Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation.

Acute infections are associated with a set of stereotypic behavioral responses, including anorexia, lethargy, and social withdrawal. Although these so-called sickness behaviors are the most common and familiar symptoms of infections, their roles in host defense are largely unknown. Here, we investigated the role of anorexia in models of bacterial and viral infections. We found that anorexia was protective while nutritional supplementation was detrimental in bacterial sepsis. Furthermore, glucose was necessary and sufficient for these effects. In contrast, nutritional supplementation protected against mortality from influenza infection and viral sepsis, whereas blocking glucose utilization was lethal. In both bacterial and viral models, these effects were largely independent of pathogen load and magnitude of inflammation. Instead, we identify opposing metabolic requirements tied to cellular stress adaptations critical for tolerance of differential inflammatory states. VIDEO ABSTRACT.

The telencephalon is a neuronal substrate for systemic inflammatory responses in teleosts via polyamine metabolism.

Systemic inflammation elicits sickness behaviors and fever by engaging a complex neuronal circuitry that begins in the preoptic area of the hypothalamus. Ectotherms such as teleost fish display sickness behaviors in response to infection or inflammation, seeking warmer temperatures to enhance survival via behavioral fever responses. To date, the hypothalamus is the only brain region implicated in sickness behaviors and behavioral fever in teleosts. Yet, the complexity of neurobehavioral manifestations underlying sickness responses in teleosts suggests engagement of higher processing areas of the brain. Using in vivo models of systemic inflammation in rainbow trout, we find canonical pyrogenic cytokine responses in the hypothalamus whereas in the telencephalon and the optic tectum il-1b and tnfa expression is decoupled from il-6 expression. Polyamine metabolism changes, characterized by accumulation of putrescine and decreases in spermine and spermidine, are recorded in the telencephalon but not hypothalamus upon systemic injection of bacteria. While systemic inflammation causes canonical behavioral fever in trout, blockade of bacterial polyamine metabolism prior to injection abrogates behavioral fever, polyamine responses, and telencephalic but not hypothalamic cytokine responses. Combined, our work identifies the telencephalon as a neuronal substrate for brain responses to systemic inflammation in teleosts and uncovers the role of polyamines as critical chemical mediators in sickness behaviors.

Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.

Acute experimental inflammation in healthy women attenuates empathy for psychological pain.

Administration of low-dose lipopolysaccharide (LPS) to healthy humans is a translational approach to analyze the effects of acute systemic inflammation and sickness behavior. Although studies documented that LPS-induced inflammation can alter social behavior, its impact on empathy remains poorly understood. In this double-blind, placebo-controlled study, 52 healthy female volunteers received an intravenous injection of either LPS (0.4 ng/kg body weight) or placebo and completed the Social Interaction Empathy Task (SIET) two hours after injection. Physiological responses (blood pressure, heart rate, body temperature, cytokines, cortisol) were analyzed along with sickness symptoms and mood before and after LPS or placebo administration. LPS application led to significant increases in plasma cytokines and sickness symptoms as well as low mood. Moreover, volunteers receiving LPS showed significantly less empathy for other's psychological pain than those who received placebo. Furthermore, LPS-injected volunteers with more severe sickness symptoms displayed higher pain ratings in the first-person perspective. Thus, low-grade inflammation reduces empathy for other's psychological pain which might reflect an adaptive strategy to save energy by not responding empathetically when sick oneself.

Fevers and the social costs of acute infection in wild vervet monkeys.

