Glu333 in rabies virus glycoprotein is involved in virus attenuation through astrocyte infection and interferon responses
Yukari Itakura,
Koshiro Tabata,
Kohei Morimoto,
Naoto Ito,
Herman M. Chambaro,
Ryota Eguchi,
Ken-ichi Otsuguro,
William W. Hall,
Yasuko Orba,
Hirofumi Sawa,
Michihito Sasaki
Affiliations
Yukari Itakura
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan
Koshiro Tabata
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan
Kohei Morimoto
Laboratory of Pharmacology, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
Naoto Ito
Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu 501-1193, Japan
Herman M. Chambaro
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan
Ryota Eguchi
Laboratory of Pharmacology, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
Ken-ichi Otsuguro
Laboratory of Pharmacology, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
William W. Hall
National Virus Reference Laboratory, School of Medicine, University College of Dublin, Dublin 4, Ireland; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan; Global Virus Network, Baltimore, MD 21201, USA
Yasuko Orba
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan
Hirofumi Sawa
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan; Global Virus Network, Baltimore, MD 21201, USA; One Health Research Center, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan
Michihito Sasaki
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan; Corresponding author
Summary: The amino acid residue at position 333 of the rabies virus (RABV) glycoprotein (G333) is a major determinant of RABV pathogenicity. Virulent RABV strains possess Arg333, whereas the attenuated strain HEP-Flury (HEP) possesses Glu333. To investigate the potential attenuation mechanism dependent on a single amino acid at G333, comparative analysis was performed between HEP and HEP333R mutant with Arg333. We examined their respective tropism for astrocytes and the subsequent immune responses in astrocytes. Virus replication and subsequent interferon (IFN) responses in astrocytes infected with HEP were increased compared with HEP333R both in vitro and in vivo. Furthermore, involvement of IFN in the avirulency of HEP was demonstrated in IFN-receptor knockout mice. These results indicate that Glu333 contributes to RABV attenuation by determining the ability of the virus to infect astrocytes and stimulate subsequent IFN responses.
