Stress Hormones Epinephrine and Corticosterone Selectively Modulate Herpes Simplex Virus 1 (HSV-1) and HSV-2 Productive Infections in Adult Sympathetic, but Not Sensory, Neurons

Abstract

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect and establish latency in peripheral neurons, from which they can reactivate to cause recurrent disease throughout the life of the host. Stress is associated with the exacerbation of clinical symptoms and the induction of recurrences in humans and animal models. The viruses preferentially replicate and establish latency in different subtypes of sensory neurons, as well as in neurons of the autonomic nervous system that are highly responsive to stress hormones. To determine if stress-related hormones modulate productive HSV-1 and HSV-2 infections within sensory and autonomic neurons, we analyzed viral DNA and the production of viral progeny after treatment of primary adult murine neuronal cultures with the stress hormones epinephrine and corticosterone. Both sensory trigeminal ganglion (TG) and sympathetic superior cervical ganglion (SCG) neurons expressed adrenergic receptors (activated by epinephrine) and the glucocorticoid receptor (activated by corticosterone). Productive HSV infection colocalized with these receptors in SCG but not in TG neurons. In productively infected neuronal cultures, epinephrine treatment significantly increased the levels of HSV-1 DNA replication and production of viral progeny in SCG neurons, but no significant differences were found in TG neurons. In contrast, corticosterone significantly decreased the levels of HSV-2 DNA replication and production of viral progeny in SCG neurons but not in TG neurons. Thus, the stress-related hormones epinephrine and corticosterone selectively modulate acute HSV-1 and HSV-2 infections in autonomic, but not sensory, neurons.IMPORTANCE Stress exacerbates acute disease symptoms resulting from HSV-1 and HSV-2 infections and is associated with the appearance of recurrent skin lesions in millions of people. Although stress hormones are thought to impact HSV-1 and HSV-2 through immune system suppression, sensory and autonomic neurons that become infected by HSV-1 and HSV-2 express stress hormone receptors and are responsive to hormone fluctuations. Our results show that autonomic neurons are more responsive to epinephrine and corticosterone than are sensory neurons, demonstrating that the autonomic nervous system plays a substantial role in HSV pathogenesis. Furthermore, these results suggest that stress responses have the potential to differentially impact HSV-1 and HSV-2 so as to produce divergent outcomes of infection.KEYWORDS herpes simplex virus, HSV-1, HSV-2, epinephrine, corticosterone, stress, reactivation

Herpes Simplex Virus 2 in Autonomic Ganglia: Evidence for Spontaneous Reactivation

“…Therefore, those models may not reflect reactivation from autonomic neurons, which are more sensitive to hormonal fluctuation than sensory neurons. Increased hormone levels, which have also been found to impact HSV reactivation (27), seem more likely to specifically target autonomic neurons, as is also likely the case for iontophoresis of epinephrine, which has been used as a reactivation stimulus in in vivo ocular models. Ex vivo and in vitro models that are focused on sympathetic neurons likely have specific relevance to clinically important reactivation from autonomic neurons (27,28), since different stimuli induce reactivation in sensory neurons (29).…”

Assessment of Oral Shedding of Herpes Simplex Virus Before and After Endodontic and Fixed Partial Prosthodontics Treatment in Patients with Recurrent Herpes Simplex

“…Therefore, immunomodulation molecules that are activated due to dental treatment-related pain can cause recurrent HSV-1 infections. In addition, specific molecular signals such as adrenalin, IL-6, cAMP, glucocorticoids and prostaglandins are released during stress (42,43).…”

Strength in diversity: Understanding the pathways to herpes simplex virus reactivation

“…Perhaps one of the best characterized in vitro systems to study HSV reactivation utilizes primary sensory or sympathetic neurons isolated from the peripheral ganglia of pre-natal rats and post-natal or adult mice (Camarena et al, 2010; Cliffe et al, 2015; Ives and Bertke, 2017; Wilcox and Johnson, 1987; Wilcox et al, 1990). Infection of these primary neuronal cultures in the presence of acyclovir or phosphonoacteic acid (PAA) results in a quiescent infection that resembles latency.…”

“…Although stress hormone-mediated immunosuppression likely plays a role in recurrence of disease in humans, there is evidence that stress hormones can have a direct effect on neurons, as well as on HSV gene expression (Du et al, 2012; Ives and Bertke, 2017; Workman et al, 2012). During productive replication in non-neuronal cells, BHV-1 lytic gene expression is stimulated by dexamethasone (Zhu et al, 2017).…”

“…During productive replication in non-neuronal cells, BHV-1 lytic gene expression is stimulated by dexamethasone (Zhu et al, 2017). Furthermore, differential expression of adrenergic and glucocorticoid receptors on sensory and autonomic neurons has been well-characterized, and differences in expression correlate with the effect of stress hormones on HSV-1 and HSV-2 replication (Ives and Bertke, 2017). The signaling pathways that ultimately result in viral gene expression in response to stress hormones are not fully understood.…”