Adenovirus Cell-to-Cell Transmission: Insights into Lytic and Non-Lytic Egress Mechanisms

Adenoviruses (AdVs) are non-enveloped double-stranded DNA viruses that cause a wide range of human diseases and are widely explored tools for vaccination, oncolytic therapy, and gene delivery. While entry and replication are well studied, the mechanisms of adenovirus egress from the cell nucleus to the extracellular environment have remained poorly understood. Traditionally, the release of adenovirus particles from infected cells has been thought to occur through lysis of the infected cell. More recent evidence indicates that AdVs can also spread through non-lytic mechanisms in a much slower and understudied pathway. In this thesis, we used advanced microscopy techniques, proteomic profiling, and virological assays to dissect the lytic and non-lytic adenovirus egress pathways. The work explored how nuclear envelope integrity changes during infection, how viral and host factors contribute to different modes of virus release, and how specific viral proteins associated with lytic spread undergo maturation and trafficking within the host cell. Particular attention was given to the adenovirus death protein (ADP), a factor long implicated in promoting cell lysis. Together, the findings in this thesis establish a foundation for a mechanistic model underlying lytic and non-lytic adenovirus egress. The model highlights key cellular processes that influence whether infection proceeds through lytic or non-lytic spread. The work underscores the relevance of these pathways for adenovirus biology and the design of adenovirus-based therapeutics. $\textit{Full-text embargoed until: 2026-11-19}$