Characterization of the molecular mechanisms that prevent successful adaptation of avian influenza virus to the human host: the nuclear import of incoming vRNPs

• Applicant: Professor Dr. Martin Schwemmle
• Subject Area: Virology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260781967

To establish a new virus lineage in humans, avian influenza A viruses have to adapt to the new host and its innate immune system. We could recently identify adaptive mutations in the viral nucleoprotein (NP) that are required to achieve resistance against the human restriction factor MxA. These adaptive mutations are highly conserved in circulating human strains and virtually absent in avian strains. Interestingly, introduction of these adaptive mutations into the NP of A/Thailand/1(KAN-1)/04 (H5N1) results in a strong attenuation in the absence of MxA. Indeed, acquisition of these adaptive mutations is still accompanied by partial attenuation in other viruses. The reason for this attenuation is unknown. Preliminary evidence indicates that the nuclear import of vRNPs harboring MxA-adaptive mutations is disturbed even in Mx-negative cells. The goal of this project is to unravel the molecular mechanisms that are responsible for this defect in nuclear vRNP import. Specifically, we want to identify the cellular factors that mediate nuclear import of vRNPs harboring these adaptive mutations in NP by biochemical and genetic approaches. Furthermore, we want to identify the compensatory changes that had occurred in seasonal influenza viruses to overcome this attenuation. Finally, we want to analyze a presumably new strategy of the human derived H7N9 (A/Anhui/1/2013) to allow unhindered nuclear vRNP import and viral growth despite the presence of Mx resistance amino acids in NP. With these studies we want to challenge our hypothesis that nuclear import of vRNP represent a major barrier for avian influenza A viruses during the adaptation process to humans. These studies may also contribute to estimate the pandemic potential of the human H7N9 isolates.

• DFG Programme: Research Grants