The Rabies Virus Glycoprotein Receptor p75 super(NTR) Is Not Essential for Rabies Virus Infection

Rabies virus glycoprotein (RVG) is known to be the only factor that mediates rabies infection. The neurotrophin receptor (p75 super(NTR)), through its cysteine-rich domain 1, is a specific receptor for RVG and neutralizes virus infectivity, but its role in virus infection has remained obscure. We used adult mouse dorsal root ganglion (DRG) neurons as a model to study the role of p75 super(NTR) in RV infection of primary neurons. We show that RV infects around 20% of DRG neurons, of which more than 80% are p75 super(NTR) positive, have large diameters, and are capsaicin insensitive. Surprisingly, RV binding and infection are absent in about half of the p75 super(NTR)-expressing DRG neurons which have small diameters and are often capsaicin sensitive. This indicates that p75 super(NTR) is not sufficient to mediate RV interaction in sensory neurons. The rate and specificity of neural infection are unchanged in RV-infected p75 super(NTRExonIV-/-) mice that lack all extracellular receptor domains and in wild-type mice infected with two independent RV mutants that lack p75 super(NTR) binding. Accordingly, the mortality rate is unchanged in the absence of RV-p75 super(NTR) interaction. We conclude that although p75 super(NTR) is a receptor for soluble RVG in transfected cells of heterologous expression systems, an RVG-p75 super(NTR) interaction is not necessary for RV infection of primary neurons. This means that other receptors are required to mediate RV infection in vivo and in vitro.