The Role of the Nuclear Import Machinery in the Adaptation of Avian Influenza A Viruses to the Mammalian Host

• Applicant: Professorin Dr. Gülsah Gabriel
• Subject Area: Virology
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 123002173

By crossing the species barrier and adaptation to a new host, highly pathogenic avian influenza viruses (HPAIV) can give rise to mammalian strains including those causing human pandemics. It is known that the viral polymerase plays an important role in the adaptation of HPAIV to humans. Upon adaptation, the polymerase needs to be transported into the nucleus of the new host cell via its cellular import machinery to ensure virus replication. The adaptor proteins of the classical cellular import machinery, the importins (α1-α7), are highly divergent in chicken and humans. The role of the cellular import machinery in the adaptation of HPAIV to the mammalian host is largely unknown and therefore, is the aim of this research proposal. In the first part of this proposal, the individual importins will be identified which mediate the transport of the viral polymerase in avian and mammalian cells. These studies will provide direct evidence on species dependent specificity or redundancy of the individual importins mediating the nuclear import of the viral polymerase of HPAIV and human influenza viruses. In the second part of this proposal, the abundance and distribution of importins in primary, differentiated human airway cells will be studied. These findings will provide new insights into the role of the importins for the tropism of influenza viruses in the human airway. In the last part of this proposal, the in vivo role of the individual importins to virus replication and dissemination will be assessed using importin knockout mice. These studies will provide us with new molecular markers for host range and pathogenicity of influenza viruses and may eventually lead to new strategies for therapeutic interventions.

• DFG Programme: Independent Junior Research Groups