Human respiratory syncytial virus (RSV) is the most common viral cause of severe lower respiratory disease in infants and young children worldwide. The global mortality rate due to RSV among infants and young children is between 66,000 and 234,000 per year. Currently, there is no licensed RSV vaccine or specific antiviral therapy available. Although a variety of approaches have been taken to develop a vaccine, host-pathogen interaction approach to identify effective countermeasures is currently underdeveloped. A genome-wide siRNA screen identified actin-related protein 2 (ARP2) as a host factor for RSV infection. RSV infection induced filopodia and increased cell migration in the respiratory epithelial cells. Filopodia are appeared to be a novel mechanism of cell-associated RSV spread. ARP2 contributes to filopodia-driven RSV cell-to-cell spread. The overall objective of this proposed research is to determine how RSV modulates the host cytoskeleton signaling in filopodia-driven cell-to-cell spread. Three specific aims are proposed to examine the central hypothesis is that RSV infection hijacks cytoskeleton signaling involved in actin polymerization and exploits it to facilitate cell-to-cell spread through filopodia. Aim 1, Delineate Rho GTPases cell signaling involved in RSV-driven filopodia induction for cell-to-cell spread; Aim 2, Identify cellular and viral factors for the filopodia-driven RSV spread; and Aim 3, Determine integrin signaling is an upstream regulator of the filopodia-driven RSV spread. This study will contribute significantly toward the understanding of a novel RSV spread mechanism. Additionally, they will lay the foundation for the identification of therapeutic targets to combat RSV infection.