Heparan Sulfate Differentially Regulates Fibroblast Binding by Extracellular Vesicles and Human Cytomegalovirus

ABSTRACT

Extracellular vesicles (EVs) are lipid‐enclosed particles produced by cells as a vehicle of intercellular communication and cargo exchange. Virus‐infected cells produce EVs with altered cargo, which can include viral components. These EVs play functional roles in multiple aspects of viral infection. Their interactions with cells, including those occurring at the cellular surface prior to internalization, which are key to their subsequent functional effects, have not been studied extensively.

In this work, we investigate the role of cellular glycosaminoglycans (GAGs)—major constituents of the extracellular matrix (ECM)—in cell binding by EVs produced by homeostatic cells and those infected with human cytomegalovirus (HCMV). We show that EVs from both HCMV‐infected and uninfected cells interact with heparin, a highly sulfated form of heparan sulfate. However, in the context of binding to fibroblast cells, we show that heparan sulfate on both the cell and the EV surface inhibits EV‐cell interactions, while promoting attachment by human cytomegalovirus. Instead of GAGs, EVs were found to interact with other ECM constituents, namely collagen and fibronectin, on the fibroblast surface.

This work shows that heparan sulfate serves as a bi‐directional negative regulator of fibroblast binding by EVs, while acting as a positive regulator of HCMV attachment. Thus, EVs and HCMV appear to utilize distinct, non‐overlapping ECM ligands for cell binding, in both homeostasis and during HCMV infection.