Unravelling the features of Influenza as entry mechanism

Influenza virus is the causative agent of the ‘flu’. According to the World Health Organisation, Influenza causes up to 5 million cases of severe flu and 500 000 deaths annually. To release its genome inside the cell and start an infection, Influenza virus must fuse its envelope with the endosomal membrane of the host, making this process an excellent drug target. In order to attempt to control, or better yet, eradicate this pathogen, a greater understanding of its entry mechanism, a fundamental aspect of the viral life cycle, is required. It is well established that Influenza A virus (IAV) fusion is driven by the viral glycoprotein hemagglutinin (HA), which when exposed to low pH transitions from a meta-stable pre-fusion to post-fusion state. However, it is becoming increasingly apparent that the ionic balance of the endosomes also has a significant role in the entry of enveloped viruses. Specifically, our preliminary studies on Influenza virus suggest that K+ concentrations within the endocytic pathway play a significant role in Influenza A fusion events. Through the use of broad-spectrum K+ channel inhibitors, a dose-dependant reduction in Influenza infectivity in tissue culture can be observed. Further to these studies, we have isolated Affimers (novel antibody-like proteins that can be produced in large quantities in E. coli) that recognise HAs from different Influenza subtypes (H3N2 and H1N1). Using these Affimers, we aim to develop an early detection method to distinguish between bacterial respiratory infections and ‘the flu’ to alleviate mounting pressures on an already diminishing antibiotic treatment system.