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Immunological memory (MEM) development is affected by stress-induced neuroendocrine mediators. Current knowledge about how a behavioral interaction, such as social defeat, alters the development of adaptive immunity, and MEM is incomplete. In this study, the experience of social disruption stress (SDR) prior to a primary influenza viral infection enhanced the frequency and function of the T cell memory pool. Socially stressed mice had a significantly enlarged population of CD8(+) T cells specific for the immunodominant NP366-74 epitope of A/PR/8/34 virus in lung and spleen tissues at 6-12 wk after primary infection (resting memory). Moreover, during resting memory, SDR-MEM mice responded with an enhanced footpad delayed-type hypersensitivity response, and more IFN-gamma-producing CD4(+) T cells were detected after ex vivo stimulation. When mice were rechallenged with A/PR/8/34 virus, SDR-MEM mice terminated viral gene expression significantly earlier than MEM mice and generated a greater D(b)NP(366-74)CD8(+) T cell response in the lung parenchyma and airways. This enhancement was specific to the T cell response. SDR-MEM mice had significantly attenuated anti-influenza IgG titers during resting memory. Similar experiments in which mice were primed with X-31 influenza and challenged with A/PR/8/34 virus elicited similar enhancements in the splenic and lung airway D(b)NP(366-74)CD8(+) T cell populations in SDR-MEM mice. This study demonstrates that the experience of repeated social defeat prior to a primary viral infection significantly enhances virus-specific memory via augmentation of memory T cell populations and suggests that social stressors should be carefully considered in the design and analysis of future studies on antiviral immunity.

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Psychological stress is associated with an increased expression of markers of peripheral inflammation, and there is a growing literature describing a link between periodontal pathogens and systemic inflammation. The hypothesis of the present work is that exposing mice to the social stressor, called social disruption (SDR), would enhance the inflammatory response to lipopolysaccharide (LPS) derived from the oral pathogen, Porphyromonas gingivalis. Mice were exposed to SDR for 2h per day on 6 consecutive days. On the morning following the last cycle of SDR, mice were tested for anxiety-like behavior in the open field test and novel object test. The mice were sacrificed the following day and their spleens harvested. Spleen cells were stimulated with LPS derived from P. gingivalis in the absence or presence of increasing doses of corticosterone. Social disruption resulted in anxiety-like behavior, and the production of IL-1beta and TNF-alpha was significantly higher in spleen cells from mice exposed to SDR in comparison to levels from non-stressed control mice. In addition, the viability of spleen cells from mice exposed to SDR was significantly greater than the viability of cells from non-stressed control mice, even in the presence of high doses of corticosterone. The use of cultures enriched for CD11b+ cells indicated that the stressor was affecting the activity of splenic myeloid cells. This study demonstrates that social stress enhances the inflammatory response to an oral pathogen and could provide a critical clue in the reported associations between stress, inflammation, and oral pathogens.

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This article summarizes the endocrine and immune changes induced by an experimental model for social stress characterized by repeated defeat. Data indicate that mice facing a social stressor may use different behavioral coping responses based on the environmental conditions and previous experiences. Although chronic stressors generally suppress immune function and increase a host's susceptibility to disease, this may not be always true in all cases. For example, under conditions in which individuals face the chance of being injured repeatedly, it may be an adaptive advantage to maintain or even enhance an immune response. The development of glucocorticoid resistance after social disruption may be such a mechanism, allowing animals to heal injuries and clear invading microbes in the presence of the anti-inflammatory stress hormones.

