cat Ba island is characterized by a population of a small size mostly living from sea farming and tourism. Dengue transmission on this island has been historically rare until the major epidemics that stroke the island in 2013. The population of Cat Ba has this specificity that a large proportion of it lives of floating villages off the island coast. We were interested in investigating whether the epidemics had different behavior on the island and the floating villages. To achieve this aim, we focused on the identification of spatio-temporal clusters of cases. Our results show a higher dengue incidence on the floating villages than on the island despite lower mosquito densities. Dengue cases were also highly clustered in space and time suggesting importation of infected mosquitoes rather than a local complete transmission cycle.The second part focuses on the environmental determinants of dengue transmission in the province of Hanoi. This study is based on the use of 31,906 geospatialized cases of dengue from 2008 to 2013 and applies GIS techniques coupled with modern machine learning techniques in order to quantify in detail the influences of each environmental covariate on dengue risk. Our results showed a strong influence of population density on dengue incidence as previously reported in other parts of the world. Dengue incidence increased with tree coverage for low levels of tree coverage and then reached very low levels for tree coverage above a given threshold. This pattern is consistent with the current knowledge of the dengue vector ecology. Finally we showed a strong association of dengue incidence with academic residential areas. Such areas are populated with students coming from locations around Hanoi with low dengue incidence. The susceptibility of this student population to dengue infection is thus higher than the rest of the Hanoian population.The final part looked at the relationships between the successive epidemics in Hanoi from 2011 to 2014. Dengue epidemiology in Hanoi is very seasonal with very few cases documented in winter. A major question in such situations is whether viruses actually persist locally between epidemics. If not, then observed cases during the winter would correspond to imported cases igniting new epidemics every summer when the local climatic conditions are favorable again for local dengue transmission. To do so, we used phylogenetic analyses of virus sampled in Hanoi combined with virus sampled in other locations in Southeast Asia from where dengue viruses could migrate. The rationale behind this method is to compare the phylogenetic distances between sequences circulating in a given location in a given year and sequences circulating either the same year in other locations or previous years in the same location. Our results suggest that every year dengue epidemics in Hanoi are started from viruses imported from Ho Chi Minh city. This seems to be the case for the 4 dengue serotypes.

Hosts have two main strategies for coping with infections: resistance and tolerance. Resistance is aimed at preventing or eliminating parasites, whereas the goal of tolerance is to maintain performance regardless of parasite burden. The balance between resistance and tolerance within a host may mediate host competence, or the propensity of a host to infect other hosts or vectors. Hosts with high tolerance and low resistance to an infection, for instance, may be highly competent and possess the greatest potential to act as superspreaders. These superspreading hosts will contribute disproportionately to transmission, thus posing the greatest risk to other hosts within a population or community. Understanding the drivers of heterogeneity in host competence therefore has broad implications for the management of infectious diseases in nature. Host tolerance is typically quantified as the slope of the relationship between host performance and parasite burden. The majority of host tolerance studies have been conducted at the level of genotypes, populations and species. Individual hosts often exhibit variation in competence, with some individuals contributing more or less to transmission than the population/species average. Despite the clear importance of understanding tolerance at the individual-level, such studies are rare and may be particularly challenging in field contexts due to the need for repeated performance-burden measurements. I used the house sparrow (HOSP) – West Nile virus (WNV) system to investigate differences among two alternative approaches to estimating individual tolerance: the scope and position methods. The scope method estimates tolerance traditionally as the slope of multiple performance-burden measurements over time within an individual; alternatively, the position method required only one measurement for each individual, thus characterizing tolerance via among-individual variation in host defense. We found strong relationships between scope and position estimates of individual tolerance, suggesting that the position method may be an appropriate proxy to use in field studies. I also compared tolerance estimates derived from different metrics of performance. There were weak correlations among these estimates of tolerance, implying that tolerance estimated by measuring a single trait may not be indicative of tolerance at the level of the whole individual or their contribution to disease processes. Understanding the physiological mediators of host competence may help to pinpoint at-risk and risky individuals (or genotypes, populations and species) within natural communities, thus facilitating the development of more targeted disease management strategies. Cytokines and glucocorticoids have been identified as potent mediators of host defense. Pro-inflammatory cytokines may act to promote resistance, whereas anti-inflammatory cytokines and glucocorticoids tend to mediate host tolerance. I investigated the dynamics of pro-inflammatory