Abstract

Simple SummaryBovine viral diarrhea virus (BVDV) is a serious disease that affects cattle worldwide, leading to significant financial losses for the livestock industry. We know that the virus is dangerous, but we do not fully understand all the ways in which it spreads while remaining hidden from the animal’s immune system. In this study, we investigated how the virus creates tiny bridge-like connections called tunneling nanotubes (TNTs) to move directly from one cell to another. We discovered that a specific part of the virus binds to a protein inside the cow’s cells. This interaction triggers a biological “construction signal” that forces the cell to build these bridges. Once formed, these tubes allow the virus to travel safely to neighboring cells, avoiding the immune system’s defenses. Our research demonstrates that by blocking this specific host protein or the internal signaling pathway it activates, we can significantly reduce the formation of these bridges and hinder the virus’s ability to multiply. These findings are valuable to society because they reveal a new target for developing treatments or vaccines that protect animal health and ensure a more stable global food supply.Bovine viral diarrhea virus (BVDV), a significant global pathogen threatening cattle industries worldwide, presents substantial challenges for disease control. Its ability to infect cattle across all age groups, coupled with incompletely understood transmission mechanisms, complicates prevention and treatment strategies. We previously reported that BVDV induced tunneling nanotubes (TNTs)—F-actin-rich cytoplasmic connections between adjacent cells—and utilizes these structures for intercellular transmission. In this study, we used lentiviral transfection to express various structural and non-structural proteins of BVDV and identified NS5A as a critical viral protein that induces the formation of TNTs. RNA-seq analysis revealed that CKAP2, a host protein, plays a key role in TNT generati