Glu(333)in rabies virus glycoprotein is involved in virus attenuation through astrocyte infection and interferon responses

The amino add residue at position 333 of the rabies virus (RABV) glycoprotein (G333) is a major determinant of RABV pathogenicity. Virulent RABV strains possess Arg(333), whereas the attenuated strain HEP-Flury (HEP) possesses Glu(333). To investigate the potential attenuation mechanism dependent on a single amino add at G333, comparative analysis was performed between HEP and (HEPR)-R-333 mutant with Arg(333). 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 (HEPR)-R-333 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 Glu(333) contributes to RABV attenuation by determining the ability of the virus to infect astrocytes and stimulate subsequent IFN responses