Comparative signature of Marburg virus cell activation as a blueprint for the identification of antiviral targets against newly emerging viruses

Identifying cellular attachment factors and functional receptors plays a critical part in developing an understanding of a newly emerging virus. However, the identification and therapeutic targeting of plasma membrane proteins critical for virus infection is often difficult due to the transient nature of virus-cell binding and the overall kinetics of the infection process. Our goal is to interrogate virus-host cell interaction and cellular uptake of Marburg virus (MARV), a highly pathogenic and clinically relevant member of the filovirus family. To specifically target virus-plasma membrane interaction we will use a unifying inverted infection platform that allows us to halt and synchronize virus infection at the cell binding stage. Our approach is compatible with BSL-4 environment and multi-Omics technologies. It will allow us to identify the signature of virus-host cell activation, i.e., proteins involved in virus-cell entry in a tissue-specific manner. This screen will be complemented by an innovative combination of proteomics, virus-host cell interaction analysis and imaging approaches to pinpoint and characterize the involved cellular and viral proteins, their post-translational modifications and how they mechanistically concert in viral uptake. Our unique combination of different technologies will lead to the identification of viral and cellular interaction partners which will in parallel be specifically targeted by high-throughput compound screening to identify small molecules that inhibit virus-receptor interaction. Moreover, we will use our gained knowledge of tissue-specific post-translational modifications to develop improved vaccine candidates as additional prophylactic countermeasures against MARV. Our project will further deliver a blueprint experimental pipeline for the streamlined identification and antiviral targeting of proteins involved in the virus attachment process, a critical cornerstone of pandemic preparedness.