Worlock, Kaylee B.;
(2023)
Airway epithelial and immune development in health and disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Cellular interactions are fundamental for healthy development and function, and need to be tightly regulated or they can lead to and perpetuate disease. My PhD study aims to characterise immuno-epithelial development and crosstalk within healthy lung and airways, utilising powerful single cell genetic tools and patient samples. With the onset of the pandemic my work expanded to look at these processes in light of pathogenesis, investigating why children present with milder forms of COVID-19 disease compared to adults. Working as part of the Human COVID-19 Challenge Study I built upon this “snap-shot”, characterising the dynamic antiviral responses to SARS-CoV-2 exposure at the single cell level across the disease-time course, pre-exposure right through to 28-days post-infections. Through the generation of three large, comprehensive single cell multi-omics datasets, each which will be made publicly available, I have been able to profile the underlying cellular landscape across a lifetime, from in utero, right through childhood into adulthood. I have provided evidence of a B-lymphocyte developmental niche in the foetal lung and described a role for IL-1β-producing myeloid cells in healthy lung epithelial maturation. In terms of COVID-19, I have suggested several key protective mechanisms relating to age and the development of different infection phenotypes. These include a pre-activated IFN-state in the upper airways of children, with a more naïve underlying immune compartment as well as several rapid and highly time-restricted cellular responses within SARS-CoV-2 challenged individuals. Lastly, through the identification of activated T cell subsets in infected participants, several shared SARS-CoV-2 specific TCR motifs were found both within our cohort and public datasets. Together, this has enabled me to elucidate the immune-epithelial crosstalk within developing airways in health and disease, offering valuable insights into what can go awry, e.g., in COVID-19, which in turn could contribute towards better treatment options and therapeutics.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Airway epithelial and immune development in health and disease |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Immunology, Developmental, SARS-CoV-2, Airway, Foetal, Pediatric |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10175138 |
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