Abstract
Previous studies have shown that wild-type (wt) rabies virus (RABV) evades the host immune response by restricting expression of glycoprotein (G), which blocks activation of dendritic cells (DCs) and induces production of virus-neutralizing antibodies (VNAs). In the present study, wt RABVs not only restricted G expression but also reduced incorporation of G into mature virions compared with laboratory-adapted viruses. A recombinant RABV expressing triple G was used to further determine whether G expression relates to incorporation. The recombinant virus showed higher expression and incorporation of G and activated more DCs than the virus that expressed a single copy of G. Removal of G from viruses using subtilisin or Dithiothreitol (DTT)/ Nonidet P-40 (NP40) almost completely abolishes DC activation and VNA production. Consequently, these G-depleted viruses cause lethal infection in mice. Thus, wt RABVs can subvert DC-induced antiviral immune response and maintain pathogenicity by decreasing G expression in infected cells and G incorporation into virions.
Highlights
rabies virus (RABV), a single-stranded and negative-sense RNA virus in the Rhabdoviridae family, causes more than 59,000 human fatalities annually throughout the world [1,2]
Our recent studies demonstrated that wt RABV evades dendritic cells (DCs)-mediated immune activation by expressing low levels of G in infected cells, which results in inefficient binding/entry into DCs [6]
The levels of these costimulatory molecules on DCs infected with DRV, B2c (DRV-G), or RABV treated with SUB or DTT/Nonidet P-40 (NP40) did not change after increasing virus doses, demonstrating that the inability of wt RABVs or G-deficient RABVs to activate DCs is not dependent on the infection dose
Summary
RABV, a single-stranded and negative-sense RNA virus in the Rhabdoviridae family, causes more than 59,000 human fatalities annually throughout the world [1,2]. The level of G incorporation into viral particles may affect the ability of the virus to activate the immune system and infect cells. Recombinant RABVs expressing innate immune genes stimulated the production of higher levels of VNAs and provided better protection by activating more DCs than the parental virus [12,14,21,22]. The wt RABV or laboratory-adapted RABV expressing G from the wt virus bind DCs less efficiently, produce lower levels of leader RNA in DCs, and induce lower levels of VNAs than those of laboratory-adapted viruses [6]. RABV carrying three copies of G expressed higher levels of G and incorporated more G into virions compared with the parental virus, enhancing G-dependent cell fusion and DC activation. These findings support a novel mechanism, in which wt RABV evades DC recognition by restricting G incorporation into mature virions
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