Bovine lactoferrin confers antiviral effect against La Crosse virus by interfering with virus-heparan sulfate proteoglycan binding.

La Crosse virus (LACV) is a mosquito-borne orthobunyavirus within the California serogroup that primarily causes neuroinvasive disease in pediatric populations in the upper Midwestern, mid-Atlantic, and southeastern states of USA. Despite its substantial impact on public health, no vaccine or effective antiviral treatment has been developed so far. In this study, we investigated the role of the cell-surface heparan sulfate proteoglycan (HSPG) in LACV cell attachment and assessed the in vitro antiviral potential of bovine lactoferrin (bLf), which interacts with both the cell surface molecules and HSPG. Our results demonstrated that HSPG facilitates LACV infection and that bLf inhibits this process in a dose-dependent manner. These observations suggest that the antiviral mechanism of bLf may involve competitive inhibition at HSPG receptor sites, thereby preventing viral attachment to the host cell membrane. This provides further insights into the antiviral activity of bLf against LACV.