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

Role of scavenger endothelial cells in elimination of virus

Alternative title: Eliminering av virus ved opptak i spesialisert opptaks ("scavenger") -endotel

Awarded: NOK 10.0 mill.

Blood borne virus is rapidly eliminated by the liver via mechanisms that are not well understood. Based on the recently emerging awareness that the liver sinusoidal endothelial cells (LSECs) are pivotal as scavengers of circulating large molecules and nano material, we hypothesize that the LSEC is a central player in the cellular arm of the anti-viral innate immune system. This theory will be studied by bringing together front-line interdisciplinary expertise in virology, optical nanoscopy, cell and molecular biology, and hepatology with the aim to study interaction of virus with LSECs to a level that has never before been attainable. We are one of very few laboratories that have access to fully functionally intact human LSECs. We will expose LSECs to several types of viruses and determine what receptors are involved in the uptake. We will use cutting edge live cell optical superresolution microscopy and correlative light and electron microscopy to follow the intracellular fate of viruses after entry into LSECs. We will study gene and protein expression in LSECs after uptake of virus and establish if treatment of the cells with selected immunomodulators can strengthen the LSEC anti-viral defense. Our studies are expected to reveal mechanisms of how pathogenic viruses enter LSECs, and how the cells can be stimulated to eliminate same viruses to avoid dissemination or latency. Our results will be important because there is an immediate need to find remedies to fight the increasing incidence of reactivation of e.g. dormant polyomavirus, and CMV associated with immunosuppressive therapy. The knowledge obtained will yield novel means of boosting hepatic metabolic elimination of normally pathogenic viruses. Moreover, the project will provide knowledge to control unwanted liver uptake of virus used as drug delivery vehicles. Results obtained in the report period 01.12.2022 to 30.11.2023: i) Continuation of in vivo studies to evaluate the organ and cellular distribution of bacteriophages, and pathogenic vs non-pathogenic viruses (model system: human and mouse betaherpesvirus) in mice. We have found that LSEC is an active player in addition to macrophages in the uptake of these viruses from blood. ii) Continuation of optimalization and establishment of methods for virus labelling, live cell imaging and quantification of virus in blood, tissues, and cells. iii) Continuation of studies on uptake and intracellular traffic of polyomavirus, betaherpesvirus, and bacteriophages in primary LSECs (mouse and human). Neuropilin-1 was found to be a binding receptor for muromegalovirus muridbeta1 in LSEC. iv) Continuation of studies on immune modulating effects in LSECs of pathogenic and non-pathogenic viruses.

Blood borne virus is rapidly eliminated by the liver via mechanisms that are not well understood. Most reports on hepatic uptake of virus have focused on Kupffer cells. Based on the recently emerging awareness that the liver sinusoidal endothelial cells (LSECs) are pivotal as scavengers of circulating large molecules and nano material, we put forward the hypothesis that the LSEC is a central player in the cellular arm of the anti-viral innate immune system. This will be studied by bringing together front line interdisciplinary expertise in virology, optical nanoscopy, cell and molecular biology, and hepatology with the aim to study interaction of virus with LSECs to a level that has never before been attainable. We are one of very few laboratories that have access to fully functionally intact human LSECs. We will expose LSECs to several types of viruses and determine what receptors are involved in the uptake. We will use cutting edge live cell optical superresolution microscopy and correlative light and electron microscopy to follow the intracellular fate of viruses after entry into LSECs. We will study gene and protein expression in LSECs after uptake of virus, and establish if treatment of the cells with selected immunomodulators can strengthen the LSEC anti-viral defense. Our studies are expected to reveal mechanisms of how pathogenic viruses enter LSECs, and how the cells can be triggered to eliminate same viruses to avoid dissemination or latency. Our results will be important because there is an immediate need to find remedies to fight the increasing incidence of reactivation of e.g. dormant polyomavirus, and CMV associated with immunosuppresive therapy. The knowledge obtained will yield novel means of boosting hepatic metabolic elimination of normally pathogenic viruses. Moreover, the project will provide knowledge to control unwanted liver uptake of virus used as drug delivery vehicles.

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

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