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KINSEY, S. G., BAILEY, M. T., SHERIDAN, J. F., PADGETT, D. A. The inflammatory response to social defeat is increased in older mice. PHYSIOL BEHAV 91(0) 000-000, 2007. Previous research indicates that repeated social defeat of mice causes increased lymphocyte trafficking to the spleen, elevated proinflammatory cytokine production, and induced glucocorticoid insensitivity in splenocytes. Social defeat also causes increases in anxiety-like behavior. This study investigated whether repeated social defeat results in similar immunoregulatory and behavioral changes in older mice as those seen previously in young adult mice. The data revealed that, regardless of age, defeated mice had significantly more splenic CD11b+ Gr-1+ monocytes and neutrophils than controls. Supernatants harvested from cultured splenocytes from older mice contained comparatively higher IL-6 and TNF-alpha than supernatants from younger animals. In addition, those same cells derived from older defeated mice were hypersensitive to lipopolysaccharide (LPS) and insensitive to glucocorticoids in vitro. As seen previously in young adult mice, social defeat caused an increase in anxiety-like behavior in the open field test, but had no effect on learned helplessness in the forced swim test. These data indicated that repeated social defeat results in a proinflammatory state that is exacerbated in older mice. The implications of these data are noteworthy, given the strong role of inflammation in many age-related diseases.

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Social stress has long been known to affect physical and psychological health in humans and a variety of animal species. In mice, disruption of the social hierarchy (social disruption, SDR) resulted in significant changes in the phenotype and function of immune cells taken from the spleen. Interestingly, there were considerable individual differences in the development of this splenic response to SDR. Studies have suggested that these individual differences were mediated by behavioral factors such as social hierarchy. To test this hypothesis, social status within cages of male mice was identified before and after SDR. Results showed that in the majority of the cages social order was stable over time. In addition, examination of the association between social status and splenic function showed that the splenic response to SDR in subordinate mice was significantly augmented compared to dominants. This relationship between subordinate social status and the splenic response to social stress was more notable in cages with stable social hierarchies. To sum up, the current study showed a role for socio-behavioral factors in determining the response to stress. This study further demonstrated the complexity of factors playing a role in mediating the physiological response to social stress resulting in considerable individual differences in the response to stress.

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Phagocytes of the innate immune system, such as monocytes/macrophages, represent a first line of defense against invading microorganisms. Psychological stress is often thought to suppress the functioning of these cells, in part due to the immunosuppressive activity of stress-induced glucocorticoid hormones. However, exposure to the stressor social disruption (SDR) has been shown to increase cytokine production by monocytes/macrophages and to reduce their sensitivity to corticosterone. Thus, it was hypothesized that splenic monocytes/macrophages from socially stressed mice would be primed to be more physiologically active than cells from nonstressed controls. Flow cytometry was used to demonstrate that exposure to SDR significantly increased the expression of Toll-like receptors (TLR) 2 and 4 on the surface of splenic macrophages. In a follow-up experiment, exposure to SDR also increased the ability of these macrophages to kill Escherichia coli ex vivo and in vivo. However, SDR failed to increase the bactericidal activity of splenic macrophages from C3H/HeJ mice, which lack functional TLR4. In mice with functional TLR4, the stress-induced increase in bactericidal activity was associated with a significant increase in macrophage gene expression for inducible nitric oxide synthase and subunits of the NADPH oxidase complex, which are responsible for generating reactive nitrogen and oxygen intermediates, respectively. This stress-induced increase in gene expression was not evident in the TLR4-deficient mice. These data indicate that SDR increases TLR expression, which in turn enhances the bactericidal activity of splenic macrophages, in part by increasing pathways responsible for reactive oxygen and nitrogen intermediate production.

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The experimental model, social disruption (SDR), is a model of social stress in which mice are repeatedly attacked and defeated in their home cage by an aggressive conspecific. In terms of the impact of this stressor on the immune response, SDR has been reported to cause hyperinflammation and glucocorticoid insensitivity. To this point however, the behavioral consequences of SDR have not been thoroughly characterized. Because social defeat has been reported to cause anxiety- and depressive-like behaviors, the current study was designed to assess whether SDR also causes anxiety- and depressive-like behaviors. Using the light/dark preference test and the open field test as tools to measure behaviors characteristic of anxiety, the data showed that C57BL/6 and CD-1 male mice subjected to SDR displayed increased anxiety-like behavior. The increase in anxiety-like behaviors persisted for at least 1 week after the cessation of the stressor. In contrast, depressive-like behaviors were not elicited by SDR as assessed by the forced swim test or the tail suspension test. These data indicate that social disruption stress causes an increase in anxiety-like behaviors, but not depressive-like behaviors.

