Sir William Dunn School of Pathology
Influenza virus replication at the molecular level.
Our laboratory focuses on the fundamental molecular mechanisms of influenza virus replication, aiming to understand the molecular determinants of host range and virulence of influenza viruses.
Specifically, we address questions ranging from how the influenza virus RNA polymerase transcribes and replicates the segmented negative-sense viral RNA genome in the nucleus of the infected cell to how the RNA genome is exported from the nucleus and assembles into infectious progeny virus particles. The RNA polymerase is a major determinant of the virulence and host range of influenza viruses, and is a key regulator of the adaptation of avian influenza viruses to mammalian hosts. We are also interested in the role of host factors in viral replication as well as in understanding the effects of virus infection on the host cell, the molecular mechanisms of innate immune sensing and host cell responses to viral infection. Our group collaborates with structural biologists, physicists, chemists and immunologists using an inter-disciplinary approach including molecular and cell biology, proteomics, single molecule and super-resolution microscopy, structural biology (x-ray crystallography and cryo-electron microscopy), and virology (reverse genetics).
Currently there are several projects available in the group, covering the structural and functional aspects of the influenza virus RNA polymerase, the mechanisms of transcription and replication of the influenza virus RNA genome, as well as virus-host interactions and cellular responses to viral infection. These projects build on our recent successes in expressing and purifying large amounts of recombinant influenza virus RNA polymerases from type influenza A, B and C viruses and their structural analysis by x-ray crystallography and cryo-electron microscopy (Hengrung et al Nature 2015) and our technical breakthrough in isolating the replicative intermediate of influenza virus, the complementary ribonucleoprotein (cRNP) complex, from infected cells (York et al PNAS 2013). Through our work on the RNA polymerase, we also discovered that defects in viral RNA genome replication result in the generation of subgenomic viral RNAs that lead to the activation of innate immune responses via detection by the cellular sensor RIG-I. Candidates will have the opportunity to familiarize themselves with current work in the group and discuss different opportunities and directions before deciding for a particular project.