Cells of the Innate Immune System

The nonspecific innate immune response to a viral infection consists of a variety of different cell types that contribute to the early defense against infection. To date, only a few studies have examined the influence of stress on these cell types in the context of an HSV infection.

Macrophages produce cytokines that influence the adaptive immune response, may present antigen to B and T lymphocytes, and eliminate virus infected cells. The role of macrophages during a primary HSV infection is not completely understood. However, both adoptive transfer and depletion studies have shown that macrophages can indeed contribute to host resistance to an HSV infection (Morahan and Morse, 1979; Pinto et al., 1997). In an ex vivo activation assay, Koff and Dunegan (1986) demonstrated that the sympathetic nervous system products epinephrine and norepinephrine can reduce the ability of macrophages to lyse HSV-1-infected target cells. In support of these in vitro findings, Davis and colleagues have recently shown that exercise stress can reduce the anti-HSV activity of macrophages (Davis et al., 2004). However, the effects of stress-induced alterations in macrophage activity on HSV pathogenesis has not yet been determined.

Natural killer (NK) cells serve as a bridge between the innate and adaptive arms of the immune response by limiting viral replication as well as producing cytokines that aid in the adaptive response. As with macrophages, the role of the NK cell during a primary HSV infection is not completely understood. For example, conflicting studies have suggested that NK cells are not necessary (Bukowski and Welsh, 1986), whereas others have shown that NK cells are required for the resolution of an HSV infection (Biron et al., 1989). The differences between these studies may primarily be due to species differences (human vs. mouse). Consistent with these conflicting reports, stress has been shown to have differing effects on NK cell activity during a primary HSV infection. For example, restraint stress has been shown to reduce splenic NK cell lytic activity after an intradermal HSV-1 infection (Bonneau et al., 1991a). However, in a model of exercise stress, running to fatigue did not have any effect on splenic NK cell activity (Davis et al., 2004). Additional studies need to be conducted to better elucidate the role of NK cells during a primary infection and how stress may affect their antiviral activities. In interpreting the findings of these and other studies, it is important not to generalize among studies but instead to consider differences such as the species being examined, the site of HSV infection, and the stage of infection (e.g., primary, latent, recurrent) being examined.

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