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

doi:10.1016/j.isci.2022.104122

Glu₃₃₃ in rabies virus glycoprotein is involved in virus attenuation through astrocyte infection and interferon responses

iScience. 2022 Mar 22;25(4):104122. doi: 10.1016/j.isci.2022.104122. eCollection 2022 Apr 15.

Authors

Yukari Itakura¹, Koshiro Tabata¹, Kohei Morimoto², Naoto Ito³, Herman M Chambaro¹, Ryota Eguchi², Ken-Ichi Otsuguro², William W Hall^{4

5

6}, Yasuko Orba^{1

5}, Hirofumi Sawa^{1

5

6

7}, Michihito Sasaki¹

Affiliations

¹ Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan.
² Laboratory of Pharmacology, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan.
³ Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu 501-1193, Japan.
⁴ National Virus Reference Laboratory, School of Medicine, University College of Dublin, Dublin 4, Ireland.
⁵ International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan.
⁶ Global Virus Network, Baltimore, MD 21201, USA.
⁷ One Health Research Center, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan.

Abstract

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.

Keywords: Cellular neuroscience; Immunology; Virology.