Identification of host restriction factors that block respiratory virus infection
Influenza and other viruses are an important cause of respiratory infections in humans. Respiratory viruses predominantly infect airway epithelial cells (AEC), resulting in productive virus replication. Many viruses, including seasonal influenza A virus (IAV), respiratory syncytial virus (RSV), parainfluenza viruses (PIV) and rhinovirus (RV) also infect airway macrophages (AMΦ), however replication is generally abortive and infectious progeny are not released. Of interest, highly pathogenic avian influenza (HPAI) H5N1 overcome this block and grow in AMΦ. We have shown that following seasonal IAV infection, both AEC and AMΦ rapidly induce thousands of genes, including hundreds of interferon stimulated genes (ISGs). While antiviral activity has been demonstrated for a small subset of ISG proteins, the vast majority have not been functionally characterised. Moreover, the specific host proteins that block respiratory virus replication in AMΦ are not known. We have identified a number of host-encoded proteins that can block infection and/or growth by a range of important human respiratory viruses, including seasonal IAV, RSV, PIV-3, RV and human metapneumovirus (HMPV). In addition, we have mapped growth of HPAI H5N1 in AMΦ to its hemagglutinin gene and identified at least one host factor that blocks seasonal, but not HPAI virus growth. Current projects aim to define the mechanisms by which specific host-encoded factors antagonise and block respiratory viruses and how virulent strains evade these host defences. This represents an important step towards the development of therapeutics targeting host cell proteins to control respiratory virus infections.
Functional consequences of coordinated integration of viral and bacterial immune sensing signals
The type and the expression pattern of innate immune sensing receptors in specific cell subsets determines the immunological outcome. Immune sensing of nucleic acid (e.g. tri- phosphate RNA by RIG-I) versus microbial molecules (e.g. LTA by TLR2, LPS by TLR4) induces distinct responses which are geared towards antiviral or antibacterial immunity respectively. However, the response of a simultaneous stimulation of host cells with bacterial and viral molecules in the course of a co-infection is much less understood. Such co-infections frequently occur during influenza viral infection, for example superinfection with pneumococcal pneumonia. Here we join forces with the Reading laboratory in Melbourne and our cooperation partners in Bonn (Kurts, Hoelzel, Schultze) i) to gain a better understanding of the coordination of bacterial and viral immune sensing signals and its impact on the course of viral and bacterial infection and the induction of adaptive immunity (PhD project 1), and ii) to clarify whether exosome formation by virus-infected cells and exosomal transfer to myeloid cells participates in the induction of an adaptive T cell response and the clearance of the virus on the single cell level (PhD project 2).