Resumen de Contribution of herpes simplex virus glycoprotein g to viral pathogenesis
Herpes simplex virus (HSV) is well-known for being one of the most prevalent neurotropic pathogens worldwide, causing a broad range of diseases in humans. Two different HSV subtypes have been traditionally associated to diverse clinical manifestation of the disease, being HSV type 1 (HSV-1) global seroprevalence much higher than that of HSV type 2 (HSV-2). Whereas HSV-1 is generally the causative agent of cold sores, keratitis or even encephalitis by infecting the oro-facial region, HSV-2 tends to infect the genital area causing pain, heat and itch, which are classical symptoms of genital herpes. Despite being both able to infect the genitalia, HSV-1 recurrent episodes are less frequent than HSV-2 infections. These data suggest that clear differences exist when comparing HSV-1 and HSV-2 pathogenesis and prevalence, suggesting a differential neurotropism for each virus. How these highly related viruses differentially manipulate the host nervous system is not properly understood yet.
HSV glycoprotein G (gG) is the most divergent viral product between the HSV subtypes, which has been identified by our laboratory as the first viral proteins able to enhance chemotaxis both in vitro and in vivo. Both HSV-1 gG (gG1) and the secreted domain of HSV-2 gG (SgG2) showed chemotaxis potentiation. In addition, SgG2 was described as the first viral protein inducing a directional enhancement of nerve growth factor (NGF)-mediated axonal growth of neurons ex vivo and in vivo. Our hypothesis is that these novel biological activities, together with the structural differences among gG1 and HSV-2 gG (gG2), may contribute to explain the preferential neurotropism of each virus.
Here, we have determined the genomic sequence of some relevant HSV laboratory strains, characterizing their genomic and genetic variability within each HSV subtype in cell culture, prior to further studies. Then, we have optimized the CRISPR/Cas9 system to efficiently generate a collection of gG mutant HSVs in order to investigate the contribution of both gG1 and gG2 to viral pathogenicity and neurotropism.
We observed that gG1 is dispensable for HSV-1 infection, while gG2 appears as a non-essential but important contributing factor in HSV-2 pathogenesis. Swapping of gGs between the HSV subtypes led to a dramatic HSV-1 attenuation, which was less pronounced in the HSV-2 case. Together with previous data, our results suggest that gG2 may facilitate access of HSV to NGF-dependent neurons, giving a different outcome of infection depending on which HSV subtype infects those neurons. We propose that gG2, likely SgG2, may play a crucial role during HSV-2 colonization of the nervous system, contributing to explain its differential neurotropism with HSV-1.
