The role of autophagy during viral infection

• Applicant: Dr. Konstantin Sparrer
• Subject Area: Virology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419123537

Autophagy is an evolutionary highly conserved and intricately regulated degradation pathway. Importantly, it represents a powerful cell-intrinsic anti-viral defense mechanism and viral infections typically induce autophagy. During autophagy, cytoplasmic cargoes are engulfed by double-membrane vesicles, which are eventually degraded upon fusion with lysosomes. Cargoes can be viruses or viral components that are recognized by dedicated receptors and directly targeted for destruction. Additionally, by exposing pathogen-associated molecular patterns to immune receptors autophagy may facilitate recognition of viruses. Moreover, peptides generated from viral components during autophagy are presented to immune cells as viral antigens. However, viruses have evolved strategies to evade autophagy or exploit it to facilitate their replication. While the basic principles of autophagy are well-characterized, there is little known about infection-triggered autophagy and the interplay between autophagy and viruses. This project aims to characterize the role of key proteins during virus-induced autophagy and their impact on viral pathogens. Our preliminary data identified Tripartide Motif protein 4 (TRIM4) and TRIM20 as required for autophagy induced by influenza A virus (IAV), but not Herpes-simplex virus 1 (HSV-1). We intend to explore the molecular mechanism(s) underlying the virus specificity of TRIM-mediated autophagy and study the TRIM-dependent interplay between autophagy, viruses and other anti-viral defense pathways. Our preliminary data further indicates that TRIM23-related ADP-ribosylation factor (ARF) proteins are involved in autophagy. Using two important human pathogens, human immunodeficiency virus-1 (HIV-1) and IAV, we aim to study the impact and regulation of ARF-dependent virus-induced autophagy. Finally, we intend to explore the molecular mechanism(s) how ARF proteins mediate autophagy induction. Taken together, studying virus-induced autophagy may help to pave the way for novel anti-viral therapies based on autophagy. Furthermore, we will gain fundamental insights on key factors mediating virus-induced autophagy and the intricate interplay between viruses and human defense mechanisms.

• DFG Programme: Research Grants