Fevers are considered an adaptive response by the host to infection. For gregarious animals, however, fever and the associated sickness behaviors may signal a temporary loss of capacity, offering other group members competitive opportunities. We implanted wild vervet monkeys (Chlorocebus pygerythrus) with miniature data loggers to obtain continuous measurements of core body temperature. We detected 128 fevers in 43 monkeys, totaling 776 fever-days over a 6-year period. Fevers were characterized by a persistent elevation in mean and minimum 24-h body temperature of at least 0.5 °C. Corresponding behavioral data indicated that febrile monkeys spent more time resting and less time feeding, consistent with the known sickness behaviors of lethargy and anorexia, respectively. We found no evidence that fevers influenced the time individuals spent socializing with conspecifics, suggesting social transmission of infection within a group is likely. Notably, febrile monkeys were targeted with twice as much aggression from their conspecifics and were six times more likely to become injured compared to afebrile monkeys. Our results suggest that sickness behavior, together with its agonistic consequences, can carry meaningful costs for highly gregarious mammals. The degree to which social factors modulate the welfare of infected animals is an important aspect to consider when attempting to understand the ecological implications of disease.

Behavioral and physiological sensitivity to natural sick faces.

The capacity to rapidly detect and avoid sick people may be adaptive. Given that faces are reliably available, as well as rapidly detected and processed, they may provide health information that influences social interaction. Prior studies used faces that were manipulated to appear sick (e.g., editing photos, inducing inflammatory response); however, responses to naturally sick faces remain largely unexplored. We tested whether adults detected subtle cues of genuine, acute, potentially contagious illness in face photos compared to the same individuals when healthy. We tracked illness symptoms and severity with the Sickness Questionnaire and Common Cold Questionnaire. We also checked that sick and healthy photos were matched on low-level features. We found that participants (N = 109) rated sick faces, compared to healthy faces, as sicker, more dangerous, and eliciting more unpleasant feelings. Participants (N = 90) rated sick faces as more likely to be avoided, more tired, and more negative in expression than healthy faces. In a passive-viewing eye-tracking task, participants (N = 50) looked longer at healthy than sick faces, especially the eye region, suggesting people may be more drawn to healthy conspecifics. When making approach-avoidance decisions, participants (N = 112) had greater pupil dilation to sick than healthy faces, and more pupil dilation was associated with greater avoidance, suggesting elevated arousal to threat. Across all experiments, participants' behaviors correlated with the degree of sickness, as reported by the face donors, suggesting a nuanced, fine-tuned sensitivity. Together, these findings suggest that humans may detect subtle threats of contagion from sick faces, which may facilitate illness avoidance. By better understanding how humans naturally avoid illness in conspecifics, we may identify what information is used and ultimately improve public health.

From mechanism to ecosystem: building bridges between ecoimmunology, psychoneuroimmunology and disease ecology.

Historically, the fields of ecoimmunology, psychoneuroimmunology and disease ecology have taken complementary yet disparate theoretical and experimental approaches, despite sharing critical common themes. Researchers in these areas have largely worked independently of one another to understand mechanistic immunological responses, organismal level immune performance, behavioral changes, and host and parasite/disease population dynamics, with few bridges across disciplines. Although efforts to strengthen and expand these bridges have been called for (and occasionally heeded) over the last decade, more integrative studies are only now beginning to emerge, with critical gaps remaining. Here, we briefly discuss the origins of these key fields, and their current state of integration, while highlighting several critical directions that we suggest will strengthen their connections into the future. Specifically, we highlight three key research areas that provide collaborative opportunities for integrative investigation across multiple levels of biological organization, from mechanisms to ecosystems: (1) parental effects of immunity, (2) microbiome and immune function and (3) sickness behaviors. By building new bridges among these fields, and strengthening existing ones, a truly integrative approach to understanding the role of host immunity on individual and community fitness is within our grasp.

Sickness and the Social Brain: How the Immune System Regulates Behavior across Species.

Many instances of sickness critically involve the immune system. The immune system talks to the brain in a bidirectional loop. This discourse affords the immune system immense control, such that it can influence behavior and optimize recovery from illness. These behavioral responses to infection are called sickness behaviors and can manifest in many ways, including changes in mood, motivation, or energy. Fascinatingly, most of these changes are conserved across species, and most organisms demonstrate some form of sickness behaviors. One of the most interesting sickness behaviors, and not immediately obvious, is altered sociability. Here, we discuss how the immune system impacts social behavior, by examining the brain regions and immune mediators involved in this process. We first outline how social behavior changes in response to infection in various species. Next, we explore which brain regions control social behavior and their evolutionary origins. Finally, we describe which immune mediators establish the link between illness and social behavior, in the context of both normal development and infection. Overall, we hope to make clear the striking similarities between the mechanisms that facilitate changes in sociability in derived and ancestral vertebrate, as well as invertebrate, species.

