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(2023)ThesisThe transmission of dengue fever is already being impacted by the changing climate. This phenomenon poses a considerable public health challenge for countries like Bangladesh, where regular seasonal outbreaks of dengue fever are already prevalent. This thesis aims to investigate how changing climate will impact long-term dengue epidemiology in Bangladesh as a whole and more specifically in Dhaka, the capital city of the country over the 21st Century. Several statistical models have been developed to estimate the short-term risk of dengue outbreaks as a function of climate variables but the underlying causal relationships that contribute to dengue transmission and the observed patterns of dengue epidemiology are not accounted for in these models. Initially, we determined the suitability of using climate projections for 21st Century from Global Climate Models (GCM) to assess the impact of changing climate on future dengue risk in Bangladesh setting. We then used the GCM output to assess the impact of changing climate on one aspect of dengue transmission by calculating the change in vectorial capacity (VC) of Aedes aegypti mosquitoes at a seasonal level for all regions in Bangladesh under two future climate change scenarios. The analysis indicates that the annual VC in all divisions of Bangladesh is expected to consistently exceed the threshold for dengue transmission throughout the 21st Century, regardless of the climate change scenarios considered. However, during the latter half of the century, there is a projected decline in the annual VC compared to the period between 1986 and 2005. Despite this, monthly VC variations reveal that the winter/dry season could see an increase in VC, potentially leading to a longer dengue season with outbreaks occurring year-round. The application of the VC calculation is limited by the fact that it only accounts for temperature and does not consider the impact of other climate variables such as rainfall and humidity, as well as the role of host immunity. To incorporate these factors, we then developed a mechanistic dengue transmission model that considers the influence of temperature, rainfall, and humidity on the transmission of two different dengue serotypes among human hosts and mosquito vectors. We calibrated and validated the model against observed dengue epidemiology data from Dhaka for 1995-2014 using observed climate data as input. We then used GCM output for two future climate change scenarios to simulate the model for two future periods (2030-2049 and 2080-2099) to assess the potential changes in dengue epidemiology in Dhaka. When utilizing observed climate data and climate projections from GCMs specific to Dhaka, our mechanistic model reasonably reproduced the observed dengue epidemiology in Dhaka between 1995 and 2014 in terms of the recurring annual dengue outbreaks, the seasonal pattern of transmission, and the increase in seroprevalence. Simulations for 2030-2049 indicate that dengue transmission is likely to increase regardless of the combination of initial seroprevalence, GCM, and climate change scenario, when compared to the baseline period of 1995-2014. However, for the period 2080-2099, the projected changes in dengue transmission vary, with some combinations of initial seroprevalence, GCM, and climate change scenario predicting a slight increase and others indicating a decrease. The simulations also suggest the seasonal pattern of dengue infections is likely to change in future, with more pronounced change projected for the 2080-2099 period, resulting in a lengthening of the dengue season. The primary contribution of this thesis is to present a modelling framework that considers the anticipated changes in the future climate and immunological factors to project the long-term risk of dengue epidemics. The model is flexible enough to be adapted to other settings and other pathogens transmitted by the same mosquito vector.
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(2024)ThesisAcanthamoeba, a free-living heterotrophic protist, typically resides in a variety of aquatic environments. It is known to pose a risk to humans, causing various diseases, including eye infections (keratitis), often transmitted through contact lenses. The primary risk factor for Acanthamoeba keratitis (AK) in developed countries is engaging in recreational water activities while wearing contact lenses. Late and misdiagnosis of AK are commonly observed, often leading to worse clinical outcomes. Treatment of Acanthamoeba infections is challenging due to the absence of drugs that can effectively eradicate both trophozoites and resilient cysts. In a remarkable dual role, Acanthamoeba behaves as a phagocytic predator, consuming other microbes, but also as an environmental host for diverse bacteria which can resist the intracellular killing mechanism of the amoebal host. Among AK patients, coinfections with various bacteria and fungi have been reported in recent years, presenting as a complex polymicrobial keratitis. The research in this thesis investigates the incidence of Acanthamoeba in Sydney's largest domestic water reservoir and determines the associations between Acanthamoeba and physicochemical as well as microbiological parameters of the water. In addition, the research evaluated the incidence of Acanthamoeba spp. within coastal lagoons on the eastern coast of Australia using a metagenomic approach and investigate their associations with aquatic bacteria. The research also examined the genotypes of Acanthamoeba species recovered from AK patients in Hyderabad, India and Sydney, Australia, along with the types of intracellular bacteria they harbor, using microbiome sequencing. Finally, the research