Approach
Virus infection begins with the attachment of the virus to host cells and subsequent activation of cellular receptors, triggering signalling pathways that lead to viral entry and genome delivery. Identifying the cellular attachment factors and mechanisms involved is crucial for understanding and stopping infections. However, the transient nature of virus-cell binding and the rapid progression of infection make this a challenging endeavour. Still, therapeutic molecules that prevent virus attachment and entry are crucial for stopping infections early and are essential for pandemic preparedness.
The COMBINE project follows a three-step approach to investigate the virus-host cell interaction and cellular uptake of Marburg virus (MARV). To specifically target virus-plasma membrane interactions, a unified inverted attachment platform that enables us to halt and synchronize infection at the cell binding stage will be employed. Our approach is compatible with BSL4 conditions and integrates multi-Omics technologies.
COMBINE will not only reveal new insights on MARV cell entry and tissue tropism but develop the approach into a blueprint experimental pipeline for the streamlined identification and antiviral targeting of proteins involved in the virus attachment process. This will include standardised protocols and training workshops to accelerate and diversify the development of therapeutic options against MARV and other viruses.
Identification
The unique combination of advanced technologies unified by a synchronized infection assay will allow us to identify the key virus and cell components involved in infection – the signature of virus-cell activation. This involves detecting plasma membrane attachment factors and functional receptors that the virus uses to bind and enter cells.
Characterisation
The next step is to characterise the roles of the identified key viral and cellular components (i.e. proteins) in the infection process. To achieve this, multi-Omics screening, including proteomics, imaging, and interaction studies, will be used to pinpoint virus-host cell activation markers in a tissue-specific manner. This will help us learn how these proteins are changed after they are made and how they work together to help the virus enter the cell. The goal is to build a mechanistic model of how MARV enters cells and which proteins are critical for this process.
Inhibition
The final step is to target the identified interactions with antiviral strategies and block virus-cell entry. To achieve this high-throughput compound screening will be used to find small molecules that can block the virus-receptor interaction or activation. By interfering with the identified viral entry factors, COMBINE aims to prevent MARV from infecting cells. The insights into how proteins in different tissues are modified during infection could aid in the design of improved vaccine candidates.