Abstract
We previously reported that HSV-1 infectivity in vitro and in vivo requires HSV glycoprotein K (gK) binding to the ER signal peptide peptidase (SPP). Anterograde-retrograde transport via peripheral nerves between the site of infection (i.e., eye) and the site of latency (neurons) is a critical process to establish latency and subsequent viral reactivation. Given the essential role of neurons in HSV-1 latency-reactivation, we generated mice lacking SPP specifically in peripheral sensory neurons by crossing Advillin-Cre mice with SPPfl/fl mice. Expression of SPP mRNA and protein were significantly lower in neurons of Avil-SPP-/- mice than in control mice despite similar levels of HSV-1 replication in the eyes of Avil-SPP-/- mice and control mice. Viral transcript levels in isolated neurons of infected mice on days 2 and 5 post infection were lower than in control mice. Significantly less LAT, gB, and PD-1 expression was seen during latency in isolated neurons and total trigeminal ganglia (TG) of Avil-SPP-/- mice than in control mice. Finally, reduced latency and reduced T cell exhaustion in infected Avil-SPP-/- mice correlated with slower and no reactivation. Overall, our results suggest that blocking SPP expression in peripheral sensory neurons does not affect primary virus replication or eye disease but does reduce latency-reactivation. Thus, blocking of gK binding to SPP may be a useful tool to reduce latency-reactivation.
Highlights
To evaluate the importance of glycoprotein K (gK) binding to signal peptide peptidase (SPP) in the peripheral nervous system, we generated SPP conditional knockout mice in peripheral nervous system using Advillin-Cre mice
We previously reported the important role of HSV-1 gK binding to SPP in HSV-1 infectivity in vitro and in vivo using SPP dominant-negative mutants, SPP shRNA, and chemical inhibitors of SPP [20,21]
There was a significant reduction in SPP expression level in trigeminal ganglia (TG) of Avil-SPP-/- mice compared to TG from wt mice (Fig 1C, p
Summary
We previously demonstrated the importance of gK in HSV-induced corneal scarring (CS) and facial dermatitis [9,10,11,12,13,14,15] In both mice and humans, gK elicited CD8+IFN-γ+ responses [16,17]. Binding of gK to SPP is known to be essential for HSV-1 infectivity both in vitro and in vivo [20,21]. These data strongly support the concept that gK plays a major role in viral immunopathogenesis
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