Stress can be defined as a state of altered homeostasis resulting from either an external or an internal stimulus. The host's response to stress is designed to restore homeostasis through a variety of adaptive neuroendocrine-mediated mechanisms (Ramsey, 1982). This restoration of homeostasis is accomplished, in part, through the increased synthesis of a variety of neuroendocrine-derived peptides and hormones. For example, the perception of a psychological stressor activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic branch of the autonomic nervous system. This activation culminates in the synthesis of both cortisol (corticosterone in rodents) by the adrenal glands and epinephrine and norepinephrine by the sympathetic nervous system. Interestingly, in addition to their roles in maintaining homeostasis, these and other products of the nervous and endocrine system pathways can also modulate immune function through their binding to specific receptors that are expressed by the many cell types that comprise the immune system. As a result, most aspects of immune function, including immunity to HSV, have the potential to be modulated under conditions of psychological stress.
Although studies in humans have established a clear relationship between stress and susceptibility to HSV infection, these studies have not been able to address each of the components of the immune response that underlie this relationship. However, the use of animal models has provided the opportunity to determine these immune components given the ability to establish an HSV infection and assess the responses at various sites throughout the body. Using a murine model, the effects of stress on susceptibility to HSV infections have been known for nearly 50 years (Rasmussen et al., 1957). Although these studies were important in establishing an association between stress and viral infection, they were unable to identify specific antiviral immune defense mechanisms that were modulated by stress and that contributed to viral pathogenesis, because the components and mechanisms of antiviral immune responses were unknown at that time. Since then, however, significant progress has been made in understanding the complex immune interactions that are necessary for the development of protective immunity to viral infections, including HSV. Thus, it is now possible to study the effects of stress on defined components of the antiviral immune response.
A number of animal-based studies have been conducted in an attempt to decipher the impact of psychological stress on immune function. Although many of the early studies had simply focused on aspects of nonspecific immune function such as lymphocyte proliferation and cytokine production, more recent studies have examined the effects of stress on the specific immune response to viral pathogens including HSV (Bonneau et al, 1991a, 1991b; Bonneau et al., 1993; Dobbs et al., 1993; Bonneau, 1996; Bonneau et al., 1997; Brenner and Moynihan, 1997; Glaser and Kiecolt-Glaser, 1997; Pariante et al., 1997; Bonneau et al., 1998; Carr et al, 1998; Delano and Mallery, 1998; Leo et al., 1998; Noisakran et al., 1998; Padgett et al, 1998a; Cruess et al, 2000; Leo and Bonneau, 2000a, 2000b; Buske-Kirschbaum et al., 2001; Wonnacott and Bonneau, 2002; Anglen et al., 2003; Ortiz et al., 2003), influenza virus (Sheridan et al., 1991; Feng et al., 1991; Hermann et al, 1993,1994a, 1994b, 1995; Dobbs et al, 1996; Padgett et al, 1998b; Cohen et al, 1999; Sheridan et al., 2000; Konstantinos and Sheridan, 2001; Hunzeker et al., 2004), adenovirus (Cohen et al., 1997), pseudorabies virus (deGroot et al., 1999a, 1999b), and Theiler's virus (Johnson et al., 2004; Mi et al, 2004; Sieve et al., 2004; Welsh et al., 2004). Some of these latter studies have also focused on the contribution of glucocorticoids and sympathetic nervous system products and have used a variety of stressors including physical restraint, social reorganization, social disruption, hypothermia, and acoustic stress to induce increased neuroendocrine levels. Despite the known widespread effects of stress on antiviral immunity, the studies described in this chapter focus specifically on the impact of stress on immunity to HSV.
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