cytokine IFN-γ, anti-inflammatory cytokine IL-10, and the major avian glucocorticoid, corticosterone (CORT), following WNV exposure in HOSP. I then assessed the influence of these three mediators on resistance and tolerance to WNV infection. I found unusual dynamics for the three mediators across the infection period: IFN-γ expression was not induced by WNV exposure, IL-10 expression was dampened by WNV exposure, and CORT levels were higher in unexposed individuals. Despite the unique response of HOSP to WNV exposure seen here, we did find that constitutive expression of IFN-γ and IL-10 mediate resistance and tolerance to WNV, respectively. Unexpectedly, we also found evidence for protective (pro-resistance) effects of CORT, which contrasts with previous evidence for the role of CORT in mediating WNV infections. Combined, the results of this study suggest that hosts with constitutively high IL-10 and low IFN-γ expression may have high potential to act as superspreaders of disease, thus becoming critical targets in designing WNV-control strategies in passerines. The methods by which we quantify host tolerance may greatly affect the conclusions we are able to draw from such studies. To date, a variety of definitions and techniques have been used to study tolerance in animals. In chapter three, I briefly summarize past plant and animal tolerance research, highlighting discrepancies among researchers in their motivations, definitions and techniques for studying tolerance. For instance, I discuss biases in the literature regarding the use of range versus point tolerance, vigor, and laboratory versus field studies. In particular, I expound upon the nature of the performance metrics used in the majority of tolerance estimations in the literature, and discuss the ecological implications of these metrics. To conclude, I offer suggestions for overcoming the challenges associated with studying tolerance and encourage a unified way forward in the field, emphasizing the selection of system-specific and ecologically relevant tolerance metrics. My thesis research has employed physiological and behavioral methods in an ecological context to better understand the heterogeneities that exist in host competence. By combining empirical data in the HOSP-WNV system with conceptual and methodological strategies for assessing host defenses, this research has broadened our knowledge of host responses in the WNV system in a manner that may be applicable to understanding and managing disease dynamics in diverse natural communities.

L'épidémie de West-Nile en Amérique du Nord en 2002, qui a touché plus de quarante états aux Etats-Unis, a conduit les Agences de santé à s'interroger sur le risque d'émergence, à l'extérieur de la zone intertropicale, de zoonoses vectorielles. Cette épidémie associée au changement climatique, a bien mis en évidence le rôle central de l'avifaune migratrice dans la diffusion du virus. La biologie des oiseaux, tout particulièrement le phénomène migratoire, permet un transport des virus sur de longues distances et entre espèces très diversifiées. Le Moyen-Orient, qui est situé au carrefour de différents continents, est extrêmement propice à la propagation des virus émergents dans les pays du Nord. La circulation du virus West Nile a été rapportée dans différents pays de la région, tels que l'Egypte, Israël, Liban, Irak, Emirats Arabes Unis et Iran. Saidi et al. (1970) ont montré la présence d'anticorps anti-virus du Nil occidental au sein de la population de la côte caspienne (Nord de l'Iran), des provinces du Khorassan (Nord-Est) et du Khuzestan (Sud-Ouest). Notre étude, conduite dans le cadre d'un programme associant TIMC-IMAG UMR 5525 UJF CNRS VetAgroSup, le Réseau International des Instituts Pasteurs et le Centre National d'Etudes Spatiales, vise: (i) à caractériser la circulation du virus de West-Nile au sein des populations équines d'Iran ; et (ii) et à modéliser l'impact sanitaire de l'environnement et du climat sur la transmission. Les résultats acquis permettent d'apprécier le risque associé à la dissémination spatio-temporelle du virus par les oiseaux migrateurs. Une attention toute particulière est portée à l'étude des déterminants environnementaux et climatiques susceptibles d'accroitre le potentiel de transmission du virus. / The outbreak of West Nile in North America in 2002, which affected more than forty states in the United States, has led Public Health Agencies to adress the risk of emergence of vectorial zoonosis, outside of the area tropical. This epidemic events associated with climate change, has highlighted the central role of migratory birds in spreading the virus. The biology of birds, especially the migratory phenomenon, ensures a transport of viruses over long distances and across very diverse species. The Middle East, located at the crossroad between different continents, is extremely prone to the spread of zoonotic diseases, like West-Nile, in the Northern countries. The circulation of WN virus has reported from different countries in the region; such as Egypt, Israel, Lebanon, Iraq, United Arab Emirates and Iran. Saidi et al. (1970) have established the presence of antibodies to West Nile among the population of the Caspian coast (northern Iran), the provinces of Khorasan (Northeast) and Khuzestan (Southwest). Our study, in the framework of a collaborative programme associating TIMC-IMAG UMR CNRS UJF VetAgroSup, International Network of Institut Pasteur and Centre National d'Etudes Spatiales, aim to: (i) characterizing the circulation of the virus from West Nile in the equine population of Iran, and (ii) and modelling the health impact of the environment and climate on the transmission. The results obtained allow us to assess the risk associated with spatial and temporal spread of the virus by migratory birds. Particular attention is given to the study of environmental and climatic determinants that may increase the potential for transmission.

