On 30 March, the Infection Program of the Amsterdam institute for Infection & Immunity (AII) announced its grant call for urgent research on Covid-19. Even with a tight submission deadline of 17 April, we received 28 high quality proposals from a diverse range of clinical and fundamental researchers. Each grant was reviewed by up to 10 reviewers and the final funding decisions were made by the Directors of AII.
Screening of COVID-19 antibodies
The first funded proposal is led by Marit van Gils from the Department of Medical Mircobiology entitled Screening of COVID-19 antibodies using binding kinetics and epitope binning for the selection of optimal therapeutic candidates and will be done in collaboration with Sanquin. Van Gils and her collaborators have recently isolated >400 SARS-CoV-2 specific monoclonal antibodies from four recovered COVID- 19 patients and selected the monoclonal antibodies with the highest binding capacity to the virus S protein.
This project will provide essential information on the best functional antibody characteristics from this large library of anti-SARS-CoV-2 antibody candidates. This will allow for rapid selection of the most potent convalescent sera for therapies in critically ill patients, generate hyperimmune Intravenous Immunoglobulin for prophylactic treatment of risk groups, and select the best monoclonal candidates for therapy.
Impact of autophagy-based therapies
The second funded proposal is led by Carla Ribeiro from the Department of Experimental Immunology entitled Fighting COVID-19 from the inside: Impact of autophagy-based therapies on intestinal SARS-CoV-2 dissemination and will be done in collaboration with the Tytgat Institute and the University of British Columbia.
Several research groups have recently reported viral RNA and infectious SARS-CoV-2 virus in the stool of infected patients as well as in wastewater. These findings, together with expression of SARS-CoV-2 entry molecules in human intestinal epithelium, strongly suggest fecal-oral transmission as an additional and potentially longer-lasting SARS-CoV-2 transmission route. In this project, Ribeiro and colleagues will use ex vivo human gut tissue model to study how the virus manages to enter the gut, the impact of virus infection on intestinal barrier function, and identify repurposable autophagy drugs that suppress virus replication in the gut.
The third funded proposal is led by Jeroen den Dunnen from Rheumatology and Clinical Immunology and will be done in collaboration with the departments of Medical Biochemistry, Medical Microbiology, and Sanquin. During SARS-CoV-2 virus infection, the early presence of IgG antibodies against the virus spike protein may contribute to severe acute lung injury.
Previous work by den Dunnen and colleagues identified that IgGs can convert wound-healing “M2” macrophages to a pro-inflammatory phenotype. Here, they will apply their tools and knowledge to identify a potential novel way to modulate macrophage activation in COVID19 patients.
Heparan sulphates as molecular traps
The fourth funded proposal is from two senior well-known Amsterdam UMC scientists: Prof. dr. Theo Geijtenbeek and Prof. dr. Rogier Sanders and is entitled Heparan sulphates as molecular traps to block SARS-CoV-2 infection. It is a collaboration between the department of Experimental Immunology and the department of Medical Microbiology. Geitjenbeek and colleagues have recently identified that low molecular weight (LMW) heparins are potent inhibitors of SARS-CoV-2 infections in vitro.
In this project, they we will investigate whether heparins can be used as prophylactics or therapeutics to prevent SARS-CoV-2 infection. Because these compounds are already used in the clinic as anticoagulant drugs, positive preclinical findings from this project could rapidly progress into clinical trials, potentially leading to another drug tool that can be used to fight the ongoing pandemic. Moreover, this proposal will strive to enable in vitro culturing of viable SARS-Cov-2 virus under strict conditions in Amsterdam UMC.