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

• Published in: PLoS pathogens 2024-07, Vol.20 (7), p.e1012348
• Main Authors: Shimojima, Masayuki, Sugimoto, Satoko, Taniguchi, Satoshi, Maeki, Takahiro, Yoshikawa, Tomoki, Kurosu, Takeshi, Tajima, Shigeru, Lim, Chang-Kweng, Ebihara, Hideki
• Format: Article
• Language: English
• Subjects: Animal diseases; Animal models; Animals; Antigens; Arachnids; Biology and Life Sciences; Bunyaviridae Infections - metabolism; Bunyaviridae Infections - virology; Bunyaviruses; Calcium; Chemokines; Deficient mutant; Disease; Fatalities; Glycan; Glycoproteins; Glycoproteins - genetics; Glycoproteins - metabolism; Glycosylation; Humans; Immune response; In vivo methods and tests; Infections; Innate immunity; Lectins; Macrophages; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Orthobunyavirus - genetics; Orthobunyavirus - metabolism; Orthobunyavirus - pathogenicity; Pathogenesis; Phenotypes; Phlebovirus - genetics; Phlebovirus - pathogenicity; Physiological aspects; Proteins; R&D; Research & development; Research and Analysis Methods; RNA polymerase; Severe Fever with Thrombocytopenia Syndrome - virology; Thrombocytopenia; Ticks; Ticks - virology; Tropism; Tropisms; Viral proteins; Viral Tropism; Virulence; Virulence (Microbiology); Virulence factors; Virus research; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012348

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.