Esther M. Sternberg

The study of host susceptibility to infectious disease has shifted focus over the decades from one primarily centered on the organism and its characteristics to one centered on the host's immune-defense mechanisms. Recent research has made clear, however, that there is a two-way relationship between host and invading microorganism in which factors released by the host in response to the microorganism alter infectivity and course of infection and in turn by which factors released by the microorganism alter host defense mechanisms to infection. The purpose of this volume is to highlight these sometimes symbiotic and sometimes detrimental bidirectional influences of host-on-pathogen and pathogen-on-host responses. In particular, this volume focuses on extraimmune host responses of the central nervous and neuroendocrine systems that are activated during stress and during infection.

This interaction is particularly relevant to infectious disease, because an infected host is "stressed" for multiple reasons. Infection itself activates the stress response, through bacterial or viral products and through host cytokines released in response to invading microorganisms. In addition, infection is also associated with psychological and physiological stressors that further activate host stress-response mechanisms. Cytokines activate central neuroendocrine stress responses directly, by crossing the blood-brain barrier at leaky sites and via active transport, or indirectly by activating second messenger enzyme systems in cerebral endothelial cells with resultant release of second messengers such as nitric oxide and prostaglandins (reviewed in Marques-Deak et al., 2005). In addition, cytokines activate central vagal autonomic pathways by binding to receptors on vagal paraganglia cells (Watkins and Maier, 1999). This volume will not focus on these afferent pathways, however, but will focus on the effects on infection of the hormonal and neurochemical products released when these stress-response systems are activated.

When considering the effects of neuroendocrine and neural systems on host defense to infection, one can analyze the relationship at a systems and anatomical level as well as at a cellular and molecular level. Much research has been done in this area at a systems level, examining the effects of the various effector arms of the central nervous system on host susceptibility and resistance to infection. These include the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic, parasympathetic, and peripheral nervous systems. It is becoming increasingly clear that there is a specificity of pattern of activation of stress-response pathways, depending upon the particular type of stressor to which the host is exposed. Thus, physiological stress such as hypovolemia and psychological stress such as pain have been shown to activate different brain regions. Furthermore, patterns of activation of central stress-response pathways differ according to route, dose, and particular pathogen products to which the host is exposed. Finally, the location at which neurotransmitters and neurohormones are released, whether locally at sites of inflammation or infection, regionally in lymph nodes or immune organs, or systemically in the bloodstream, also determine the ultimate effects of these molecules on host responses to infectious agents.

This volume will address such systemic physiological responses, including the role of stress activation of the neuroendocrine stress response (HPA axis) on an important aspect of innate first-line host defense—immune cell trafficking (Dhabhar)—and on viral infection (Theiler's virus: Welsh et al.). It will address the effects of activation of the sympathetic nervous system on cellular and molecular aspects of innate and cell-mediated immunity (Fleshner; Sanders) and the effects of the autonomic nervous system on HIV infection (Sloan et al.). In addition, the effects on viral infection of psychological activation of these stress-response systems by stressful and early life events and naturalistic stressors will be addressed (HSV: Bonneau and Hunzeker; influenza: Bailey, Padgett, and Sheridan; Theiler's virus: Meagher). New research also reviewed in this volume is increasingly showing that different types of stress, such as restraint versus social stress, have different effects not only on stress-response activation patterns but also on susceptibility to and course of infection. In addition, such stressors differentially affect the course and severity of infection with specific microorganisms, whether specific viruses (HSV, influenza) or bacteria.

It is also important to consider these relationships at a cellular and molecular level not only in order to fully understand the pathogenesis of the effects of physiological stresses on the infected host but also as potential therapeutic targets. Thus the effects of bacterial toxins on repressing trans-activation of nuclear hormone receptors such as the glucocorticoid receptor is another level of interaction between microorganism and host that may play an important role in altering host defenses. In this context, the microorganism could potentially induce a state of glucocorticoid resistance that would interfere with the host's ability to suppress inflammation through release of glucocorticoids from the adrenals—an event that ordinarily occurs during infection as a result of HPA axis stimulation by cytokines or bacterial products and should counter excessive host inflammatory responses. Defining the precise molecular mechanism of such effects could lead to development of new therapeutic approaches that bypass the block and reinstate appropriate glucocorticoid modulation of inflammation in the context of infection.

Such interactions also underscore the concept that pathology in the context of infection may result from either inadequate host immune/ inflammatory defenses that are unable to contain the invading microorganism or from excessive immune/inflammatory host responses that result in tissue damage from inflammation. An appropriate inflammatory/immune response is necessary to control and clear infectious agents from the host. However, during stress, excessive release of glucocorticoids reduces immune-defense mechanisms, resulting in worse infection. In contrast, glucocorticoid resistance induced by bacterial products may prevent control of inflammatory responses to the pathogen, thus worsening tissue damage from excessive host responses. In addition, activation of different arms of the central nervous system stress response may also alter the balance of appropriate inflammatory responses to pathogens. In some contexts, glucocorticoids or adrenergic factors may enhance and in others they may suppress inflammatory/immune responses. Also addressed in this text is the important role of sex hormones, in particular estrogens, on this balance of inflammation and infection.

An additional level at which host defense responses may alter infection is through the direct effects of neurohormones and neurotransmitters on microorganism replication. In some cases, mediators released during stress, such as NO or Hsp72, may facilitate recovery from infection (E. coli: Flesh-ner), while in others neurotransmitters such as catecholamine accelerate viral replication (HIV-1: Sloan et al.). Not addressed in this volume, but also a direct effect of host mediators on pathogens, is the antibacterial effect of chromogranins released from adrenal medullary cells during adrenergic activation (Briolat et al., 2005).

Given the complexity of the many hormones and neurotransmitters released during infection and the changing inflammatory/immune responses that occur over time as the infection evolves, it is not surprising that host responses to infectious agents vary greatly depending on host and environmental and pathogen factors. In some cases, environmental factors such as psychological stress may contribute to this variability, and in others internal physiological variables such as physiological stress may contribute. Interactions of pathogen products with these host response pathways at a system's cellular and molecular level also alter host defenses. Similarly, mediators released by the host in the course of infection alter the infectiv-ity of pathogens. Careful dissection of these pathogen-host interactions at all levels will provide insights into pathogenesis of infection and the many environmental and host factors that alter the course of infection and could ultimately yield important new therapeutic approaches and targets for treatment of infection.


Briolat, J., Wu, S.D., Mahata, S.K., Gonthier, B., Bagnard, D., Chasserot-Golaz, S., Helle, K.B., Aunis, D., and Metz-Boutigue, M.H. (2005). New antimicrobial activity for the catecholamine release-inhibitory peptide from chromogranin A. Cell. Mol. Life Sci. 62:377-385.

Marques-Deak, A., Cizza, G., and Sternberg, E. (2005). Brain-immune interactions and disease susceptibility. Mol. Psychiatry 10:239-250.

Watkins, L.R., and Maier, S.F. (1999). Implications of immune-to-brain communication for sickness and pain. Proc. Natl. Acad. Sci. U. S. A. 96:7710-7713.

Part I

Neural and Neuroendocrine Mechanisms in Host Defense: Molecular and Cellular Mechanisms

Stress-induced Changes in Immune Cell Distribution and Trafficking: Implications for Immunoprotection versus Immunopathology

Firdaus S. Dhabhar

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