Type I IFN plays a major role in clearing mouse norovirus24–26. It is effective in limiting norovirus replication in human norovirus sub-genomic replicon culture system17. In spite of the well-established antiviral potency of type I IFN against noroviruses, IFN therapy is not translated into clinical practice because subcutaneous or intramuscular injection of IFN-α/β is associated with various side effects56,57. Our results, demonstrating the prophylactic antiviral activity of γ-PGA in mice using MNV-1 as a model for enteric viruses infecting the small intestine, accentuates its potential use as a safe and prophylactic candidate for the treatment of acute norovirus infection. Although norovirus infection is typically limited to an acute infection that lasts for 2–3 days in most healthy subjects58, it is associated with significant clinical outcomes with ~200,000 deaths related with gastroenteritis in children under 5 years of age59. In young children, the elderly, and immunocompromised patients for whom IFN might not be the best treatment option, γ-PGA can be used as an alternative prophylactic antiviral agent for HuNoV. It is important to note that unlike the MNV replicating mainly in macrophages and dendritic cells25, HuNoV, which was shown to replicate in B cells36, also targets IECs60–62. Therefore, the IFN produced by the sentinel cells in the lamina propria of villi upon sending the γ-PGA might restrict HuNoV infection more effectively at the early stage of infection by acting on nearby IECs through paracrine signaling.