A high throughput genetic screen to uncover novel antiviral mechanisms of the interferon system

Abstract

Abstract The innate immune responses provide the first line of host defense against virus infection. Type I interferon (IFN) system is a well-known mediator of the host innate antiviral responses. Virus infection is recognized by the cellular sensors, also known as pattern recognition receptors, which via a series of signaling pathways, induce the synthesis of IFNs and the IFN-stimulated genes (ISGs). The ISG-encoded protein products function as viral restriction factors, either by interfering with the stages of viral life cycle or by promoting cell death. We have shown that the IRF3, a key transcription factor responsible for inducing IFNs and ISGs, also provides antiviral responses by triggering apoptosis of the infected cells (Chattopadhyay et al Immunity, 2016). To investigate how the IRF3-inducible genes provide antiviral protection, we performed a high throughput genetic screen of human ISGs. Using an shRNA library of the human ISGs, we have identified a novel antiviral ISG, tudor domain containing 7 (TDRD7). TDRD7 inhibits virus replication by interfering with the cellular autophagy pathway, which is required for the replication a number of viruses. Mechanistically, TDRD7 inhibits the autophagy-initiating kinase, AMPK to suppress virus-induced autophagy pathway. We reported that multiple paramyxoviruses, including the clinically relevant human pathogens, respiratory syncytial virus (RSV) and human parainfluenza virus (HPIV3), are inhibited by the new antiviral mechanism of TDRD7 (Subramanian et al PLOS Pathogens, 2018). Using additional RNA and DNA viruses, which activate autophagy during infection, we are investigating whether the new antiviral mechanism similarly inhibits them.