Psychological stress impairs the local CD8+ T cell response to mucosal HSV-1 infection and allows for increased pathogenicity via a glucocorticoid receptor-mediated mechanism

Abstract

Summary Psychological stress and its associated increases in corticosterone are generally immunosuppressive and contribute to increased herpes simplex virus (HSV)-associated pathogenicity. However, the impact of stress on local control of the initial mucosal-based HSV infection has not been elucidated, nor have the ramifications of such failures of the immune response in terms of viral spread. To address these gaps in knowledge, the studies described herein sought to determine how psychological stress and associated increases in corticosterone may increase susceptibility to HSV encephalitis by allowing for increased viral titers at the site of initial infection. We have shown that in mice intranasally infected with HSV-1, a cell-mediated immune response occurs in the nasopharyngeal-associated lymphoid tissue (NALT), mediastinal lymph nodes (MLN), and superficial cervical lymph nodes (CLN). However, psychological stress induced by restraint decreased the number of lymphocytes in these tissues in HSV-infected mice. Surprisingly, the effects of this restraint stress on HSV-specific CTL function varied by immune tissue. Increased viral titers were found in the nasal cavity of stressed mice, an observation which correlated with an increased CD8+ cell response in the CLN. These findings led us to extend our studies to also determine the ramifications of decreased numbers of locally-derived lymphocytes on viral titers following infection. Using an approach in which the NALT was surgically removed prior to infection, we confirmed that decreased numbers of NALT-derived lymphocytes at the time of infection allows for increased viral replication. We conclude that the increased viral titers observed in mice experiencing psychological stress are the consequence of a glucocorticoid-mediated reduction in the numbers of lymphocytes responsible for resolving the initial infection.

Psychological stress exacerbates primary vaginal herpes simplex virus type 1 (HSV-1) infection by impairing both innate and adaptive immune responses

“…We have previously reported that our model of restraint stress increases serum corticosterone levels to approximately 300 ng/mL, whereas food-andwater-deprived control mice have serum corticosterone levels of less than 100 ng/mL (Ashcraft et al, 2008). Consistent with our hypothesis, mice that experienced restraint stress displayed more extensive vaginal pathology than did mice that were food-and-water deprived throughout infection (Figure 1).…”

“…Such studies have indicated that psychological stress and associated neuroendocrine peptides and hormones are generally immunosuppressive. Despite the multitude of studies on restraint stress during primary HSV-1 infection (Anglen et al, 2003;Ashcraft et al, 2008;Bonneau et al, 1993b;Bonneau et al, 1991;Brenner and Moynihan, 1997;DeLano and Mallery, 1998;Nair et al, 2007;Ortiz et al, 2003), there have been no publications on the effect of stress on primary vaginal HSV-1 infection. Therefore, the studies presented here aimed to determine the impact of restraint stress during primary vaginal HSV-1 infection on the number and function of immune cells governing both the innate and adaptive immune response.…”

“…Previous studies examining the impact of psychological stress on immune function have focused on HSV-1 infection via footpad (Bonneau et al, 1993b;Bonneau et al, 1991), ocular (Freeman et al, 2007;Kip et al, 2001) and intranasal (Anglen et al, 2003;Ashcraft et al, 2008;Nair et al, 2007) routes. In one or more of these studies, stress at the time of infection has been shown to delay CD8 + T cell infiltration, limit microglial MHC class I surface expression, and increase the titer of infectious HSV at the site of infection.…”

“…Recently, psychological stress during gastrointestinal infection has been demonstrated to reduce the concentration of intestinal IgA (Jarillo-Luna et al, 2007), the numbers of intraepithelial lymphocytes (Jarillo-Luna et al, 2008), and the production of interferon-γ (IFN-γ) (Yang et al, 2006). Our laboratory has recently shown that psychological stress reduces the number of immune cells responsible for limiting mucosal HSV infection via the intranasal route (Ashcraft et al, 2008), resulting in increased viral replication.…”

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

“…Psychosocial stress has been correlated with oral herpes recurrences in humans (8). Psychological stress at the time of infection increases HSV-1 titers and pathology following intranasal or vaginal infection in mice (7,9). Epinephrine (EPI), a catecholaminergic hormone secreted by the adrenal medulla to induce the "short-term" fight-or-flight stress response, is regulated by the sympathetic nervous system.…”