Molecular Mechanisms of Defective Viral Genome Formation and Immune System Interaction in Influenza Viruses

• Applicant: Professorin Dr. Linda Brunotte
• Subject Area: Virology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569051248

Defective viral genomes (DVGs) are naturally occurring viral products harboring internal deletions that have emerged as promising antiviral candidates due to their ability to interfere with viral replication and modulate immune responses. While DVGs have demonstrated therapeutic potential against influenza viruses, they have also been implicated in excessive immune activation in highly pathogenic avian influenza (HPAIV) strains. Despite their significance, the molecular mechanisms underlying DVG formation and their interaction with the host immune system remain poorly understood. Our preliminary data indicates that DVGs patterns produced during infection are virus-specific, and that not all DVGs are ligands for immune sensors. We hypothesize that severe disease induction in HPAIV is related to the formation of specific immune activating DVGs. The objective of this proposal is to elucidate the mechanisms of DVG formation in influenza viruses and to characterize their packaging and interaction with the immune system. Using a multidisciplinary approach, comprising established and new methodologies from virology, immunology, and RNA biology, we will analyse the DVG landscapes of several influenza viruses and determine how the differences relate to viral RNA sequence, RNA structure, and the activity of the viral RNA polymerase. Furthermore, we will determine which DVGs are packaged into viral particles and examine how DVGs stimulate the immune system. Finally, we will employ human lung explants and organoids to explore the formation and therapeutic potential of selected DVGs. Taken together, this project will lead to a mechanistic model of DVG formation, identification of key structural motifs governing immune activation, and development of criteria for selecting therapeutic DVGs. This comprehensive understanding will advance our knowledge of virus-host interactions and potentially guide the development of more effective antiviral strategies based on DVG biology.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Dr. Redmond Smyth, Ph.D.