Project Details
Projekt
Manipulation of nuclear determinants by Human Adenovirus to exploit PML nuclear bodies and chromatin regulators for efficient viral gene expression
Applicant
Professorin Dr. Sabrina Schreiner
Subject Area
Virology
Cell Biology
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 443644894
Incompletely defined initial steps of transcription and temporal silencing are decisive in the establishment of productive or persistent HAdV infections with potential reactivation events later that cause death in the absence of protective immunity. With the data obtained in the initial funding period, we plan a collaborative comprehensive approach to identify the interactions between HAdV types and host cell defenses with three objectives. (i) We will analyze the exact protein composition at the specific PML-NBs representing the sites of efficient viral DNA synthesis (vDNA-PML-NBs) and the molecular microenvironment at those foci in a time-resolved manner. (ii) We identified fractions of the HUSH component MPP8 at the sites of viral replication compartments prior to efficient re-localization into PML track-like structures, and observed proteasomal degradation of MPP8, TASOR, PPHLN and MORC2 by viral proteins. Unravelling this fine-tuned HAdV/HUSH regulation in detail and investigating the contribution of further HUSH regulators will help to understand the control of transcriptional silencing during lytic infection, persistent states and reactivation events. (iii) We will elaborate on the precise mechanism behind the critical and complex step from the early phase of infection in which early proteins are expressed to viral replication prior to late phase including the assembly of progeny virions. This event is called the early-to-late switch and we will analyze viral chromatin accessibility and repressor occupancy in dependency of our hit candidates that we identified in a genome-wide manner within the first funding period. In sum, we will then understand the hidden switches between silencing and activation of early versus late viral gene expression. Our focus will also extend to how these mechanisms differ among non-C-type HAdV (species A-G) that impede different entry routes and manifestations, enabling insights into how different viral species may employ distinct strategies for gene regulation and immune evasion. Ultimately, this planned project seeks to contribute to a comprehensive understanding of productive infection, reactivation and persistence leading to the development of innovative strategies for therapeutic purposes in a collaborative manner with DEEP-DV members.
DFG Programme
Research Units
