Rabies Virus Glycoprotein G Variation Is Associated with Neurovirulence and Reduced Vamp2 Abundance in a Mouse Model of Direct CNS Infection

Abstract

Simple Summary Rabies virus infection causes a severe and usually fatal neurological disease, but the viral determinants underlying differences in neurovirulence remain incompletely understood. The rabies virus glycoprotein G is exposed on the viral surface and plays essential roles in viral entry, spread, and host–cell interactions. In this study, recombinant RABVs carrying G proteins from the attenuated SAD-B19 strain or the more virulent CVS11 strain were rescued within the same LBNSE genetic background. Although G replacement did not significantly affect viral replication in cultured cells, rLBNSE-CfG exhibited enhanced neurovirulence after intracerebral injection and increased early infection of primary neurons. Proteomic analysis of mouse brain tissue revealed that rLBNSE-CfG was associated with reduced expression of proteins involved in the synaptic vesicle cycle and neurotransmitter release, including a SNARE-associated module containing Snap25, Stx1a, and Vamp2. In primary neurons, decreased Vamp2 abundance was associated with rLBNSE-CfG infection and expression of the CVS11-G extracellular-domain construct. Immunofluorescence confirmed the neuronal expression and distribution of CVS11-G domain constructs in Map2-positive neurons. These findings associate CVS11-derived G variation with reduced Vamp2 abundance and a presynaptic vesicle-related proteomic signature, although whether these molecular alterations directly affect synaptic vesicle release remains to be determined.