During an HSV-1 infection, mice exposed to social disruption stress (SDR) prior to a primary HSV infection had enhanced trafficking of monocytes/macrophages to the trigeminal ganglia (TG) 3 to 6 days p.i. Immune cell infiltration into the cornea, however, could not be determined due to low cell numbers. Although gene expression of IFN-β was decreased, SDR increased gene expression of IFN-α, TNF-α, and iNOS 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. The detection of viral genes in the TG suggests that the neurons were infected; however, expression of those genes was suppressed. This observation suggests that SDR may be changing the microenvironment of the neurons so that the virus cannot fully replicate to form complete infectious viral particles and/or establish latency. This could be due to the enhancement of the cytokine response that alters the microenvironment of the neurons, and/or due to an alteration in host transcription factors necessary for viral replication. 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.
Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine for recruiting monocytes/macrophages to sites of infection by acting on its receptor CCR2. As monocytes respond to the chemokine, the β2 integrin (CD11b) on the surface of the cell binds to its ligand, ICAM-1, on the endothelium so that the CD11b+ cells can infiltrate infected tissue. Because studies have shown that SDR enhances trafficking of monocytes/macrophages to the trigeminal ganglia, it was hypothesized that SDR increases production of MCP-1 and ICAM-1 in the TG and expression of CCR2 and CD11b on monocytes/macrophages. Protein levels of MCP-1 were found to be significantly increased in mice exposed to SDR compared to controls. 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. The data suggest that increased expression of CD11b and CCR2 on monocytes/macrophages and increased expression of ICAM-1 and MCP-1 in the TG contributes to the enhanced infiltration of monocyte/macrophages to the infected TG.
Stress has been shown to be associated with reactivation of latent HSV-1 infections in humans and animals. However, the molecular mechanisms involved with stress-induced reactivation need to be further investigated. 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. (Abstract shortened by UMI.)