Putative involvement of sirtuin modulators in LPS-induced sickness behaviour in mice.

NAD+-dependent histone deacetylases (sirtuins 1-7) have been shown to be involved in various pathophysiological conditions including their involvement in cardiovascular, cancerous, neurodegenerative, immune dysregulation and inflammatory conditions. This study investigates the inflammomodulatory potential of resveratrol (RES), a sirtuin activator and sirtinol (SIR), a sirtuin inhibitor in lipopolysaccharide (LPS)-induced model of sickness behaviour in mice. Male Swiss albino mice were divided into five groups (n = 6) consisting of saline (SAL), LPS, RES, SIR, and fluoxetine (FLU) respectively, each group except LPS was prepared by intraperitoneally (i.p.) administration of SAL (10 mL/kg), RES (50 mg/kg), SIR (2 mg/kg) and FLU (10 mg/kg). Thirty minutes after the treatments, all the groups, except SAL were administered LPS (2 mg/kg, i.p.). The behavioural assays including, open field test, forced swim test, and tail suspension tests were conducted 1 h after LPS challenge. LPS administration significantly reduced the locomotor activity along with inducing a state of high immobility and that was prevented by pretreatment with RES and SIR. Further, various proinflammatory cytokines (TNF-α, IL-6, and IL-1ß), and oxidative stress markers (MDA and GSH) were found to be significantly elevated in the brain homogenates after LPS treatment. SIR pretreatment abrogated the LPS-induced neuroinflammatory and oxidative stress changes, whereas RES was only effective in reducing the oxidative stress and TNF-α levels. The results of this study speculate that the role of SIRT modulators in neuroinflammatory conditions could vary with their dose, regimen and chemical properties. Further studies with detailed molecular and pharmacokinetic profiling will be needed to explore their therapeutic potentials.

[Systemic inflammation, "sickness behavior" and expectations : What role do expectations play in inflammation-associated symptoms?] / Systemische Entzündung, "Sickness Behavior" und Erwartungsprozesse : Welche Rolle spielen Erwartungen bei entzündungsassoziierten Symptomen?

BACKGROUND: Systemic inflammation is accompanied by unspecific physical and psychological symptoms of sickness, including pain and affective symptoms. These symptoms (commonly called "sickness behavior") are mediated by the central nervous effects of immune messengers such as pro-inflammatory cytokines. While adaptive during acute inflammation, sickness symptoms can have detrimental effects on quality of life during chronic inflammation and may contribute to comorbidity in chronic pain conditions. Despite the high clinical relevance of sickness behavior, psychological interventions aiming to modulate sickness symptoms have hardly been investigated. One approach could be the use of expectation effects, since positive and negative expectations (placebo or nocebo effects) have been shown to have an influence on pain and affect-related symptoms. OBJECTIVES: Herein, we summarize immunological and psychobiological factors that contribute to pain in the context of sickness behavior, with a major focus on findings from experimental endotoxemia. Against this background, we discuss how expectations could help to improve immune-mediated sickness symptoms and outline potential psychological and psychobiological mechanisms underlying this putative effect.

Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium.

