Adaptation of avian influenza virus polymerase to humans during pandemic emergence.

Influenza viruses cause intermittent pandemics and seasonal outbreaks that affect millions of humans every year. My goal is to chart the adaptation of influenza virus to the human host from emergence from birds, often associated with severe infections, to endemicity as a seasonal flu virus. I will focus on the viral polymerase because it is a key determinant of host range, pathogenicity and viral evolution. Using next generation sequencing we will establish accurate quantification of the viral polymerase error rate to test whether polymerase constellation determines pandemic potential. Polymerase interacts with a plethora of host proteins, some permissive and others that restrict it. We recently discovered a key host factor, ANP32A, that differs between birds and mammals and explains the major barrier to avian influenza virus polymerase activity in humans. We will uncover the mechanism by which this host factor supports viral replication using a combination of familiar and novel techniques. We will also discover other species-specific host factors that act on polymerase to support or restrict it. Finally, we will explain why partially adapted avian viruses lead to a devastating cytokine storm in humans they infect, as this may guide therapeutic options and inform pandemic preparedness plans.