Ives Angela M, Bertke Andrea S
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
Department of Population Health Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
J Virol. 2017 Jun 9;91(13). doi: 10.1128/JVI.00582-17. Print 2017 Jul 1.
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. 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.
单纯疱疹病毒1型和2型（HSV - 1和HSV - 2）感染外周神经元并在其中建立潜伏感染，在宿主的一生中，它们可重新激活并引发复发性疾病。在人类和动物模型中，应激与临床症状的加重以及复发的诱导有关。这些病毒优先在不同亚型的感觉神经元以及对应激激素高度敏感的自主神经系统神经元中复制并建立潜伏感染。为了确定应激相关激素是否调节感觉神经元和自主神经元内HSV - 1和HSV - 2的有效感染，我们在用应激激素肾上腺素和皮质酮处理原代成年小鼠神经元培养物后，分析了病毒DNA和病毒子代的产生。感觉三叉神经节（TG）和交感神经颈上神经节（SCG）神经元均表达肾上腺素能受体（由肾上腺素激活）和糖皮质激素受体（由皮质酮激活）。HSV的有效感染在SCG神经元中与这些受体共定位，但在TG神经元中并非如此。在用肾上腺素处理的有效感染的神经元培养物中，显著增加了SCG神经元中HSV - 1 DNA复制水平和病毒子代的产生，但在TG神经元中未发现显著差异。相比之下，皮质酮显著降低了SCG神经元中HSV - 2 DNA复制水平和病毒子代的产生，但在TG神经元中未降低。因此，应激相关激素肾上腺素和皮质酮选择性地调节自主神经元而非感觉神经元中的急性HSV - 1和HSV - 2感染。应激会加重HSV - 1和HSV - 2感染引起的急性疾病症状，并与数百万人复发性皮肤病变的出现有关。尽管应激激素被认为通过抑制免疫系统影响HSV - 1和HSV - 2，但被HSV - 1和HSV - 2感染的感觉神经元和自主神经元表达应激激素受体并对应激激素波动有反应。我们的结果表明，自主神经元比感觉神经元对肾上腺素和皮质酮更敏感，这表明自主神经系统在HSV发病机制中起重要作用。此外，这些结果表明应激反应有可能对HSV - 1和HSV - 2产生不同影响，从而产生不同的感染结果。
