Investigating HCMV-Driven Alterations in the Virus Microenvironment

Abstract

Human cytomegalovirus (HCMV) is a master manipulator of host cell biology, not only altering directly infected cells but also reshaping the surrounding tissue environment through secreted factors. In this study, we uncover how conditioned media (CM) from HCMV-infected fibroblasts exerts rapid and transient effects on neighboring uninfected cells, reprogramming their proteome and phosphoproteome in a manner that bypasses classical immune signaling. Central to this paracrine reprogramming is the activation of mitotic kinases such as CDK1, CDK4, AURKB, and particularly Aurora kinase A (AURKA); a master regulator of mitosis and interphase remodeling. We demonstrate that AURKA is both induced and phosphorylated in recipient cells exposed to CM, even in the absence of extracellular vesicle (EV) trafficking and type I interferon pathways. These findings suggest that HCMV-infected cells secrete non-vesicular, non-canonical factors capable of mimicking proliferative cues. Beyond its well-characterized mitotic roles, AURKA also governs mitochondrial dynamics, ciliary disassembly, and DNA replication licensing; functions that viruses increasingly exploit to favor replication and immune evasion. The engagement of AURKA by paracrine signaling thus represents a novel strategy by which HCMV may prime the surrounding cellular landscape for enhanced viral fitness or persistence. Our data support a model in which the virus-modified environment (VME) serves not only as a reservoir of viral proteins and EVs but also as a conduit for soluble signals that transiently rewire the cell cycle and stress response pathways of uninfected bystanders. These insights position AURKA as a potential therapeutic node at the intersection of viral pathogenesis, host cell cycle control, and long-term tissue homeostasis.