examined whether naturally acquired intracellular bacteria in Acanthamoeba led to more severe ocular infections in an animal model. In this thesis, two review papers (chapters 1B and 1C) summarised the growing importance of Acanthamoeba as a potential human pathogen, elucidating its role as an environmental predator. An invited narrative review (chapter 1B) highlighted how Acanthamoeba predation in environmental habitats can be a key factor shaping the structure and composition of microbial populations. This review comprehensively examined and listed Acanthamoeba-resisting bacteria, along with in vitro interactions and adaptations between Acanthamoeba and bacteria. A systematic review in this thesis (chapter 1C) examined the diversity of microbial species identified in environmental and clinical isolates of Acanthamoeba spp. The comprehensive systematic review also outlined the knowledge gap of whether Acanthamoeba minimicrobiome contains phylogenetically distinct bacteria. In the past, approximately 20% of AK patients in the Sydney metropolitan reported swimming in seawater or freshwater while wearing their contact lenses before they became infected. The current research identified that 34.5% of water samples from Warragamba dam, the largest water reservoir in Sydney contained viable Acanthamoeba spp. (chapter 2), and the incidence of Acanthamoeba spp. in the dam was positively correlated with a higher concentration of algal biovolume. Additionally, 38% of water samples from four lagoons on the NSW, Central Coast were positive for Acanthamoeba, with significantly higher numbers observed in summer compared to other seasons (chapter 3). Water from a highly urbanised area were more commonly infested with Acanthamoeba than non-urbanised areas. Most strains belonged to the pathogenic genotype T4 clade. Water turbidity, temperature, intl1 gene concentration (a proxy measure of anthropogenic pollution), and dissolved oxygen were significantly associated with Acanthamoeba numbers. This study (chapter 3) found a positive correlation between the abundance of Acanthamoeba in coastal waterways and the levels of cyanobacteria, Pseudomonas spp., Candidatus Planktoluna, Curvibacter sp., Polynucleobacter cosmopolitanus, Mycobacterium spp., Vibrio pacinii, and marine bacteria of the Bacteroidota phylum. Overall, the presence of Acanthamoeba spp. had a significant influence on the composition of bacterial communities in lagoons (chapter 3). Subsequent studies in this thesis investigated the genotypes of Acanthamoeba recovered from ocular infections in Hyderabad (chapter 4A) and Sydney (chapter 4B). Most Indian (92.3%) and all Australian corneal isolates belonged to genotype T4. Among Indian isolates, nine strains harboured intracellular bacteria and one contained the fungus Malassezia restricta. The presence of intracellular microbes was associated with a higher proportion of stromal infiltrates, epithelial defect and hypopyon compared to AK cases without intracellular microbes. Ocular trauma was the major reported risk factor among AK patients in Hyderabad, India where 46.2% required surgical intervention, and one case underwent evisceration. This study also analysed domestic tap water of nine AK patients in Sydney, and Acanthamoeba was detected in four of them. Notably, one isolate was found to harbor viable Pseudomonas aeruginosa (chapter 4B). Chapter 5 of this thesis assessed the intracellular microbiome composition of 51 Acanthamoeba species isolated in Australia and India, 41% harboured intracellular bacteria which were clustered into four major phyla: Pseudomonadota, Bacteroidota, Actinomycetota, and Bacillota. Distinct microbial abundance patterns were observed among the samples; Pseudomonas species were abundant in Australian corneal isolates, Enterobacteriales in Indian ocular isolates, and Bacteroidota was abundant in Australian water isolates. More diverse intracellular bacteria were identified in water isolates as compared to clinical isolates. The beta diversity measure of bacterial communities in corneal isolates of Acanthamoeba exhibited significant difference based on the country of origin, while alpha diversity did not vary significantly as per the source of isolation or country of origin. Chapter 6 of this thesis examined the impact of naturally acquired viable intracellular P. aeruginosa in the development of AK in rats cornea. The findings from this study (chapter 6) demonstrated that AK infection in rat's corneas, using an Acanthamoeba strain containing intracellular P. aeruginosa, resulted in acute keratitis with a high neutrophil response, whereas Acanthamoeba alone induced only very mild infections. During the infection in rat corneas, intracellular P. aeruginosa cells were expelled, as no intracellular bacteria were observed in Acanthamoeba trophozoites reisolated from the rats' corneas. No severe keratitis developed when Acanthamoeba and intracellular P. aeruginosa were separately inoculated in distinct groups of rat corneas, unlike their combined inoculation. These findings suggest that the concurrent infection of Acanthamoeba, coupled with the release of intracellular bacteria onto a compromised cornea, can contribute to the development of complex microbial keratitis. In summary, this thesis observed a relatively high prevalence of pathogenic Acanthamoeba in both the water reservoir and coastal waterways of Sydney. It also identified potential contributors in water habitats that could promote the proliferation of Acanthamoeba strains, determined circulating genotypes of Acanthamoeba among AK patients in Hyderabad and Sydney, comprehensively characterised the microbiome that can inhabit Acanthamoeba spp., and assessed the impact of a member of this microbiome on corneal infection in rats.