Bovine Lactoferrin Inhibits Pseudorabies Virus Attachment Through Blockade of Glycoprotein C-Heparan Sulfate Interaction.

Pseudorabies virus (PRV) is an important swine pathogen that causes significant economic losses in the pig industry. In addition to its swine host, PRV also infects a wide variety of animals as well as humans, posing a threat to veterinary public health. Thus, the development of potent antiviral drugs against PRV is required. Bovine lactoferrin (BLF) is widely known as an iron-binding glycoprotein in the transferrin family, which gains great attention for biomedical applications due to its beneficial physiological functions to human health as an antioxidant, antimicrobial, antiviral, anticancer, and immunomodulatory agent. In the work described here, we identified BLF as a novel and potent antiviral agent against PRV. BLF exhibited strong antiviral activity against PRV infection in multiple pig, human, and mouse permissive cells. Systematic analysis of the effect of BLF on PRV inhibition revealed that BLF blocks PRV attachment to target cells. Through surface plasmon resonance (SPR) analysis, BLF was demonstrated to directly interact with heparan sulfate (HS) proteoglycan (HSPG), a primary attachment receptor for PRV. Addition of exogenous HS completely abolished BLF inhibition of PRV attachment, demonstrating that BLF represses PRV attachment by interacting with cell-surface HS. However, BLF failed to inhibit the attachment of a PRV mutant virus with the deletion of glycoprotein C (gC), the primary viral envelop component for HS binding, suggesting that PRV gC is required for BLF inhibition of PRV infection. Cumulatively, these findings demonstrated that BLF inhibits PRV attachment by binding cell-surface HS to block the interaction between viral gC and HS.