Epstein-Barr virus, a human gammaherpesvirus (γ-HV), establishes chronic infections and causes B cell cancers. Efforts to produce a vaccine have failed. Murid Herpesvirus-4 (MuHV-4) provides a tractable approach to identify critical events during γ-HV colonisation and dissemination. Inoculations via footpad and peritoneal infection demonstrate a key role for type 1 interferon (IFN-1) in MuHV-4 infection, specifically in limiting infection of subcapsular sinus macrophages and marginal zone macrophages respectively. While useful for revealing fundamental characteristics of infection, a more realistic route of infection is through spontaneous inhalation of virus particles by alert mice, which would be reflective of natural environmental sampling. Infection spreads consecutively from nasal epithelium to superficial cervical lymph nodes (SCLN) to the blood and then the spleen. MuHV-4 spread from primary epithelial sites of infection to lymph node B cells, where latency is established, is facilitated by dendritic cells (DC). We wanted to discern the role of IFN-1 in early MuHV-4 spread after nasal challenge.

Blocking the IFN-1 receptor (IFNAR) increased lytic infection in the olfactory epithelium and respiratory epithelium. Anti-IFNAR also resulted in accelerated MuHV-4 spread from the nose to lymphoid tissue. In SCLN, increased titres post anti-IFNAR revealed greater viral antigen in subcapsular sinus macrophages (SSM), and increased DC infection. IFNAR knockout in LysM⁺ and CDllc⁺ myeloid cell subsets through Cre-Lox recombination demonstrated a role for IFN-1 in restricting host colonisation through acting on DC. Taken together, these studies demonstrate a critical role for IFN-1 in myeloid cell containment of MuHV-4 infection. Understanding the role of IFN-1 in limiting virus spread from peripheral sites could reveal antiviral strategies that target early intervention and prevention of B cell colonisation.