The role and mechanism of the interplay between the interferon system and autophagy in anti-viral defenses and infection-induced inflammation

• Applicant: Dr. Konstantin Sparrer
• Subject Area: Virology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561980062

For effective control of viral pathogens, a concerted and rapid innate immune defense is essential. Coordinated innate immune activity also prevents detrimental aberrant or chronic inflammation by introducing checks and balances. The interferon (IFN) system and autophagy are two integral parts of innate immunity. However, the molecular interplay between the IFN system and autophagy is currently poorly understood. We found that IFNs induce de novo autophagy via an unusual STAT1/STAT5B transcription factor dependent pathway inducing autophagy-associated controlled genes such as RSAD2 and SOCS1. Notably, autophagy induced by Sendai Virus infection was almost exclusively dependent on STAT5B. Furthermore, our results show that IFN or virus-induced inflammatory gene expression is elevated in the absence of autophagy. Thus, I hypothesize that IFN-induced autophagy contributes to the termination of (pro-)inflammatory cytokine signaling to prevent excessive inflammation. Our aim is to define the molecular mechanisms leading to IFN-induced autophagy and their implications in anti-viral defenses and proper termination of inflammatory responses. To achieve this, we will dissect the impact of STAT1/5B controlled FN-stimulated genes that mediate autophagy induction. Next, we will explore formation of STAT5B/STAT1 heterodimers and contribution of IFN-mediated autophagy to total autophagy induction during infection with model respiratory pathogens Coronavirus 229E, Respiratory Syncytial virus and Influenza A virus. Furthermore, we will determine the impact of IFN-induced autophagy on innate restriction of these viruses. To clarify how IFN-induced autophagy modulates inflammation, we will monitor (pro-)inflammatory gene and cytokine expression and their stability in the absence and presence of STAT5B-dependent autophagy during late-stage respiratory model virus infections in air-liquid interface culture models. The proposed studies will establish the role of IFN-induced autophagy in viral infections and define how coordinated activity of the IFN system and autophagy may safeguard against excessive or chronic inflammation. Targeting IFN-induced autophagy may provide means to curb harmful inflammation. Beyond virology, our results will thus be relevant for diseases associated with pathogenic inflammation, such as cancer or neurodegenerative diseases.

• DFG Programme: Research Grants