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For 20 years, Brain, Behavior, and Immunity has provided an important venue for the publication of studies in psychoneuroimmunology. During this time period, psychoneuroimmunology has matured into an important multidisciplinary science that has contributed significantly to our knowledge of mind, brain, and body interactions. This review will not only focus on the primary research papers dealing with psychoneuroimmunology, viral infections, and anti-viral vaccine responses in humans and animal models that have appeared on the pages of Brain, Behavior, and Immunity during the past 20 years, but will also outline a variety of strategies that could be used for expanding our understanding of the neuroimmune-viral pathogen relationship.

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This review summarizes the endocrine and immune changes induced by an experimental model for social stress that is termed SDR. Further, the differences between this stressor and other chronic stress models in mice are compared and contrasted. Individual differences in the response to SDR are described and discussed in the context of the unique characteristics of this stressor and the importance of a variety of behavioral and environmental factors in modulating the response to social stress. The collection of data indicates that mice facing a social stressor may use different behavioral coping responses based on the environmental conditions and previous experiences. These different adaptational responses are reflected in their behavioral, endocrine, and immune changes in response to the stressor [7], [8]. In conclusion, although generally it is understood that chronic stressors suppress immune function and increase a host's susceptibility to disease, this may not be dogma. For example, under conditions in which individuals face the chance of being injured, which may be a chronic or reoccurring likelihood, it may be an adaptive advantage to maintain or even enhance an immune response. The development of GCR after SDR may be such a mechanism, allowing animals to heal injuries and clear invading bacteria in the presence of the anti-inflammatory stress hormones. Thus, individual differences in response to SDR are associated with specific behavioral strategies that can have substantive implications for host resistance to infectious disease.

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Restraint stress (RST) delays wound closure and suppresses pro-inflammatory gene expression by a glucocorticoid-dependent mechanism. Because androstenediol (AED) ameliorates many of the anti-inflammatory influences of glucocorticoids (GC) in vitro, it was hypothesized that treatment of stressed animals with AED would ameliorate the suppressive influence of restraint and restore healing to control levels. To test this hypothesis, male CD1 mice were subjected to nightly cycles of RST beginning 3 days prior to placement of two 3.5 mm full-thickness cutaneous wounds. To assess the influence of AED treatment on wound repair, mice were injected subcutaneously with 2.0 mg of AED or an equivalent volume of delivery vehicle (VEH) prior to wounding. The rate of wound closure was assessed daily by photoplanimetry. In addition, at 3, 6, 12, and 24 h post wounding, IL-1beta, MCP-1, and PDGF RNAs were quantified in wounds as a measure of inflammatory gene expression. The data showed that RST significantly delayed closure as compared to controls. In parallel, RST significantly decreased IL-1beta and PDGF gene expression as early as 12 h after wounding. In contrast, treatment with AED prevented the stress-induced delay in healing. Whereas wounds on VEH/RST mice did not achieve 50% closure until day 7, wounds on AED-treated animals, whether subjected to RST or not, had closed by 50% within 3 days of wounding. In addition, AED treatment prevented the stress-induced suppression of IL-1beta and PDGF gene expression 24 h after injury. Therefore, AED may provide a pharmacologic approach to ameliorate the anti-inflammatory effects of behavioral stress and in doing so, may improve tissue repair.

