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A multipronged approach to characterize interferon lambda 4

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandlingForskning

The interferons (IFNs) are classic antiviral cytokines, which constitute a crucial first-line of defence against infections. They are divided into three groups where the primary role of the type III IFNs, also known as IFNλs, appears to provide an efficient first line defence of mucosal surfaces. The family of IFNλs includes four members: IFNλ1, -2, -3, and -4. The newest member, IFNλ4, is encoded by the IFNL4 gene, which is a pseudogene due to a single nucleotide polymorphism (SNP) located inside IFNL4 in a proportion of the human population. Genetic variation within the IFNL4 gene has been associated with poor spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infections as well as fibrosis development in patients with non-alcoholic fatty liver disease (NALFD), hepatitis B virus, and HCV.
In this thesis, I present work, which reveals that the IFNL4 possesses a functional promoter and that the expression of this gene is quite different compared to the three other IFNλ family members. These conclusions are based on studies of IFNL1-IFNL4 promoter chimeras as well as carcinoma cell lines expressing high levels of IFNL4 mRNA. Furthermore, I present my effort in order to create an in vitro cell system to study the influence of IFNL4 SNPs on the IFN response and inflammation by the use of CRISPR/Cas9 technology, which in time might be able to provide a cell system to study the functional IFNλ4 haplotypes.
I then present data, which demonstrate that the IFNL4 can affect the progression of NAFLD. Based on several IFNαR1 knockout studies in mice and IFNα treatment of rats showing reduction in liver fibrosis, I hypothesise that treatment of an animal model of non-alcoholic steatohepatitis (NASH) with rat IFNα potentially could reduce fibrosis. Therefore, I purify rat IFNα before performing a treatment study on a rat animal model of NASH. I present results showing that the treated animals, contradictory to expectation, develop a higher degree of fibrosis. Additionally, I analyse the genetic of three IFNL4 SNPs in a cohort of Danish NAFLD patients, which show a significantly different distribution of the SNPs compared to reference cohorts as well as a significant association between the non-functional IFNλ4 haplotype and liver fibrosis.
The final part of this thesis concerns the relationship between IFNλ and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as COVID-19. I investigate the first line of defense against SARS-CoV-2 by studying the IFN response of the alveolar macrophages (AMs). The results revealed that AMs are efficient producers of IFNs upon challenge with respiratory virus such as influence A and Sendai virus, however, not upon challenge with SARS-CoV-2. Finally, I also present data on the genetic influence of IFNL4 upon the susceptibility towards SARS-CoV-2 infection or the following adaptive immune response towards the virus, however, I do not find any differences between the functional IFNλ4 haplotypes.
Antal sider198
StatusUdgivet - aug. 2021

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