Amino acids at positions 273 and 394 in rabies virus nucleoprotein are important for both evasion of host RIG-I-mediated antiviral response and pathogenicity

We previously reported that nucleoprotein (N) is related to the different pathogenicities of the virulent rabies virus strain Nishigahara (Ni) and avirulent strain Ni-CE and also that Ni N, but not Ni-CE N, functions to evade retinoic acid-inducible gene I (RIG-I)-mediated innate immunity. There are three amino acid differences between Ni and Ni-CE N (at positions 273, 394 and 395), indicating that one of these mutations or a combination of mutations is important for the pathogenicity and evasion of innate immunity. We generated Ni-CE mutants in which the amino acids in Ni-CE N were replaced with those of Ni in all combinations. Among the mutants, CE(NiN273/394) with mutations at positions 273 and 394 evaded activation of RIG-I-mediated signaling most efficiently and also showed the highest pathogenicity. This correlation reinforces the relation between evasion of host RIG-I-mediated innate immunity and pathogenicity of rabies virus.