Importance of rabies virus nucleoprotein in viral evasion of interferon response in the brain

Abstract

By using a cultured neuroblastoma cell line, the present authors recently showed that the N protein of virulent rabies virus fixed strain Nishigahara (Ni), but not that of the attenuated derivative Ni-CE, mediates evasion of induction of type I interferon (IFN). In this study, to determine whether Ni N protein indeed fulfills this function in vivo, the abilities to suppress IFN responses in the mouse brain of Ni-CE and the virulent chimeric virus CE(NiN), which has the N gene from Ni in the genetic background of Ni-CE, were compared. It was demonstrated that CE(NiN) propagates and spreads more efficiently than does Ni-CE in the brain and that IFN response in brains infected with CE(NiN) is weaker than in those infected with Ni-CE. It was also shown that amino acids at positions 273 and 394 in the N protein, which are known as pathogenic determinants, affect the ability of the viruses to suppress IFN response in the brain. These findings strongly suggest that, in the brain, rabies virus N protein plays important roles in evasion of innate immune responses and thereby in efficient propagation and spread of virus leading to lethal outcomes of infection.

Expression of Interferon Gamma by a Recombinant Rabies Virus Strongly Attenuates the Pathogenicity of the Virus via Induction of Type I Interferon

“…Since type I IFN signaling is important for protection against infection, it is not surprising that the RABV itself dedicates substantial resources to blocking type I IFN signaling. Both the N and P genes of RABV express products that interfere with type I IFN signaling (50,51), and mutation of P can attenuate the virus (52). The blockade of type I IFN by RABV is a "leaky" process, however, and the host response is able to impede replication and spread to some degree despite this immunoevasion strategy (48).…”

Comparison of the protective efficacy between single and combination of recombinant adenoviruses expressing complete and truncated glycoprotein, and nucleoprotein of the pathogenic street rabies virus in mice

“…Additionally, N protein was related to RABV pathogenicity in adult mice in a comparison between nonlethal strain Ni-CE and virulent strain Nishigahara [36]. The virulent RABV N protein suppresses induction of interferon and chemokines in neuroblastoma cells and is important for inhibition of innate immune response, viral propagation, and spread of pathogenicity in the mouse brain [37, 38]. Thus it is assumed that vaccination of mice in our study with street RABV N protein contributed to their survival after IC exposure to RABV.…”

Subversion of the Immune Response by Rabies Virus

“…The complete encapsidation is hypothesized to protect the RNA from recognition by the innate immune system of the host—more specifically recognition by Toll-like receptors (TLRs) and RLRs [166]. Furthermore, the N protein has a vital role in the suppression of the innate immune response during infection, allowing for increased viral replication and spread in the brain and CNS of the infected individual [167,168,169]. …”

“…This was shown both in vivo and in vitro and was not related to the specific expression of viral genomic RNA. In a series of studies performed by Masatani and colleagues [167,168,169], the N gene from the pathogenic Nishigahara strain was inserted in place of the N gene in the attenuated Ni-CE strain, resulting in the formation of CE(NiN). The CE(NiN) and Ni strains showed greater inhibitions of the innate immune response—specifically IFN-β and chemokine (C-X-C motif) ligand 10 (CXCL10)—when compared to the attenuated wild-type Ni-CE strain.…”