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Epstein-Barr virus (EBV) encodes for several enzymes that are involved in viral DNA replication. There is evidence that some viral proteins, by themselves, can induce immune dysregulation that may contribute to the pathophysiology of the virus infection. In this study, we focused on the EBV-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase) and present the first evidence that the dUTPase is able to induce immune dysregulation in vitro as demonstrated by the inhibition of the replication of stimulated peripheral blood mononuclear cells (PBMCs) and the upregulation of several proinflammatory cytokines including TNF-alpha, IL-1beta, IL-8, IL-6, and IL-10 produced by unstimulated PBMCs treated with purified EBV-encoded dUTPase. Depletion of CD14-positive cells (monocytes) eliminated the cytokine profile induced by EBV dUTPase treatment. The data support the hypothesis that at least one protein of the EBV early antigen complex can induce immune dysregulation and may be involved in the pathophysiology of EBV-associated disease.

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We have previously shown that moderate exercise significantly increased survival after influenza virus (A/PR/8/34) infection in mice. We hypothesized that this brief duration of exercise would either increase innate immune defences and/or shift the immune response from a Th1 inflammatory to a Th2 anti-inflammatory response resulting in decreased lung pathology. Adult male BALB/cByJ mice (5-6 months old) were infected with 50 microL of A/PR/8/34 virus (40HAU) intranasally and randomized to either an exercise (EX) or sedentary (SED) group. EX mice performed 20-30 min of moderate exercise (8-12 m/min) on a motorized treadmill 4 hr post-infection and then exercised similarly for 4 consecutive days. SED mice were exposed to similar environmental conditions but did not exercise. Mice from both EX and SED groups were sacrificed 1, 3, or 5 days post-infection (p.i.) and lungs, mediastinal lymph nodes (MLNs) and spleens were harvested. EX significantly reduced total cellular infiltration and IFN-gamma gene expression in lungs at Days 3 and 5 p.i. and there was a qualitative shift in the expression of cytokines in the lung from a Th1 to a Th2 response. There was also a tendency toward a reduction in influenza M1 protein mRNA expression. There was no difference in IFN-beta protein levels between groups. These data suggest that moderate exercise when applied early after infection shifts the immune response away from a Th1 profile in mice infected with influenza virus. This exercise-induced shift in immune response may be responsible for improved survival after influenza virus infection.

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Over the past decade it has become clear that stress can significantly slow wound healing: stressors ranging in magnitude and duration impair healing in humans and animals. For example, in humans, the chronic stress of caregiving as well as the relatively brief stress of academic examinations impedes healing. Similarly, restraint stress slows healing in mice. The interactive effects of glucocorticoids (e.g. cortisol and corticosterone) and proinflammatory cytokines [e.g. interleukin-1beta (IL-1beta), IL-1alpha, IL-6, IL-8, and tumor necrosis factor-alpha] are primary physiological mechanisms underlying the stress and healing connection. The effects of stress on healing have important implications in the context of surgery and naturally occurring wounds, particularly among at-risk and chronically ill populations. In research with clinical populations, greater attention to measurement of health behaviors is needed to better separate behavioral versus direct physiological effects of stress on healing. Recent evidence suggests that interventions designed to reduce stress and its concomitants (e.g., exercise, social support) can prevent stress-induced impairments in healing. Moreover, specific physiological mechanisms are associated with certain types of interventions. In future research, an increased focus on mechanisms will help to more clearly elucidate pathways linking stress and healing processes.

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We wanted to determine if different doses of exercise, performed in the initial days after infection when the host is mounting an immune response, altered mortality, and morbidity to influenza virus infection in mice. Forty hemagglutinating units of influenza virus (A/Puerto Rico/8/34) were administered intranasally to lightly anesthetized mice. Male Balb/cByJ mice were randomized to one of three groups: sedentary control (CON); moderate (MOD) exercise (20-30 min at 8-12 m/min); or prolonged (PRO) exercise (2.5 h at 8-12 m/min). Mice exercised on a treadmill 4 h post-infection and for three more consecutive days before symptom onset. Mortality, morbidity, bodyweight, and food intake were assessed. MOD had a significantly (p = .007) higher survival (18 of 22; 82%) rate when compared to CON (10 of 23; 43%). There was no difference in morbidity between MOD and CON, despite improved survival. PRO exhibited a survival rate of 30% (p = .29 vs. CON) and demonstrated significantly higher morbidity on several days. While all groups exhibited anorexia and significant body weight loss (approximately 30-35%) post-infection, exercise had little effect on these variables. We demonstrate that moderate exercise, performed in the initial days after influenza infection, significantly decreased mortality in mice. Prolonged exercise led to increased morbidity and tended to decrease survival.

