Herpes simplex virus type 1 (HSV-1) infections lead to misery and discomfort for millions of persons worldwide. Cell-mediated immunity has been pointed out as an important component of the host's defense against herpes simplex virus. It has been demonstrated that the activation of the hypothalamic-pituitary-adrenal axis by stressful events results in an elevation of corticosteroids in the serum that may impair immune function. Although the skin is the primary site for recurrent HSV-1 infections we still do not understand the immunological mechanisms in which stress modulates immune responses toward cutaneous herpes simplex virus infections. Cytokines are important mediators of inflammation and viral clearance in herpes virus infections, but despite their importance in antigen specific recruitment of immune cells and in the inflammatory process, little is known about local cytokine expression during the course of a cutaneous herpes viral infection. During stress events, activation of the hypothalamic-pituitary-adrenal axis occurs and catecholamines and glucocorticoids are produced. Glucocorticoids have an immunosuppressive action such as inhibiting the activities of neuropeptides and cytokines. The hypothesis that we intent to test in this proposal is that restraint stress will induce changes in the pathophysiology of a HSV-1 infection by depressing early inflammatory mediators which will lead to a severe and longer lasting infections. Gene expression of pro-inflammatory cytokine will be down-regulated leading to a decrease in inflammatory cell infiltrate, which will lead to an increased number of infective viral particles at the site of the infection. We also hypothesize that restraint stress will induce a down-regulation of the gene expression of Th1 derived cytokines, causing a shift into a Th2 mediated response. Shifting to a h2 mediated response has been shown to make the host more susceptible to severe HSV-1 infections. An elevated level of glucocorticoids in plasma is the underlying factor in the depressed immune response. The following specific aims have been developed in order to test the hypothesis:
In Specific Aim I, we will evaluate and characterize the HSV-infection severity and healing time in restrained animals. We will perform histological evaluations of the inflammatory cells present in the tissues at different times during the course of the infection; we will also evaluate for the presence of viral particles at the site of the infection, and we conduct assays to determine infectious viral titers. Later in Specific Aim II, we will focus our attention on the gene expression of pro-inflammatory cytokines and Th1 and Th2 cytokine profiles. We will study the gene expression of IL-1alpha, TNF-alpha, pro-inflammatory cytokines involved in the recruitment of inflammatory cells; Th1 profile cytokines IL-2, INF-gamma, which have important proliferative functions for T-cells and potent antiviral effects, respectively, Down-regulation of IL-2 and INF-gamma may induce shifting of a TH1 mediated response to a Th2 dominated response. Correlations of the clinical, histological, and immunological findings will be done in order to understand the mechanisms in which restrain stress modulates HSV-1 infections.
| Ortiz, Griselle C; Sheridan, John F; Marucha, Phillip T (2003) Stress-induced changes in pathophysiology and interferon gene expression during primary HSV-1 infection. Brain Behav Immun 17:329-38 |
| Loe, H; Anerud, A; Boysen, H (1992) The natural history of periodontal disease in man: prevalence, severity, and extent of gingival recession. J Periodontol 63:489-95 |
