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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Endothelial programs that activate or blunt antiviral responses

Alternative title: Hvordan endotel hemmer eller fremmer antivirale vertsresponser

Awarded: NOK 9.1 mill.

Project Number:

302191

Project Period:

2020 - 2024

Location:

Endothelial cells (the inner cellular layer of blood vessels) are central players in viral disease. This has been best demonstrated in avian influenza, where the ability to infect endothelial cells is closely linked to the virus' potential to cause disease. Many other viruses of great importance to human and animal health infect and replicate in endothelial cells, but we do not know if this is important for disease development. Furthermore, an even larger number of viruses upset vascular function, leading to disturbed coagulation, loss of vascular integrity, and uncontrolled inflammation. This is very evident in COVID-19, which causes severely disrupted coagulation in many patients. Despite all this, it is not clear how the interplay between virus and endothelial cells influence the outcome of viral infection. In this project we use infectious salmon anaemia virus as a model. By profiling thousands of individual cells from infected fish, we seek to identify cellular profiles that promote or inhibit viral replication. We will also explore if the virus may use endothelial cells as a hiding place to escape detection by the immune system. Finally, we will purify and analyse endothelial cells from infected salmon to understand how the infection disturbs vascular function. The project will increase our knowledge of the general crosstalk between virus and cells during infection, especially with regards to effects on the vascular system and whether infection of endothelial cells may influence the ability of the host to eliminate viral infection. The project will also strengthen our ability to control and fight infectious salmon anaemia, a disease with great economical and welfare consequences to the salmon farming industry, and that has sharply risen in prevalence in Norway over the past 2 years.

Endothelial cells are central players in the pathogenesis of viral disease. The ability to infect endothelial cells (the inner cellular layer of blood and lymphatic vessels) is a hallmark of the conversion from low to high pathogenic avian influenza, and when high pathogenic H5N1 is prevented from replicating in endothelial cells, it no longer causes disease. A range of viruses with high relevance to human health infects endothelial cells, including ebola, dengue, hanta, measles, and human herpes virus 8, and even more interact with the endothelium to severely disturb coagulation, vascular integrity, and the ability to control inflammation. This project will be the first to dissect viral infection of the endothelium at the single cell level and has significant potential to underpin novel strategies to treat viral disease. I will map the coregulation of host and viral genes during active infection of the endothelium in tissues and purified cells from infected Atlantic salmon by use of single cell transcriptomics and deep RNA sequencing. The project will break new ground by: 1. Identifying cellular profiles that permit or limit viral replication 2. Characterising endothelial programs that activate or blunt immune cell activation in response to virus 3. Revealing mechanisms that confer virally induced vascular pathology The project is embedded in an excellent project group of international and national researchers in bioinformatics, single cell techniques, vascular biology, virology, and immunology, and contains all elements necessary to ensure success. It adheres to the call and UN sustainability goals by using a bold and original approach to address important knowledge gaps, and by allowing me, the project manager, to produce high quality publications and acquire advanced skills in bioinformatics that together with my strong background in immunology creates a dual competence that enhances my competitiveness for future grants and collaborative projects.

Publications from Cristin

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Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol