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Sample Thesis Title with a Concise and Accurate Description ELUCIDATION OF NOVEL PHYSIOLOGICAL AND GENETIC ELEMENTS ASSOCIATED WITH THE COLD ADAPTABILITY AND SURVIVAL OF LISTERIA MONOCYTOGENES IN THE FOOD PROCESSING CONTINUUM by Patricia Hingston B.A.Sc., Dalhousie University, 2010 M.Sc. Dalhousie University, 2013 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Food Science) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2017 © Patricia Hingston, 2017 i Abstract Novel physiological and genetic factors associated with the survival of Listeria monocytogenes in the food-processing continuum were investigated, with an emphasis on its cold- growth ability. Food-related L. monocytogenes strains (n=166) were sequenced and subsequently evaluated on their ability to tolerate cold (4°C), salt (6% NaCl, 25°C), acid (pH 5, 25°C), and desiccation (33% RH, 20°C) stress. Stress tolerances were associated with serotype, clonal complex, full-length inlA profiles, and plasmid harbourage. Notably, strains possessing full length inlA (as opposed to a truncated version) exhibited significantly (p<0.001) enhanced cold tolerance and plasmid-positive strains demonstrated enhanced (p=0.013) acid tolerance. Relative gene expression indicated that several plasmid-encoded genes (e.g., NADH peroxidase, clpL, proW) are induced in L. monocytogenes during growth in 6% NaCl and at pH 5. Additionally, a whole- genome sequence phylogeny revealed closely related stress sensitive and tolerant strains, highlighting that minor genetic differences impact strain phenotypes. Strand-specific RNA sequencing showed that L. monocytogenes suppresses 1.3× more genes than it induces at 4°C relative to 20°C. The largest number (n=1,431) and greatest magnitude (>1,000-fold) of differentially expressed (e.g., >2-fold, p<0.05) genes occurred in late stationary- phase cells. A core set of 22 genes were upregulated at all five growth phases investigated and included nine genes required for branched-chain fatty acid (BCFA) synthesis. Correspondingly, BCFA levels increased by 15% during cold stress exposure. Transcription of antisense RNA (asRNA) was 2.5× higher in cells grown at 4°C relative to 20°C, with the most asRNA transcripts upregulated in lag phase cells. Spontaneous L. monocytogenes variants displaying enhanced cold tolerance (ECT) were isolated from a cold-sensitive strain culture following 84 days of storage at 4°C. While the parent ii strain had an impaired ability to produce BCFAs, the ECT variants were able to overcome this limitation which is hypothesized to be a result of mutations identified in acetyl-coA carboxylase. Collectively this work has improved our understanding of the response of L. monocytogenes to to cold stress and genotypes associated with stress-tolerance phenotypes. This information may be useful for developing biomarkers to quickly predict the risks associated with food isolates, or aid in developing new and/or improved intervention strategies. iii Lay Summary Listeria monocytogenes is a potentially fatal human bacterial pathogen found ubiquitously in nature and accordingly, is frequently isolated from foods and food production facilities. While this pathogen is not heat tolerant, it can grow at temperatures as low as 0°C and therefore outbreaks are commonly associated with refrigerated, ready-to-eat foods that permit the pathogen to reach dangerous levels during the shelf-life. Currently, the regulations surrounding the presence of L. monocytogenes in foods assume that all strains behave similarly; however, we know this is not true. The goal of this research was to identify genetic elements associated with L. monocytogenes strains displaying enhanced abilities to tolerate food-related stresses (cold, salt, acid, and desiccation) with the hope of discovering biomarkers that can be used to quickly access the risks associated with a particular strain. Furthermore, this research aimed to improve our understanding of the ability of L. monocytogenes to grow at cold temperatures. iv Preface A version of Chapter 2 has been published in the Frontiers in Microbiology Journal (Hingston, P., Chen, J., Dhillon, B. K., Laing, C., Bertelli, C., Gannon, V., Tasara, T., Allen, K., Brinkman, F. S., Hansen, L. T. and Wang, S. 2017. Genotypes associated with Listeria monocytogenes isolates displaying impaired or enhanced tolerances to cold, salt, acid, or desiccation stress. Front. Microbiol. 8:369 doi: 10.3389/fmicb.2017.00369). I was responsible for the majority of the work and manuscript preparation. Liang, C. assembled the whole genome sequences, Chen, J. conducted the targeted genomic element screenings, Bertelli, C. investigated the relationship between phenotypes and the presence of genomic islands, Dhillon, B. performed the single nucleotide polymorphism analysis and whole genome sequence phylogeny. Dr. Franco Pagotto and his team at the Listeriosis Reference Service at the Bureau of Microbial Hazards in Ottawa, Canada performed serotyping on our isolates. Wang, S., Truelstrup Hansen, L., and Brinkman, F. and Chen, J. helped with reviewing the experimental design and reviewing and editing the manuscript. Allen K. was involved in the concept formation and Gannon, V. and Tasara, T. generously donated their L. monocytogenes strains and contributed to the final editing of the manuscript. Wang, S. was the supervisory author. I performed and analyzed the research described in Chapters 3 and 5. Chen, J., Truelstrup Hansen, L., and Wang, S. provided feedback on the experimental design and helped with critical review and editing of the chapters. A version of Chapter 4 has been published in the PLoS ONE journal (Hingston, P., Chen, J., Allen, K., Hansen, L. T., and Wang, S. 2017. Strand specific RNA-sequencing and membrane lipid profiling reveals growth phase-dependent cold-stress response mechanisms in Listeria monocytogenes. PLoS ONE, 12(6), e0180123). I was responsible for the majority of the work and v manuscript preparation. Chen, J., Wang, S., and Truelstrup Hansen, L. helped in reviewing the experimental design and reviewing and editing the manuscript. Allen K. was involved in the concept formation. Wang, S. was the supervisory author. vi Table of Contents Abstract .......................................................................................................................................... ii Lay Summary ............................................................................................................................... iv Preface .............................................................................................................................................v Table of Contents ........................................................................................................................ vii List of Tables ................................................................................................................................xv List of Figures ............................................................................................................................ xvii List of Supplementary Materials ................................................................................................xx List of Symbols ........................................................................................................................... xxi List of Abbreviations ................................................................................................................ xxii Acknowledgements ....................................................................................................................xxv Dedication ................................................................................................................................ xxvii Chapter 1: Introduction and literature review ...........................................................................1 1.1 Introduction ................................................................................................................... 1 1.2 Research overview ........................................................................................................ 4 1.3 Literature review ........................................................................................................... 6 1.3.1 Overview of Listeria monocytogenes ................................................................. 6 1.3.1.1 L. monocytogenes genomics ............................................................................... 9 1.3.1.2 L. monocytogenes subtypes ............................................................................... 11 1.3.1.2.1 Genetic lineages and serotypes ................................................................... 11 1.3.1.2.2 Clonal complexes and sequence types ........................................................ 13 1.3.1.3 L. monocytogenes pathogenicity ....................................................................... 14 vii 1.3.2 L. monocytogenes physiology and food-related stress tolerances .................... 18 1.3.2.1 Acid tolerance ................................................................................................... 20 1.3.2.2 Cold and heat tolerance ..................................................................................... 21 1.3.2.3 Osmotolerance .................................................................................................. 24 1.3.2.4 Desiccation tolerance .......................................................................................
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