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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Defining the immune cells in COVID-19 that correlate with disease severity

Alternative title: Undersøkelse av immunceller ved alvorlig covid-19-sykdom

Awarded: NOK 3.2 mill.

Sars-CoV-2-infected cells in the lungs and intestine spread virus infection to the environment and to neighboring cells. It is unknown why some patients develop severe inflammatory reactions in the lungs and breathing difficulties that require a respirator. It is also unknown which cells, signaling substances and processes cause the severe acute lung injury. It is possible that the injury may be linked to the immune system's failure to respond at the onset of the disease. In addition, it is possible that the immune system in some patients late in COVID-19 inappropriately overreacts causing a severe adverse immune response that damages the body's own tissues. The immune system limits virus infection through 1) making antibodies that block viruses from entering cells and 2) by killing virus-infected cells. Both responses are necessary for protection. In the project, we will use advanced mass cytometry to define 40 properties on single cells simultaneously on cells that develop in the inflammatory reaction. The Oslo university hospital has initiated a clinical study in which patients with severe COVID-19 can receive plasma from blood bank patients who have high neutralizing antibody levels. We will collect cells from the antibody recipients in the trial and define the effect of blocking antibodies on the inflammatory response. We will also collect samples from a study where the goal is to inhibit the malfunctioning and harmful immune response that may occur, but this study is currently on hold due to few relevant patients. We will also investigate family members participating in the Household Study where NIPH researchers recruit participants and collect blood from families where one or more have developed covid-19 disease. The project will benefit by contributing to our understanding of immune responses and adverse consequences of the sars-CoV-2 virus and in addition let us characterise the effect of transfer of protective antibodies to patients with severe COVID-19. We are currently hiring, have offered the position to an international top level candidate. The project has started by us and OUS, NIPH and UiO collaborators.

The ongoing COVID-19 pandemic requires information that could stratify patient treatment and new treatment options for the minority that develop fatal lung injury of unclear pathogenesis. Very few studies have focused on defining SARS-CoV-2 viral interaction with the host immune system, natural history and the pathogenesis of severe disease. This project is designed to discover important pathogenesis principles that may guide triage and choice of therapy, allow an understanding if immune inhibition should play a role, facilitate clinical trials and suggest novel biomarkers that can point to patients that risk developing life threatening lung disease. We propose a multidisciplinary groundbreaking study of material from COVID-19 patients that develop acute lung injury. We will define the pathogenic disease course and biomarkers of disease with single cell mass cytometry and RNA sequencing. Cells from two international clinical trial launched in accordance with the “Proposed next steps” in the 2020 WHO Roadmap will be compared for inflammatory signature. We ask what exact types and subsets of inflammatory cells that secrete pro-inflammatory cytokines, a cytokine storm and inflammation that destroys lung tissue. We ask if there is too weak or too strong immune responses in fatal COVID-19. We ask if convalescent patient serum with neutralizing antibodies can reduce the inflammatory cells that cause lung injury. We also ask if cell therapy with immune inhibitory decidua stroma cells (DSC) can negate the cellular inflammatory responses and fatal lung injury in COVID-19, but this study is currently on hold due to few relevant patients. Results will suggest new biomarkers for risk stratification, and triage, test the effect of convalescent serum and immune inhibitory DSC, have importance for the use of cheap anti-inflammatory medication in low-income countries, and will be disseminated in a European lab network to allow improved laboratory prediction of severe lung disease.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering