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Bacteria Present Mechanisms to Evade Cellular and Humoral Responses Mediated Through Peptidoglycan Recognition by PGRP-SA and PGRP-LC

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Bacteria Present Mechanisms to Evade Cellular and Humoral Responses Mediated Through Peptidoglycan Recognition by PGRP-SA and PGRP-LC Bacteria present mechanisms to evade cellular and humoral responses mediated through peptidoglycan recognition by PGRP-SA and PGRP-LC Filipa Baltazar da Costa Vaz Insert here an image with rounded corners Dissertation presented to obtain the Ph.D degree in Biology Instituto de Tecnologia Química e Biológica António Xavier | Universidade Nova de Lisboa Oeiras, December, 2016 Bacteria present mechanisms to evade cellular and humoral responses mediated through peptidoglycan recognition by PGRP-SA and PGRP-LC Filipa Baltazar da Costa Vaz Dissertation presented to obtain the Ph.D degree in Biology Instituto de Tecnologia Química e Biológica António Xavier | Universidade Nova de Lisboa Oeiras, December, 2016 Title Bacteria present mechanisms to evade cellular and humoral responses mediated through peptidoglycan recognition by PGRP-SA and PGRP-LC Cover image Temporal Color Code of Drosophila melanogaster GFP- Moesin macrophages phagocytosing Staphylococcus aureus NCTC 8325-4 strain. Second Edition March 2017 Author Filipa Baltazar da Costa Vaz All Rights Reserved Printed in the UK Acknowledgements It seems that in Science great discoveries started with “Eureka!”, “This is interesting…” and similar expressions that translate excitement and curiosity. The first major discovery I did that put me on the track to some of the findings that I present in this thesis started with an expression that translates annoyance. As soon as my supervisor stepped into the lab, I followed him to his office and said “Sergio, I did something wrong”. After I told him the results of my last pull-down assay, without blinking, he looked at me and said “You didn`t do anything wrong, that makes total sense”. As I stared at him from his office door waiting for him to follow me to my bench, he added “I mean, I don´t think you did anything wrong in the experimental procedure”. For not doubting my results, when I am pretty sure everyone else would (and some did), I am profoundly grateful. This is something that even after all these years I had never expressed. It turns out that the following steps were the hardest. Sergio demanded me several experimental controls with repeats. After long and hard hours of work, I had ended any doubts that what I was observing was merely a result that was only reproducible in certain specific conditions. Naturally, I am thankful to Sergio for giving me the opportunity to do my PhD, for all the excellent conditions that he provided me and to allow me to pursue my sometimes (I admit it) crazy and out-of-the-box ideas, without any judgement. Also, I deeply appreciate that he gave me the freedom to perform experiments on my own initiative which sometimes were a little bit out of the aims of the work, just because… Just because I thought something was fun and wanted to try it! At his own terms and ways, with the interaction and working dynamics that I developed with him, I was able to learn from him how to build elegant experiments that give results which are convincing and explicit to others and to anticipate variables that can interfere and tackle them from the beginning. If others cannot understand your ideas and the reason for presenting certain data, you will most likely not thrive, no matter how good or smart you may be. I hope in the future to continue developing such an exciting work (at least exciting for me) and Sergio certainly has a major impact in helping me to one day become (hopefully) a successful scientist. Mariana Pinho, “the Lady next door”, was the best neighbour I could have encountered. Her outsider-insider role in my work throughout all these years proved to be valuable in several moments. With Mariana I learnt to stay focused on a certain topic, to not allow myself diverge from the “main road”, whilst keeping in mind all the observations that I would eventually need to interpret my data and/or to get “unstuck” from a puzzling data. I learnt that the success of a project relies in a sharp and objective mind where at all times it is key to determine very well what I aim to get with a certain experiment. In sum, she showed me that my time is valuable so I might as well spend it properly going straight to point. However, I admit that I still occasionally indulge myself in experiments just for fun and mere curiosity… I guess some things never really change! I am very grateful to Petros because he invested in me, in my work, he believed in my data and he received me as a member of his Lab. Without him, probably I would have never been able to finish this work the way I did and without his investment in my study of the macrophages I would probably have never been able to find the role of the lytic activity of PGRP- SA. Thank you very much for everything! The faith and enthusiasm that you deposited in me was something that I had never been given before. It was indeed a great experience to go through. I will certainly remember this for my future and I hope to be able to one day provide similar experience to others. To Maria João Gravato-Nobre, you are a sunshine in the Department of Biochemistry, a great friend and you opened me the doors to figure out the optimum conditions for the Zymography assays of PGRP- SA. All the optimisations I performed using other extracts and enzymes, had the secret goal to prove the lytic activity of PGRP-SA. I remember your words “I saw and felt that you were living a moment that many people work for many years in Science and never live.” I am glad you could put words into that moment, because even today I still cannot quite describe it. Thank you! To Dr. Jonathan Hodgkin, thank you for being so welcoming by letting me use your lab space and trusting in me without knowing me at all, that I would be able to do the zymopgraphy experiments for Maria`s paper. Thank you for reading my thesis and all the support for my next adventure! Richard Parton, the microscopy guru, thank you very much for your time, help and sharing the knowledge with me. In particular, thank you for the patience and giving me the mini-courses on “microscopy for dummies”! To everybody from the Micron Unit – David, Andrew, Vick and Ian – thanks for your help, good mood and fast responses in solving all the problems. David, thank you for letting me steal your teas and tea pot (I replaced some teas anyway) and I am sorry that I made go crazy looking for you tea pot in every single place of the entire building when it was right next door…. I really thought you had figured by then that I stole your tea pot every night for my shifts! Andrew, thank you for the help, chats and cookies! Vick thanks for sharing the knowledge and help and also for the great times we had! To Dr. Alberto Baena, I have to give a big thanks for the help in the analysis of the behaviour of the macrophages and the type of cell death. Your help was crucial for me to be able to interpret and analyse my data. Also, I am very thankful for your interest in reading my thesis and for the suggestions and critics that truly helped me to seat down and improve it to what it is now here presented. Prof. Carlos Romão, I cannot thank you enough for your patience, support and help. At the end of the day, I feel that I was lucky to have met someone like you, who stands by good and positive values and makes a difference in this little world of the Academia. Thank you for making this day possible and helping me to conclude a personal/professional journey that I started when I was 15 years old. To Karina Xavier, I have to thank for your constant interest in my work to make sure that my work would reach this day in the best possible way. You surprised me in a positive way by reminding me that there are people who still care about the Science for what it is. Even if it is not their field of work and they will not get a direct and evident advantage for themselves at the end of that day, they still care and show genuine interest. Also, thank you for showing me that some people still care about people and remembering that a PhD student is a person, not a slave. Teresa Baptista da Silva, you are an angel walking in the ITQB corridors! Not only you are fast, efficient and do everything right, but also you have a great spirit and lovely presence. I feel good whenever you are around. I always do everything myself to make sure that if something fails I can spot every step and figure out where I went wrong. However, with you, I trusted all my buffers and media in a way that I am not sure that in the future I will trust someone else. To Rupal and Ilias, many big thanks for the friendship, flyroom moments, pub, allotment and I could go on… Rupal, I was really glad that we met, I know the feeling is mutual – you changed my out of the work PhD moments! To my 22 year-old drama queen, Maria, you are the best kiddo, sorry for being away lately, but I will now be cheesy as you like me to be “you were always on my mind!”.
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