Chapter one introduces the concept of disease emergence and factors associated with emergence. The role of wildlife as reservoirs of emerging diseases and specifically the history of bats as reservoirs of zoonotic diseases is previewed. Finally, the aims and structure of the thesis are outlined. In Chapter two, the literature relating to the emergence of Hendra virus, Nipah virus, and Australian bat lyssavirus, the biology of flying foxes, methodologies for investigating wildlife reservoirs of disease, and the modelling of disease in wildlife populations is reviewed. Chapter three describes the search for the origin of Hendra virus and investigations of the ecology of the virus. In a preliminary survey of wildlife, feral and pest species, 6/21 Pteropus alecto and 5/6 P. conspicillatus had neutralizing antibodies to Hendra virus. A subsequent survey found 548/1172 convenience-sampled flying foxes were seropositive. Analysis using logistic regression identified species, age, sample method, sample location and sample year, and the interaction terms age*species and age* sample method as significantly associated with HeV serostatus. Analysis of a subset of the data also identified a significant or near-significant association between time of year of sampling and HeV serostatus. In a retrospective survey, 16/68 flying fox sera collected between 1982 and 1984 were seropositive. Targeted surveillance of non-flying fox wildlife species found no evidence of Hendra virus. The findings indicate that flying foxes are a likely reservoir host of Hendra virus, and that the relationship between host and virus is mature. The transmission and maintenance of Hendra virus in a captive flying fox population is investigated in Chapter four. In study 1, neutralizing antibodies to HeV were found in 9/55 P. poliocephalus and 4/13 P. alecto. Titres ranged from 1:5 to 1:160, with a median of 1:10. In study 2, blood and throat and urogenital swabs from 17 flying foxes from study 1 were collected weekly for 14 weeks. Virus was isolated from the blood of a single aged non-pregnant female on one occasion. In study 3, a convenience sample of 19 seropositive and 35 seronegative flying foxes was serologically monitored monthly for all or part of a two-year period. Three individuals (all pups born during the study) seroconverted, and three individuals that were seropositive on entry became seronegative. Two of the latter were pups born during the study period. Dam serostatus and pup serostatus at second bleed were strongly associated when data from both years were combined (p<0.001; RR=9, 95%CI 1.42 to 57.12). The serial titres of 19 flying foxes monitored for 12 months or longer showed a rising and falling pattern (10), a static pattern (1) or a falling pattern (8). The findings suggest latency and vertical transmission are features of HeV infection in flying foxes. Chapter five describes Australian bat lyssavirus surveillance in flying foxes, insectivorous bats and archived museum bat specimens. In a survey of 1477 flying foxes, 69/1477 were antigen-positive (all opportunistic specimens) and 12/280 were antibody-positive. Species (p<0.001), age (p=0.02), sample method (p<0.001) and sample location (p<0.001) were significantly associated with fluorescent antibody status. There was also a significant association between rapid focus fluorescent inhibition test status and species (p=0.01), sample method (p=0.002) and sample location (p=0.002). There was a near-significant association (p=0.067) between time of year of sampling and fluorescent antibody status. When the analysis was repeated on P. scapulatus alone, the association stronger (p=0.054). A total of 1234 insectivorous bats were surveyed, with 5/1162 antigen–positive (all opportunistic specimens) and 10/390 antibody-positive. A total of 137 archived bats from 10 species were tested for evidence of Australian bat lyssavirus infection by immunohistochemistry (66) or rapid focus fluorescent inhibition test (71). None was positive by either test but 2 (both S. flaviventris) showed round basophilic structures consistent with Negri bodies on histological examination. The findings indicate that Australian bat lyssavirus infection is endemic in Australian bats, that submitted sick and injured bats (opportunistic specimens) pose an increased public health risk, and that Australian bat lyssavirus infection may have been present in Australian bats 15 years prior to its first description. In Chapter six, deterministic state-transition models are developed to examine the dynamics of HeV infection in a hypothetical flying fox population. Model 1 outputs demonstrated that the rate of transmission and the rate of recovery are the key parameters determining the rate of spread of infection, and that population size is positively associated with outbreak size and duration. The Model 2 outputs indicated that that long-term maintenance of infection is inconsistent with lifelong immunity following infection and recovery. Chapter seven discusses alternative hypotheses on the emergence and maintenance of Hendra virus and Australian bat lyssavirus in Australia. The preferred hypothesis is that both Hendra virus and Australian bat lyssavirus are primarily maintained in P. scapulatus populations, and that change in the population dynamics of this species due to ecological changes has precipitated emergence. Future research recommendations include further observational, experimental and/or modeling studies to establish or clarify the route of HeV excretion and the mode of transmission in flying foxes, the roles of vertical transmission and latency in the transmission and maintenance of Hendra virus in flying foxes, and the dynamics of Hendra virus infection in flying foxes.

