Glycoprotein-mediated induction of apoptosis limits the spread of attenuated rabies viruses in the central nervous system of mice

Abstract

Induction of apoptosis by rabies virus (RV) has been reported to be associated with the expression of the glycoprotein (G), but inversely correlated with pathogenicity. To further delineate the association between the expression of the G and the induction of apoptosis, recombinant RVs with replacement of only the G gene were used to infect mice by the intracerebral route. Recombinant viruses expressing the G from attenuated viruses expressed higher level of the G and induced more apoptosis in mice than recombinant RV expressing the G from wild-type (wt) or pathogenic RV, demonstrating that it is the G gene that determines the level of G expression and, consequently, the induction of apoptosis. Likewise, recombinant viruses expressing the G from wt or pathogenic RV are more pathogenic in mice than those expressing G from attenuated RV, confirming the inverse correlation between RV pathogenicity and the induction of apoptosis. To investigate the mechanism by which induction of apoptosis attenuates viral pathogenicity, mice were infected with wt or attenuated RV by the intramuscular route. It was found that low doses of attenuated RV induced apoptosis in the spinal cord and failed to spread to the brain or produce neurological disease. On the other hand, apoptosis was not observed in the spinal cord of mice infected with the same doses of wt RV and the virus spread to various parts of the brain and induced fatal neurologic disease. These results suggest that glycoprotein-mediated induction of apoptosis limits the spread of attenuated rabies viruses in the central nervous system (CNS) of mice.

Amino Acid Substitution at Position 95 in Rabies Virus Matrix Protein Affects Viral Pathogenicity

“…These data suggest that suppression of apoptosis plays an important role in the pathogenicity of CE(NiM95) strain. Many previous studies have demonstrated that RABV G protein plays an important role in induction of apoptosis with a close relation to the attenuated phenotype [7,11,12]. The results of this study, taken together with our previous data [10], suggest that apoptosis induced by an M protein-mediated mechanism is also inversely correlated with viral pathogenicity.…”

“…Results of many previous studies support this idea by demonstrating an inverse correlation between pathogenicity and apoptosis-inducing ability of RABV [7,11,12]. More specifically, Jackson et al [7] reported that, compared to virulent SAD-L16 strain, the attenuated mutant SAD-D29 strain strongly induces apoptosis in neurons in the infected mouse brain, resulting in inefficient spread of infection in the brain.…”

“…Many studies have shown that pathogenicity in adult mice is altered by amino acid substitutions in the G protein [2,5,13,[15][16][17]. These substitutions affect biological properties of the virus, such as cell-to-cell spread [1,6], membrane fusion [3] and apoptosis-inducing ability [7,12]. While the mechanism by which the G protein determines viral pathogenicity is becoming increasingly clear, little is known about the contribution of viral proteins other than the G protein to pathogenicity.…”

The Inability of Wild-Type Rabies Virus To Activate Dendritic Cells Is Dependent on the Glycoprotein and Correlates with Its Low Level of theDe Novo-Synthesized Leader RNA

“…Recombinant CVSB2c expressing G [B2c(DRV-G)] or P [B2c(DRV-P)] from DRV-Mexico was constructed as described previously (35,36). Virus stocks were prepared in 1-day-old suckling mice as described previously (37). When moribund, mice were euthanized and brains removed.…”

Glycoprotein from street rabies virus BD06 induces early and robust immune responses when expressed from a non-replicative adenovirus recombinant

“…Studies have shown that attenuated RABVs appeared to activate, while pathogenic RABVs evaded, the host innate immune responses, and the evasion was due to the restricted expression of the G protein [28,33]. In street RABV strains, G protein expression is more controlled than in attenuated strains [24,37].…”