Virus entry is a multistep process that triggers various cellular pathways that interconnect into a complex network; yet the molecular complexity of this network remains largely elusive. Here, by employing systems biology approaches, we reveal a systemic virus-entry network initiated by human cytomegalovirus (HCMV), a widespread opportunistic pathogen. This network contains ten functional modules (i.e., groups of proteins) that coordinately respond to HCMV entry. Functional modules activated (up- and downregulated) in this network dramatically decline shortly within 25 minutes post infection. While modules annotated as receptor system, ion transport, and immune response are continuously activated during the entire process of HCMV entry, those annotated for cell adhesion and skeletal movement are specifically activated during viral early attachment. The up-regulated network contains various functional modules, such as cell surface receptors, skeletal development, endocytosis, ion transport, and chromatin remodeling. Interestingly, macromolecule metabolism and chromatin remodeling module predominates this over-expressed system, suggesting that the fundamental nuclear process modulation is one of the most important events in HCMV entry. The entire up-regulated network is primarily controlled by multiple elements like SLC10A1. Thus, virus entry triggers multiple cellular processes especially nuclear processes to facilitate its entry.
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