The Dynamics of death: determining the relationship between within-host pathogen dynamics and host mortality

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O'Sullivan, Tim Sean
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Infectious diseases remain a major cause of global mortality, yet basic questions concerning the relationship between within-host pathogen processes and epidemiological patterns of mortality remain obscure. Following an introductory chapter one, we lay out the conceptual challenge in chapter two – how do within-host pathogen dynamics (pathogen burden p(t) as a function of time since infection t) link to changes in epidemiological risk of death, m(t)? We perform a structured literature review of the existing biomedical literature on controlled animal infections, and find consistent support across 28 experiments for an exponentially increasing risk of death m(t) with time since infection. We then illustrate that survival data alone is insufficient to infer pathogen dynamics p(t), with multiple models of pathogen growth and host-pathogen interactions consistent with observed survival data. In chapter three we develop an experimental C. elegans / Pseudomonas aeruginosa infection model platform to allow non-invasive tracking of p(t), via fluorescence-tagged pathogen imaging. Our calibration results show that quantitative inference to pathogen density from fluorescence intensity is not reliable. As a result of this roadblock, in chapter four we turn to a destructive sampling approach, coupled to non-invasive imaging to identify live and dead worms. Estimating pathogen burden in both live and dead worms indicates that pathogen growth is approximately exponential across the transition from host life to death. Our control experiments indicate substantial background mortality in our experimental design, limiting our ability to map mortality onto pathogen dynamics. In chapter five we discuss methodological improvements to our platform, plus potential avenues for future research building on the results presented in this thesis.
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