Objectives
COMBINE strives is to create a versatile experimental pipeline that serves as a blueprint for ad hoc cross-country collaborations aimed at developing novel drugs and vaccines against emerging viruses. The project will significantly advance our understanding of how viruses enter cells, using Marburg virus (MARV) as a model. To reach this goal COMBINE has set the following four objectives:
1. Molecular analysis of the virus-host cell interface
COMBINE aims to study how MARV interacts with host cell factors during the critical first step of infection—when the virus attaches to the cell. Specifically, focussing on understanding how these host factors vary between different tissue types. This research will give a detailed picture of how MARV attaches to cells and will identify potential tissue-specific receptors that the MARV uses to infect different parts of the body.
2. Identification of host cell and viral PTM fingerprint
The unique post-translational modifications (PTMs) of the MARV glycoprotein in different tissues will be identified. Furthermore, it will be examined how these modifications affect its ability to bind with specific cellular proteins involved in virus cell entry. Comparing viral PTMs with the modifications on host cell surface proteins will provide insights into how MARV targets specific tissues, manipulates host cells to suppress immune defences, enhances replication and adapts to invade new ones.
3. Characterising the dynamics of virus-receptor interaction & mechanism of virus uptake
COMBINE will investigate how the identified host cell proteins are organised in live target cells and how they respond to MARV infection, using advanced microscopy tools. By tracking individual viruses and using multi-colour imaging, it will be examined how MARV enters cells, from cell attachment and receptor activation to cell uptake. This will allow us to understand the full process of virus entry.
4. Interference with virus entry
Building on the new understanding of virus-host cell interactions we will screen for small molecules with the potential to block these interactions and prevent infection at an early stage. Since MARV uses multiple pathways to infect cells, combinations of small molecules that target different pathways simultaneously will also be explored. The gained knowledge will help design improved universal vaccine candidates that activate both antibody production and T-cell responses.