Project number 8

Influenza virus biology at the host-pathogen interface: towards new therapeutics

Each year, human influenza viruses claim more than 250.000 lives. These respiratory pathogens are extremely well adapted to human as evidenced by their capacity to swiftly evade the innate and adaptive immune response of their host. From an evolutionary perspective, influenza viruses thrive at a delicate balance between robust replication and allowing the host to mount a sufficiently strong immune response such that the host survives and ensures virus transmission. At the molecular level, this balance is controlled by delicate interactions between the viral gene products and host factors. Many of these interactions remain unexplored and new knowledge in this area has the potential to lead to new, much needed anti-influenza therapeutics. This project application is hypothesis driven and will focus on a limited set of host factors with a likely but hitherto unexplored role in influenza virus pathogenesis. The contribution of these factors will be studied by taking advantage of unique mouse strains with conditional (in time and in different cell types) genetic defects in the corresponding genes. These mice will be subjected to primary and secondary influenza A virus challenge and the ensuing disease and viral replication will be monitored at different time points after challenge. Parameters include body weight changes, histopathology, virus replication, innate and adaptive antiviral immune responses. In vivo findings will be recapitulated in state of the art in vitro cell systems, including primary airway epithelial cell cultures and CRISPR/Cas9 mediated gene ablation. It is anticipated that this project will result in fundamental new knowledge on the interactions between influenza viruses and the human host.
This project proposal integrates the expertise and knowledge in mammalian inflammatory pathogenesis from the group of Geert van Loo (IRC) with the Influenza expertise of the Molecular Virology group of Xavier Saelens (MBC). Work distribution of the successful candidate between the two labs will be 50/50.

Keywords
influenza, host-virus interactions, in vivo mouse targeting and disease modelling, therapeutic

Supervisors
Xavier Saelens, VIB Medical Biotechnology Center, UGent, Gent
Geert van Loo, VIB Inflammation Research Center, UGent, Gent