Project Details
Projekt
Mechanistic insights into the interferon-stimulated gene product zinc finger antiviral protein during lytic and latent human cytomegalovirus infection
Applicant
Professorin Dr. Melanie Brinkmann
Subject Area
Virology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 443644894
Pattern recognition receptors induce type I interferon (IFN) and interferon-stimulated gene (ISG) transcription upon recognition of viral infection. The ISG expression profile and their function(s) vary depending on the virus and cell type. Here, we focus on the relationship between the zinc finger antiviral protein (ZAP), an RNA-binding ISG, and human cytomegalovirus (HCMV), a herpesvirus which infects various cell types lytically and establishes lifelong latency in cells of the myeloid lineage. The antiviral and even proviral roles of ISGs have mostly been studied in cells promoting lytic HCMV infection, and we have shown in the initial funding period that ISG induction upon HCMV infection is efficiently counteracted by viral antagonists. Further, our previous work identified an antiviral role for ZAP during lytic HCMV infection, showing that ZAP directly binds HCMV transcripts and mediates their degradation. ZAP is differentially expressed as four isoforms (ZAP-S/-M/-L/-XL) with distinct antiviral functions, acting against a broad range of virus families. Yet many aspects remain unknown, including which of the ZAP isoforms are responsible for the antiviral phenotype, the molecular mechanism(s) by which ZAP acts antivirally during the immediate-early phase of the HCMV lytic replication cycle, and whether HCMV encodes ZAP antagonists. We will address these open questions while also investigating the role of ZAP during HCMV latency using our recently established iPSC-derived latency model. Additionally, we will examine ZAP’s effect on the herpesviruses HSV-1 and KSHV, adenovirus, and BK polyomavirus. This will allow an integrative analysis of cells supporting lytic replication and latency of HCMV using harmonised protocols and state-of-the-art bioinformatic analyses of the DEEP-DV Atlas, and will facilitate a comparison of the regulatory processes during early infection events across different nuclear DANN viruses.
DFG Programme
Research Units
