Öppna denna publikation i ny flik eller fönster >>2024 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
En systembiologisk studie av differentiering av immunförsvaret och antiviral respons på nivån av individuella celler
Abstract [en]
This thesis leverages the power of single-cell RNA and ATAC sequencing to enhance our understanding of the innate and adaptive immune systems in higher mammals. The primary focus is on the transcriptional networks that guide the activation and differentiation of human primary CD4+ T cells into Th1, Th2, Th17, and iTreg subsets, using a GMP-based protocol and ex vivo/in vitro approaches. Additionally, computational models for gene regulatory network (GRN) inference and analysis were employed to elucidate gene regulation using a data-driven, multi-omics approach. This research also encompasses viral response-related studies to provide a comprehensive view of the immune response, specifically targeting the central nervous system (CNS) upon TBEV infection and lung tissues during SARS-CoV-2 infection.
In Paper 1, a multi-omics linear and non-linear approach is developed to predict gene popularity using a large number of high-throughput sequencing datasets. We show that additional omics layers are beneficial to construct GRNs capable of accurately predicting gene popularity. In Paper 2, a comprehensive atlas of human primary CD4+ T cell activation and differentiation is created using in vitro cell differentiation and single-cell RNA and ATAC sequencing. Novel gene regulatory dynamics of JUNB are identified, and a new probabilistic approach based on Markov chains for GRN analysis and interpretation is introduced. In Paper 3, the connection between type I interferon response in the mouse brain and TBEV infection is explored using single nuclei RNA sequencing. In Paper 4, the role of intrinsic resistance factors in human COVID-19 susceptibility is investigated using both single-cell and bulk RNA sequencing, and identifies SERPINS as critical regulators of the process.
The findings of this thesis contribute significantly to the understanding of transcriptional networks governing human CD4+ T cell differentiation and activation. This work aims to improve therapy and demonstrate the efficacy of NGS and computational tools in deciphering the transcriptional networks involved in various viral infections.
Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2024. s. 84
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2332
Nyckelord
scRNA-seq, scATAC-seq, snRNA-seq, innate immune system, adaptive immune system, CD4+ T cells, Th1, Th2, Th17, iTreg, gene regulatory networks, community detection, multi-omics, tick-borne encephalitis virus, SARS-CoV-2, NGS, SERPIN, type I interferon, mouse, human
Nationell ämneskategori
Cell- och molekylärbiologi Bioinformatik (beräkningsbiologi) Immunologi Genetik och genomik Bioinformatik och beräkningsbiologi
Forskningsämne
molekylärbiologi; genetik; biologi; immunologi; datalogi
Identifikatorer
urn:nbn:se:umu:diva-231112 (URN)9789180705462 (ISBN)9789180705479 (ISBN)
Disputation
2024-11-25, Major Groove 6L, Norrlands universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
2024-11-042024-11-012025-02-05Bibliografiskt granskad