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Strong clinical and experimental evidence has suggested the involvement of Chlamydia pneumoniae (C. pneumoniae) in the development of atherosclerosis. However, the direct role of C. pneumoniae infection in vascular remodelling processes in the absence of a host immune response remains undetermined. To study the direct effect of this pathogen within the arterial wall, we developed a novel ex vivo porcine coronary artery model that supported bacterial growth for up to two weeks in culture. Employing this approach, we demonstrated that C. pneumoniae infection could alter vascular functions parameters, including endothelial-dependent relaxation responses. This impairment was associated with a decrease in eNOS expression and increased oxidative stress, changes that are also noted in atherosclerotic plaques. We further demonstrated that C. pneumoniae infection initiates medial thickening via vascular smooth muscle cell (VSMC) proliferation. This proliferative response was associated with an increase in expression of endogenous heat shock protein 60 (Hsp60) and alterations in nuclear protein import machinery. Additionally, C. pneumoniae infection and Hsp60 overexpression in primary VSMCs resulted in alteration in nuclear protein import parameters leading to the cell proliferation. Using a rabbit atherosclerotic model, we demonstrated that Hsp60 is induced during atherosclerotic lesion growth and correlated with both the proliferative status and the expression of protein involved in nuclear protein import within the atherosclerotic vessel. In summary, our work has demonstrated the feasibility of studying the molecular mechanisms of infection-induced atherosclerosis using an ex vivo coronary culture system. Importantly, our data has provided the first direct evidence that an active C. pneumoniae infection alone, without contributions from a host immune system, can mediate endothelial dysfunction and stimulate arterial thickening, two key remodelling processes present during atherosclerotic progression. Our findings further suggest the involvement of Hsp60 as a key contributor in growth-based pathologies like C. pneumoniae-mediated atherosclerosis possibility through modulation of nuclear protein import.

Chytridiomycosis is an emerging infectious disease of amphibians caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd). Chytridiomycosis has caused declines and extinctions of amphibian species worldwide. Although the disease can be highly virulent, there are large differences both within and between amphibian species in response to Bd infection. Environmental factors are increasingly shown to be critical in the outcome of Bd-infection and emergence of the disease, although these factors remain poorly defined. Using a series of mesocosm experiments, I examine the influence of different environmental and ecological factors on the outcome of exposure to Bd in red-legged frog (Rana aurora) tadpoles, a species in decline in British Columbia. First, I tested the hypothesis that Daphnia, a keystone genus of zooplankton in shallow freshwater ecosystems, consume Bd zoospores in the water column to decrease the transmission of Bd infection in tadpoles. Although Daphnia are nearly always included in amphibian mesocosm experiments, their effects in these systems are overlooked. As such, I also examined the effect of Daphnia on R. aurora in general. I found that Daphnia had dramatic beneficial effects on tadpoles, that ostensibly herbivorous tadpoles consumed large numbers of Daphnia, and that Daphnia interacted with the presence of Bd to influence tadpole survival, with tadpole survival highest in the absence of Bd and presence of Daphnia. Although Daphnia consumed Bd zoospores in the laboratory, they had no discernible effect on transmission in mesocosms. These results have broad implications for the interpretation of mesocosm studies in general. Climate change has been implicated as a trigger of outbreaks of chytridiomycosis, yet, paradoxically, high temperatures are lethal to Bd. Climate change has also impacted amphibian communities by uncoupling the phenology of interacting species. I manipulated the temperature in mesocosms to test the effects of small temperature changes on the outcome of Bd-exposure in R. aurora. I also tested the effect of the presence of the sympatric Boreal chorus frog (Pseudacris regilla) on R. aurora at different temperatures, and in the presence and absence of Bd. I found that negative effects of Bd on tadpole body condition increased with temperature, although when Bd was absent tadpoles benefitted at higher temperatures. Furthermore, both Bd and temperature increased the development rates of P. regilla but not R. aurora, uncoupling the phenology of the species. Increased temperatures thus favoured P. regilla at the expense of R. aurora. In general, slightly higher and more variable temperatures shifted the host-pathogen balance to the detriment of the R. aurora, helping to explain a mechanism by which increasing temperatures may trigger chytridiomycosis outbreaks in susceptible. Together, these experiments clearly demonstrated the importance of ecological context in the outcome of Bd exposure in tadpoles. / Graduate / 0472

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