När influensavirus infekterar människor kan det orsaka mild till akut luftvägs-infektion. Förutom individens existerande immunitet och hälsostatus, är vari-ation i viruset också en viktig faktor för utfallets allvarlighet. Hos viruset är det ofta relaterat till dess evolutionsförmåga att undvika individens existe-rande immunitet. Mekanismen för detta är att variera proteinerna på virusets yta, hemagglutinin (HA) och neuraminidas (NA). Detta sker på två sätt, med hjälp av antigeniskt drift (ackumulering av mutationer i dessa proteiner), eller antigeniskt skift (utbyte av HA eller NA mellan två olika influensavirus som infekterar samma cell).
I mitt arbete har jag använt NA för att förstå evolutionen hos influensaviruset under påtryckning av immunförsvaret, hur den samtidigt kan bevara nödvän-diga proteinfunktioner, samt hur den samtidigt kan anpassa sig för att utnyttja den infekterade cellen för att göra fler viruskopior.
NA är ett svampformat membranprotein, vars ”huvud” (kallad huvuddomän) är lokaliserad utanför cellen, och vars ”fot” (kallad transmembran domän) är inuti cellmembranet. Vanligtvis sker antigeniskt drift på ytan av proteiner, ef-tersom det är där antikroppar har möjlighet att binda. Överraskande har vi i mitt arbete hittat två gömda proteinregioner som också genomgår antigeniskt drift. Den ena är i membranbundna transmembrana domänen, och den andra är i centrala fickan på huvuddomänen som calciumjoner vanligtvis binder till.
Denna upptäckt indikerar att NA, som en helhet istället för som separata do-mäner, evolverar för att förhindra antikroppsigenkänning.
För att studera antigeniskt skift har jag utvecklat en väldigt känslig och speci-fik metod för RNA-detektion för att visualisera influensagenomet under in-fektionsprocessen, som gör det möjligt att i detalj studera vart genomet befin-ner sig i varje stadie. Och eftersom metoden är så specifik går det att studera utbyte av gensegment mellan olika virus utan att behöva titta på proteiner.
31
Acknowledgments
First, I would like to thank my supervisor, Rob Daniels, for giving me oppor-tunity to work in your lab. During these years, you have shown me the fun working in research. Thank you for being so helpful and always providing so many ideas for the projects. I have learned a lot and I am very grateful for the experience.
A special thanks to Jan-Willem de Gier for being my co-supervisor and to Stefan Nordlund, Pia Ädelroth and Martin Ott for organizing the phD pro-gram and for doing the check points during my phD time.
Thanks to Professor Schwemmle, Professor Masucci, Patrik Ellström and Professor Högbom for being my opponent and committee.
Thanks to the former and current lab members: Diogo, you were my ‘guide man’ in the lab and I am so grateful to have you as my teacher. You are always so supportive and taking care of me. Johan, discussing with you always in-spires me, and it has been a quite year without you. Also, thanks for fixing all my Mac problems. Hao, 感谢你在工作中和生活中给我的一切支持 ❤. An-nika, thank you for go through my thesis and give me advice on the thesis manuscript. Henrik, thank you for sharing your opinions about Swedish soci-ety and Swedish education. Rebecca, it has been nice working with you.
Thanks to my collaborators: Thanks to Mats Nilsson for your valuable input in the project and give me opportunity to be in your lab. Ivan, you are such a nice guy and always support me when I need help with experiment. Thanks for the hard work and expertise contributed in the padlock project. Xiaoyan, thanks for helping me with microscope and imaging analysis.
Thanks to the everyone in DBB for creating a convenient working environ-ment. And a big hug to my previous and current lab neighbors at DBB: Cata, Beta, Pedro, Bill, Patrick, Thomas, Zhe, Grant, Nir, Candan, Chenge,
32
Weihua, Biao, Xin, Fan, Huabin, thank you for the accompany and for mak-ing these years so enjoyable.
At last, thanks to my parents, my parents-in-law, and my uncle and aunt (我的 姨和舅舅) for supporting me during these years. And also to my little family:
你们是我前行的动力和方向.
33
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