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In the present study the global effect of restraint stress on gene expression in the murine lung during an experimental influenza A/PR8 viral infection was examined. Gene expression profiling using high density oligonucleotide microarrays revealed that the expression of 95 genes was altered on day 3 post infection (p.i.), while 48 genes were altered on day 7 p.i. Restraint stress reduced and delayed the expression of specific cytokines, cell adhesion molecules and cell surface receptors indicating alterations in cell migration to the site of infection. Furthermore, mapping of the candidate genes to known pathways revealed that genes associated with host defense and immune responses, including chemotaxis and chemokine function, antigen presentation and processing, MHC class II receptor function and inflammation were the major pathways affected by restraint stress.

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Antibodies to several Epstein-Barr virus (EBV)-encoded enzymes are observed in patients with different EBV-associated diseases. The reason for these antibody patterns and the role these proteins might play in the pathophysiology of disease, separate from their role in virus replication, is unknown. In this series of studies, we found that purified EBV deoxyuridine triphosphate nucleotidohydrolase (dUTPase) can inhibit the replication of human peripheral blood mononuclear cells in vitro and upregulate the production of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10. It also enhanced the ability of natural killer cells to lyse target cells. The EBV dUTPase also significantly inhibited the replication of mitogen-stimulated lymphocytes and the synthesis of IFN-gamma by cells isolated from lymph nodes and spleens obtained from mice inoculated with the protein. It also produced sickness behaviors known to be induced by some of the cytokines that were studied in the in vitro experiments. These symptoms include an increase in body temperature, a decrease in body mass and in physical activity. The data provide a new perspective on how an early nonstructural EBV-encoded protein can cause immune dysregulation and produce clinical symptoms observed in patients with chronic fatigue syndrome (CFS) separate from its role in virus replication and may serve as a new approach to help identify one of the etiological agents for CFS. The data also provide additional insight into the pathophysiology of EBV infection, inflammation, and cancer.

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Activation of the hypothalamic-pituitary-adrenal axis (HPA) and sympathetic nervous system by stress has been shown to modulate both innate and adaptive immunity during an experimental influenza A/PR8 viral infection. HPA activation alters levels of glucocorticoids (GC) and opioids which are associated with suppression of lymphoid cellularity and NK activity. These experiments were designed to investigate the role that stress-induced GC and opioids have in modulating NK activity during an influenza viral infection. C57BL/6 mice were treated daily with mifepristone (RU486), a GC receptor antagonist or naltrexone (NTX), a non-specific opioid receptor antagonist. Mice were infected intranasally with A/PR8 virus and underwent daily restraint stress (RST). Phenotypic analysis of splenic cell populations and NK cytotoxicity were assessed at 3 days post-infection. RST of infected mice significantly suppressed splenic CD3(-)DX5+ cellularity and NK cytolytic activity. RU486 administration fully restored splenic NK cellularity but not cytolytic activity. NTX administration restored NK cytolytic activity but not splenic NK cell number. A similar restoration in NK cytolytic activity was observed after administration of beta-funaltrexamine (FNA), a mu-specific opioid receptor antagonist, but not the delta- or kappa-specific opioid receptor antagonists naltrindole or nor-binaltorphimine, respectively. Co-administration of RU486 and NTX restored both NK cellularity and cytolytic activity. The restoration of RST-induced suppression of NK activity by RU486 and NTX or FNA suggests that glucocorticoids modulate NK cellularity and opioids that bind to the mu-opioid receptor modulate NK cytotoxicity during periods of stress and viral infection.

