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

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 <i>in vitro</i> and <i>in vivo</i>. 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.