Stankovic, Milena;
(2020)
Genetic determinants of the magnitude of type-I interferon responses in mice: a-protein kinase I as a novel candidate gene.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Flu disease is an important public health burden worldwide, caused by the influenza virus that rapidly mutates and can cause severe disease and even death. While host genetic factors can also contribute to disease severity and susceptibility, no precise genetic determinant has been elucidated yet. Type-I IFNs, IFN-a/b, are hallmark molecules of the host innate immune responses, indispensable to the elimination of viruses. Previous work in our team directly correlated IFN-a/b levels in the lung to influenza susceptibility in a mouse model. Influenza-susceptible 129 mice exhibited higher IFN-a/b levels upon infection than resistant BL/6 mice, although all parameters of infection were similar. This PhD project was focused on uncovering the genetic determinants of excessive IFN-a/b production in mice. In this thesis, I present the impact of a novel candidate Chromosome 3 region in IFN-a/b responses: the R17 locus. A homozygous congenic BL/6 allele of the R17 locus contributed to reducing IFN-a/b and cytokine levels and to rescuing the susceptibility to influenza of the otherwise susceptible 129 mice. I report increased susceptibility in vivo and IFN-a/b production in vitro of BL/6 mice deficient in a candidate gene from the R17 locus, the a-protein kinase 1: ALPK1. Finally, this work reports some progress on elucidating the role of ALPK1 in IFN-a/b production pathways. By means of global phospho-proteome assays, a novel putative phosphorylation target of ALPK1, WWC2, is reported. This finding suggests a role for a previously unreported interaction between IFN-a/b responses and the Hippo pathway in innate immunity
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Genetic determinants of the magnitude of type-I interferon responses in mice: a-protein kinase I as a novel candidate gene |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices 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 Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10090246 |
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