The majority of the adult world population has been infected with the oral pathogen, HSV-1. Approximately 30% of those infected with HSV-1 will have recurrences throughout their lifetime due to the fact that the virus establishes latency in sensory neurons that innervate the infected tissue. Reactivation occurs upon certain stimuli, such as ultraviolet light or psychological stress, which results in re-infection of tissue in the periphery. Because stress is a common and unavoidable process people experience on a daily basis, it is important to understand how stress impacts primary and recurrent HSV infection.
Social disruption stress (SDR) has been shown to generate glucocorticoid-resistant monocytes/macrophages. Furthermore, SDR enhances the trafficking of glucocorticoid-resistant monocytes/macrophages from the bone marrow to the spleen, and increases pro-inflammatory cytokine production both in vitro and in vivo. In addition, SDR has also been shown to reliably reactivate HSV-1 in latently infected Balb/c mice.
During an HSV-1 infection, mice exposed to SDR prior to a primary HSV infection had enhanced trafficking of monocytes/macrophages to the trigeminal ganglia 3 to 6 days p.i. This is likely due to increased protein levels of MCP-1 in SDR mice. In addition, the receptor for MCP-1, CCR2, was significantly increased on CD11b+ cells in SDR mice. Expression of CD11b was also increased in SDR mice compared to controls which corresponded with increase in the expression of its ligand, ICAM-1. Although gene expression of IFN-β was decreased, SDR increased gene expression of IFN-α and TNF-α in the cornea and TG. Examination of viral proteins showed decreased expression of ICP0, gB, gH and LAT in the TG, however, expression of ICP0 and gB were elevated in the cornea of SDR mice. Because there was a reduction in viral replication, it was likely that fewer neurons were latently infected thus diminishing the frequency and severity of future recurrences.
Previous in vitro studies have shown that NGF deprivation from latently infected neuronal cells leads to reactivation, with the host cell transcription factors, Oct-1, Oct-2, and Inducible cAMP Early Repressor (ICER), playing an important role in this reactivation. Therefore, it was hypothesized that SDR alters expression of these host transcription factors resulting in viral reactivation. In the TG, SDR and UV irradiated groups showed increased gene expression for host transcription factors associated with reactivation as well as viral genes compared to the control. These experiments demonstrate that social stress has an effect on host gene transcription factors associated with reactivation in the TG.
These studies reveal that stress impacts primary and recurrent HSV infections in different ways. Data suggests that SDR has a beneficial effect during a primary infection by enhancing the immune response. This enhanced immune response can potentially determine the frequency and severity of recurrences in the future. However, stress is not always beneficial in that it can also cause a latent infection to reactivate by altering host transcription factors associated with reactivation. Understanding how stress affects susceptibility to and resolution of HSV infections will lead to the development of therapies that will improve health.