Chapter one introduces the concept of disease emergence and factors associated with emergence. The role of wildlife as reservoirs of emerging diseases and specifically the history of bats as reservoirs of zoonotic diseases is previewed. Finally, the aims and structure of the thesis are outlined. In Chapter two, the literature relating to the emergence of Hendra virus, Nipah virus, and Australian bat lyssavirus, the biology of flying foxes, methodologies for investigating wildlife reservoirs of disease, and the modelling of disease in wildlife populations is reviewed. Chapter three describes the search for the origin of Hendra virus and investigations of the ecology of the virus. In a preliminary survey of wildlife, feral and pest species, 6/21 Pteropus alecto and 5/6 P. conspicillatus had neutralizing antibodies to Hendra virus. A subsequent survey found 548/1172 convenience-sampled flying foxes were seropositive. Analysis using logistic regression identified species, age, sample method, sample location and sample year, and the interaction terms age*species and age* sample method as significantly associated with HeV serostatus. Analysis of a subset of the data also identified a significant or near-significant association between time of year of sampling and HeV serostatus. In a retrospective survey, 16/68 flying fox sera collected between 1982 and 1984 were seropositive. Targeted surveillance of non-flying fox wildlife species found no evidence of Hendra virus. The findings indicate that flying foxes are a likely reservoir host of Hendra virus, and that the relationship between host and virus is mature. The transmission and maintenance of Hendra virus in a captive flying fox population is investigated in Chapter four. In study 1, neutralizing antibodies to HeV were found in 9/55 P. poliocephalus and 4/13 P. alecto. Titres ranged from 1:5 to 1:160, with a median of 1:10. In study 2, blood and throat and urogenital swabs from 17 flying foxes from study 1 were collected weekly for 14 weeks. Virus was isolated from the blood of a single aged non-pregnant female on one occasion. In study 3, a convenience sample of 19 seropositive and 35 seronegative flying foxes was serologically monitored monthly for all or part of a two-year period. Three individuals (all pups born during the study) seroconverted, and three individuals that were seropositive on entry became seronegative. Two of the latter were pups born during the study period. Dam serostatus and pup serostatus at second bleed were strongly associated when data from both years were combined (p<0.001; RR=9, 95%CI 1.42 to 57.12). The serial titres of 19 flying foxes monitored for 12 months or longer showed a rising and falling pattern (10), a static pattern (1) or a falling pattern (8). The findings suggest latency and vertical transmission are features of HeV infection in flying foxes. Chapter five describes Australian bat lyssavirus surveillance in flying foxes, insectivorous bats and archived museum bat specimens. In a survey of 1477 flying foxes, 69/1477 were antigen-positive (all opportunistic specimens) and 12/280 were antibody-positive. Species (p<0.001), age (p=0.02), sample method (p<0.001) and sample location (p<0.001) were significantly associated with fluorescent antibody status. There was also a significant association between rapid focus fluorescent inhibition test status and species (p=0.01), sample method (p=0.002) and sample location (p=0.002). There was a near-significant association (p=0.067) between time of year of sampling and fluorescent antibody status. When the analysis was repeated on P. scapulatus alone, the association stronger (p=0.054). A total of 1234 insectivorous bats were surveyed, with 5/1162 antigen–positive (all opportunistic specimens) and 10/390 antibody-positive. A total of 137 archived bats from 10 species were tested for evidence of Australian bat lyssavirus infection by immunohistochemistry (66) or rapid focus fluorescent inhibition test (71). None was positive by either test but 2 (both S. flaviventris) showed round basophilic structures consistent with Negri bodies on histological examination. The findings indicate that Australian bat lyssavirus infection is endemic in Australian bats, that submitted sick and injured bats (opportunistic specimens) pose an increased public health risk, and that Australian bat lyssavirus infection may have been present in Australian bats 15 years prior to its first description. In Chapter six, deterministic state-transition models are developed to examine the dynamics of HeV infection in a hypothetical flying fox population. Model 1 outputs demonstrated that the rate of transmission and the rate of recovery are the key parameters determining the rate of spread of infection, and that population size is positively associated with outbreak size and duration. The Model 2 outputs indicated that that long-term maintenance of infection is inconsistent with lifelong immunity following infection and recovery. Chapter seven discusses alternative hypotheses on the emergence and maintenance of Hendra virus and Australian bat lyssavirus in Australia. The preferred hypothesis is that both Hendra virus and Australian bat lyssavirus are primarily maintained in P. scapulatus populations, and that change in the population dynamics of this species due to ecological changes has precipitated emergence. Future research recommendations include further observational, experimental and/or modeling studies to establish or clarify the route of HeV excretion and the mode of transmission in flying foxes, the roles of vertical transmission and latency in the transmission and maintenance of Hendra virus in flying foxes, and the dynamics of Hendra virus infection in flying foxes.