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Gene Expression Patterns of the Female Genital Tract and Immunomodulation by Lactobacillus Species

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Gene Expression Patterns of the Female Genital Tract and Immunomodulation by Lactobacillus Species Gene expression patterns of the female genital tract and immunomodulation by Lactobacillus species Andrea Gillian Abrahams ABRAND006 Supervisor: Dr Lindi Masson Co-Supervisors: Dr Arghavan Alisoltani-Dehkordi Dr Heather Jaspan Presented for Master of Science Degree (MSc) in Medical Virology Division of Medical Virology Faculty of Health Sciences University of Cape Town 23 September 2020 The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgement of the source. The thesis is to be used for private study or non- commercial research purposes only. Published by the University of Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University of Cape Town Plagiarism Declaration “This thesis/dissertation has been submitted to the Turnitin module (or equivalent similarity and originality checking software) and I confirm that my supervisor has seen my report and any concerns revealed by such have been resolved with my supervisor.” Name: Andrea Gillian Abrahams Student number: ABRAND006 Signature: Date: 23 September 2020 i Acknowledgements First and foremost, I thank God for His grace and strength that has sustained me during this study and the completion of this thesis. To my supervisor, Dr Lindi Masson, I cannot thank you enough for all the support and encouragement you’ve given me these past two years. Thank you for your understanding and kindness during every challenge I’ve faced. You have taught me so much in this field and I am very grateful to you. A special thanks to my co-supervisor Dr Arghavan Alisoltani-Dehkordi for assistance in microarray data analysis training. Thank you to Associate Professor Jo-Ann Passmore for generously providing the Lactobacillus isolates included in this study. Thank you to the WISH and Groote Schuur clinic cohorts, without these participants, this research would not be possible. Thank you to SATVI and CIDRI for the use of your ELISA and Luminex plate readers. Thank you to Professor Carolyn Williamson for the use of the RNA extraction lab. Thank you to the Centre for Proteomics and Genomics Research for the professional service provided. Thank you to my parents Paul and Dawn Abrahams, my siblings Linieve, Lyle and Allison Abrahams, Uncle Clyde and Aunty Karin Ebden, for your constant love and support. You’ve seen the highs and lows of these past two years and supported me every step of the way. A special thanks to Paul Abrahams, Dawn Abrahams, Ps Andrew Lamb, Kulsum Lamb, Ps Junaid Esau, Kelly-Anne Esau, Hendrisa Swanepoel, Robin Brooks, Lynn Brooks, Clyde Ebden, Karin Ebden, Vernon Daniels, Peter Daniels, Lavona Daniels, Quintin McLaren, Ingrid McLaren, Janine McLaren and Neville McLaren for all your prayers. Thank you to my amazing friend Nina Radzey for your constant support. Thank you to the National Research Foundation (NRF) who has funded my MSc. Degree. ii Contents List of figures ....................................................................................................................... 1 List of tables ......................................................................................................................... 5 List of units .......................................................................................................................... 5 Abstract ............................................................................................................................... 6 Abbreviations ....................................................................................................................... 7 Chapter 1: Introduction ..................................................................................................... 11 1.1 The vaginal microbiome in optimal and non-optimal states ................................ 12 1.2 The innate immune response in the FGT .............................................................. 14 1.2.1 Mucosal barrier of the FGT .............................................................................. 15 1.2.2 Pathogen detection in the FGT ........................................................................ 15 1.2.3 Downstream inflammatory networks ................................................................ 16 1.3 BV-associated bacteria cause inflammation in the FGT ....................................... 17 1.4 Anti-inflammatory effect of Lactobacillus species ................................................ 18 1.4.1 Effect of FGT bacteria on the expression and activation of PRRs .................... 19 1.4.2 The effect of FGT bacteria on intracellular inflammatory pathways .................. 20 1.5 Aims and Objectives ............................................................................................... 21 Chapter 2: Materials and Methods .................................................................................... 22 2.1 Comparison of gene expression in CMC and PBMC samples.............................. 22 2.1.1 Groote Schuur study cohort and sample collection .......................................... 22 2.1.2 CMC and PBMC sample processing ................................................................ 22 2.1.3 Gene expression analysis of CMC and PBMC samples using microarray Illumina platform ....................................................................................................... 22 iii 2.2 Effect of vaginal Lactobacillus isolates on inflammatory responses to G. vaginalis .................................................................................................................. 23 2.2.1 Women’s Initiative in Sexual health (WISH) study .......................................... 23 2.2.2 Isolation of Lactobacillus bacteria .................................................................. 23 2.2.3 Bacterial isolate selection .............................................................................. 24 2.2.4 Bacterial culture and standardisation ............................................................. 24 2.2.5 Human primary vaginal epithelial cell (VK2) culture ....................................... 25 2.2.5.1 Thawing VK2 cells .................................................................................. 25 2.2.5.2 VK2 cell subculture ................................................................................. 25 2.2.6 Optimization of methods for bacterial-VK2 cell coculture ............................... 26 2.2.6.1 VK2 cell culture in transwells .................................................................. 26 2.2.6.2 Bacterial stimulation of VK2 cells in transwell culture systems................ 27 2.2.6.3 Bacterial stimulation of VK2 cells in 24 well plates .................................. 28 2.2.7 RNA extraction ............................................................................................... 29 2.2.8 Cytokine detection by Luminex assay ............................................................ 29 2.2.9 Detection of lactic acid in stimulated VK2 cell culture supernatants and pH measurement .......................................................................................... 30 2.2.10 Microarray Affymetrix assay ......................................................................... 31 2.2.11 Data analysis ............................................................................................... 32 2.2.11.1 Illumina microarray data ....................................................................... 32 2.2.11.2 Luminex cytokine data .......................................................................... 33 2.2.11.3 Affymetrix microarray data .................................................................... 33 iv Chapter 3: Results ........................................................................................................... 35 3.1 Groote Schuur study cohort ..................................................................................... 35 3.2 Gene transcription of matched CMCs and PBMCs .................................................. 36 3.3 Genes differentially expressed in CMCs compared to PBMCs and downstream signalling pathways detected ......................................................................................... 38 3.4 WISH study cohort and Lactobacillus selection ....................................................... 49 3.5 Quality of RNA extracted from VK2 cells stored in RLT lysis buffer compared to RNALater ...................................................................................................................... 51 3.6 Cytokine responses by VK2 cells stimulated with Lactobacillus species and G. vaginalis in transwells compared to stimulation in 24 well plates ............................... 53 3.7 Lactic acid production by Lactobacillus isolates in the VK2 cell 24 well culture system ............................................................................................................. 60 3.8 Quality of RNA extracted from VK2 cells stimulated with Lactobacillus species and G. vaginalis in 24 well plates ......................................................................................... 64 3.9 Overall gene transcription of VK2 cells stimulated by Lactobacillus isolates and G. vaginalis in combination ............................................................................................ 67 3.10 Differential gene expression and signalling pathways in G. vaginalis stimulated VK2 cells compared to unstimulated
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