N-glycosylation of viral glycoprotein is a novel determinant for the tropism and virulence of highly pathogenic tick-borne bunyaviruses.

Severe fever with thrombocytopenia syndrome (SFTS) virus, a tick-borne bunyavirus, causes a severe/fatal disease termed SFTS; however, the viral virulence is not fully understood. The viral non-structural protein, NSs, is the sole known virulence factor. NSs disturbs host innate immune responses and an NSs-mutant SFTS virus causes no disease in an SFTS animal model. The present study reports a novel determinant of viral tropism as well as virulence in animal models, within the glycoprotein (GP) of SFTS virus and an SFTS-related tick-borne bunyavirus. Infection with mutant SFTS viruses lacking the N-linked glycosylation of GP resulted in negligible usage of calcium-dependent lectins in cells, less efficient infection, high susceptibility to a neutralizing antibody, low cytokine production in macrophage-like cells, and reduced virulence in Ifnar^-/- mice, when compared with wildtype virus. Three SFTS virus-related bunyaviruses had N-glycosylation motifs at similar positions within their GP and a glycan-deficient mutant of Heartland virus showed in vitro and in vivo phenotypes like those of the SFTS virus. Thus, N-linked glycosylation of viral GP is a novel determinant for the tropism and virulence of SFTS virus and of a related virus. These findings will help us understand the process of severe/fatal diseases caused by tick-borne bunyaviruses. Author summary: Ticks sometimes contain small pathogens in their bodies. Because ticks need blood to survive, upon bloodsucking, the pathogens spread to humans as well as animals and cause diseases in some cases. One such pathogen is the bunyavirus, which includes severe fever with thrombocytopenia syndrome virus, and diseases caused by these viruses are often fatal. Most details of bunyavirus-driven diseases are poorly understood, but a viral protein, NSs, was shown to disturb immune responses in humans. This study reports the discovery and characteristics of a novel virulence factor within another bunyaviral glycoprotein. The novel virulence factor is N-glycosylated modification and involves the viral targets for infection. Mutant viruses lacking the modification in the glycoprotein had limited infection potential in cell culture experiments and weakened virulence in animal experiments. Our findings will help us understand bunyavirus-driven diseases and, hopefully, promote countermeasures against the diseases, leading to safer outdoor activities. [ABSTRACT FROM AUTHOR]