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Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis (IM). In addition, latent infections with EBV are associated with nasopharyngeal carcinoma (NPC) and Burkitt's Lymphoma (BL). Antibodies to several EBV-encoded early antigens (EA) are often observed in patients with NPC and BL, however, the role of EBV-encoded proteins in the etiology of these and other EBV-associated diseases is not completely understood. The EA complex encodes for at least six different viral enzymes including deoxyuridine triphosphate nucleotidohydrolase (dUTPase). dUTPase has recently been shown to modulate activation of human peripheral blood mononuclear cells in vitro (unpublished data). Therefore, these studies were designed to test whether dUTPase would modulate immune function in an in vivo model. Mice were injected with purified EBV dUTPase, and baseline immune function and sickness behaviors were measured. EBV dUTPase treatment inhibited replication of mitogen-stimulated lymphocytes obtained from treated mice. These lymphocytes were also less able to synthesize interferon-gamma after re-stimulation. In addition, treatment with dUTPase induced sickness behaviors. For example, as compared to control animals, dUTPase-treated animals lost body mass, had elevated body temperature, and displayed diminished locomotor activity. These data suggest that individual viral proteins may play a role in the pathophysiology of EBV associated disease.

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These experiments were designed to examine the influences of restraint stress (RST) on natural killer (NK) activity and to determine its consequences on influenza A/PR8 (A/PR8) viral replication in mice. The data showed that RST delayed the recruitment of NK1.1+ cells into the lung parenchyma during infection. Quantification of MIP-1alpha and MCP-1 gene expression by real-time PCR revealed that RST suppressed the chemokines responsible for NK cell recruitment into the infected tissue. Additionally, RST suppressed the expression of several macrophage-derived cytokines involved in the effector response of NK cells. IL-15, which is the main cytokine involved in NK cell development and homeostasis, and IL-12, which is important for NK cytotoxicity, were both suppressed. As the NK cell response is an important innate response to control viral replication, we hypothesized that the RST-mediated reduction in NK cell numbers and function would enable viral replication to continue unchecked. In fact, there was enhanced viral replication in the lungs of RST animals. Interestingly, expression of the anti-viral type I interferons (IFN-alpha and IFN-beta) was elevated presumably in response to the elevated viral load in the stressed mice. Together, these data show that RST suppressed expression of the cytokine genes involved in the recruitment and activation of NK cells during an experimental influenza viral infections. The consequence of this effect was diminished NK cell function and enhanced viral replication.

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Social disruption (SDR) in male mice reduces the sensitivity of their splenocytes to the actions of glucocorticoids. To determine whether physical defeat is necessary for the development of this reduced sensitivity, a modification of the SDR paradigm was employed in which mice were exposed to fighting conspecifics in the presence or absence of physical contact. This was accomplished by dividing a cage of 5 resident male C57BL/6 mice in half with a wire mesh partition so that 2 of the mice in the cage (SDR Physical Contact mice) fought and were defeated by an aggressive male C57BL/6 intruder that was placed into the cage for 2h for up to 6 days, while the remaining 3 resident mice (SDR Sensory Contact mice) were on the opposite side of the partition and thus prevented from physically interacting with the intruder. Although both the SDR Physical Contact and the SDR Sensory Contact mice had significantly elevated corticosterone levels and displayed submissive postures toward the intruder, only the SDR Physical Contact animals developed functional glucocorticoid resistance. The viability of LPS-stimulated splenocytes cultured from the SDR Physical Contact mice was not affected by pharmacological doses of corticosterone, whereas splenocyte viability was significantly reduced by corticosterone in cultured cells from SDR Sensory Contact and control mice. This study indicates that exposure to a stressful environment in the absence of physical attack does not reduce the sensitivity of murine splenocytes to the suppressive effects of corticosterone.

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