The idea that psychological stress may cause measurable changes in an individual's susceptibility to infectious disease is not new. One of the earliest proposals was put forth by Ishigami (1919) in which he described "the influence of psychic acts on the progress of pulmonary tuberculosis." Now, it is generally acknowledged that humans and animals exposed to chronic psychological or physical stressors have decreased resistance to microbial pathogens. The consequences of stress-induced modulation of the immune system include increased susceptibility and frequency of disease, prolonged healing times, and a greater incidence of secondary health complications associated with infection (Bailey et al., 2003). However, knowledge about how the perception of stress is processed in the central nervous system and then transmitted to peripheral physiological systems is incomplete. Therefore, information about the mechanism(s) by which a stressor, through its effects on the immune system, might increase susceptibility or severity of infectious disease is lacking.
Recently, it has been recognized that the immune system functions as a "sensory system" alerting the central nervous system to the dangers implicit in the invasion of its tissues by pathogenic microorganisms. This recognition has led to intense study of the bidirectional communication among the nervous, endocrine, and immune systems. Many of these studies focus on the HPA axis, which is one of the major pathways activated by stress (Bailey et al., 2003). Stress activates the HPA axis resulting in upregulation of mRNA expression and production of specific hormones including glucocorticoids and endogenous opioids (Hunzeker et al., 2004; Hermann et al., 1995). When examined in toto, these findings suggest a rudimentary mechanism by which stress-induced activation of the HPA axis results in increased neuroendocrine hormone production, followed by release of these "stress mediators" into circulation, and subsequent modulatory inter actions of these hormones with cells of the innate and adaptive arms of the immune system. The response to stress, however, is not always health aver-sive, and in fact it may serve to restore homeostasis and thus provide an adaptive response to environmental and internal stressors. This is not a new concept as the literature dating back to the first half of the 20th century contains the beginnings of a quest to understand how organisms successfully respond to environmental challenges (Selye, 1936). The conceptualization of a eustress, or "the good" stress, was articulated in this period and it provided a useful working model to explain the adaptive benefits of the host's response to challenge.
The goal of the studies conducted by our laboratories has been to experimentally model stress in a way that will identify points of intersection among the autonomic nervous system, the HPA axis, and the immune system that lead to meaningful alterations in health. Employing infectious challenge models, we have identified significant changes in the host's ability to generate and/or maintain a protective immune response during stress. These findings are detailed below.
In chronological terms, our work on stress and the immune system began as a collaboration with colleagues in the Ohio State University Medical Center (see Kiecolt-Glaser et al., 1993). Human studies of chronic stress, in which the subjects were caring for spouses with dementia, demonstrated that chronically stressed caregivers responded less well to a number of different commercially prepared vaccines that elicit protective responses to viral and bacterial pathogens (Glaser et al., 1992; Kiecolt-Glaser et al., 1993; Glaser et al., 2000). In an influenza vaccine study, the percentage of care-givers who seroconverted (defined as a fourfold rise in antibody titers to an influenza vaccine by ELISA and HAI) was lower than controls at 1 month postvaccination, and the IL-2 responses of peripheral blood lymphocytes from controls stimulated with influenza vaccine antigen was significantly higher at 30,90, and 180 days postvaccination than in the caregiver subjects (Kiecolt-Glaser et al., 1993).
Although studies such as these were illuminating and confirmed the negative effect of stress on the generation of protective immunity, it was left to nature to provide the appropriate infectious challenge (e.g., an influenza viral infection). So far, sufficient data have not been available to assess the state of protective immunity in naturally acquired influenza viral infections in these subjects.
Thus, questions about the mechanisms by which stress affects susceptibility and severity of an infection led to the development of animal models of stress and viral infection. The use of well-characterized stressors in rodent models provided an opportunity to conduct infection and immunity studies using microbial challenges with bacteria or viruses. This has been a very useful approach built on detailed knowledge of microbial pathogene-sis and antimicrobial immunity in the extant literature.
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