Activation and function of the phosphatidylinositol-3-kinase signalling pathway in influenza virus infected cells

• Applicant: Professorin Dr. Christina Ehrhardt
• Subject Area: Virology
• Term: from 2008 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 61949045

Starting with a publication from our laboratory in 2006, the phosphatidylinositol-3 kinase (PI3K) and its role in influenza A virus (IAV) infection received increasing attention in the influenza research community. The PI3K was introduced as a seemingly antiviral acting signalling factor that is also misused by IAV to support its replication, early and late during the infection cycle. Within the current funding period we continued our investigations towards a requirement of PI3K in the IAV internalisation processes. First, we developed a rapid Western-blot procedure to detect virionassociated matrix protein (M1) during the entry process. Using this method we were able to unravel a novel mode of signalling-mediated IAV uptake into host cells. Receptor tyrosine kinases (RTKs) – activated by IAV binding - were identified as mediators of entry promoting signals across the cellular membrane. These findings introduced a completely novel concept of signalling induced uptake of IAV. Addressing additional aspects of the PI3K signalling network, we elucidated the requirement of CRK adapter proteins for efficient replication of avian IAV and control of JNK-mediated apoptotic responses. To complement our investigations we now aim to further study the role of the PI3K in IAV infected cells not only in vitro but in vivo, whereby we will characterise the PI3K class IA subunits. We will target up- and downstream signalling mediators of PI3K and assess their functional role, both in vitro and in vivo. Furthermore, the time dependent capacity of the viral NS1 protein as a differential regulator of particular signalling molecules or multi-protein complex formation in determining virus pathogenicity will also be in the focus of our interest.

• DFG Programme: Research Grants