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, which while adaptive, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here, we used bacterial lipopolysaccharide (LPS) in female C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 µg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1ß (25 µg/kg) but not prevented in IL-1RI-/- mice, nor by IL-1 receptor antagonist (IL-1RA; 10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentrations, was mitigated by exogenous glucose (2 g/kg), and was exacerbated by 2-deoxyglucose (2-DG) glycolytic inhibition, despite preventing IL-1ß synthesis. Using the ME7 model of chronic neurodegeneration in female mice, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 µg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition selectively in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in CSF in humans during inflammatory trauma-induced delirium. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with acutely altered brain energy metabolism. Collectively, the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.SIGNIFICANCE STATEMENT Acute systemic inflammation alters behavior and produces disproportionate effects, such as delirium, in vulnerable individuals. Delirium has serious short and long-term sequelae but mechanisms remain unclear. Here, we show that both LPS and interleukin (IL)-1ß trigger hypoglycemia, reduce CSF glucose, and suppress spontaneous activity. Exogenous glucose mitigates these outcomes. Equivalent hypoglycemia, induced by lipopolysaccharide (LPS) or insulin, was sufficient to trigger cognitive impairment selectively in animals with existing neurodegeneration and glucose also mitigated those impairments. Patient CSF from inflammatory trauma-induced delirium also shows altered brain carbohydrate metabolism. The data suggest that the degenerating brain is exquisitely sensitive to acute behavioral and cognitive consequences of disrupted energy metabolism. Thus "bioenergetic stress" drives systemic inflammation-induced dysfunction. Elucidating this may offer routes to mitigating delirium.

Enhanced lipid utilization is coupled to the sickness responses triggered by lipopolysaccharide.

Sickness symptoms exerted via inflammatory responses occur in several infectious and chronic diseases. A growing body of evidence suggests that altered nutrient availability and metabolism are tightly coupled to inflammatory processes. However, the relationship between metabolic shifts and the development of the sickness response has not been explored fully. Therefore, we aimed to evaluate metabolic phenotypes with a mouse model showing sickness symptoms via systemic administration of lipopolysaccharide (LPS) in the present study. LPS injection elevated the lipid utilization and circulating levels of fatty acids. It also increased the levels of ß-hydroxybutyric acid, a ketone body produced from fatty acids. We confirmed the functional connectivity between nutrient utilization and inflammatory responses and demonstrated enhanced lipid utilization in the hypothalamus providing insights into hypothalamic control of sickness responses. Collectively, these findings could help develop new therapeutic strategies to treat patients with severe sickness symptoms associated with infectious and chronic human diseases.

Post-COVID-19 Epidemic: Allostatic Load among Medical and Nonmedical Workers in China.

BACKGROUND: As the fight against the COVID-19 epidemic continues, medical workers may have allostatic load. OBJECTIVE: During the reopening of society, medical and nonmedical workers were compared in terms of allostatic load. METHODS: An online study was performed; 3,590 Chinese subjects were analyzed. Socio-demographic variables, allostatic load, stress, abnormal illness behavior, global well-being, mental status, and social support were assessed. RESULTS: There was no difference in allostatic load in medical workers compared to nonmedical workers (15.8 vs. 17.8%; p = 0.22). Multivariate conditional logistic regression revealed that anxiety (OR = 1.24; 95% CI 1.18-1.31; p < 0.01), depression (OR = 1.23; 95% CI 1.17-1.29; p < 0.01), somatization (OR = 1.20; 95% CI 1.14-1.25; p < 0.01), hostility (OR = 1.24; 95% CI 1.18-1.30; p < 0.01), and abnormal illness behavior (OR = 1.49; 95% CI 1.34-1.66; p < 0.01) were positively associated with allostatic load, while objective support (OR = 0.84; 95% CI 0.78-0.89; p < 0.01), subjective support (OR = 0.84; 95% CI 0.80-0.88; p < 0.01), utilization of support (OR = 0.80; 95% CI 0.72-0.88; p < 0.01), social support (OR = 0.90; 95% CI 0.87-0.93; p < 0.01), and global well-being (OR = 0.30; 95% CI 0.22-0.41; p < 0.01) were negatively associated. CONCLUSIONS: In the post-COVID-19 epidemic time, medical and nonmedical workers had similar allostatic load. Psychological distress and abnormal illness behavior were risk factors for it, while social support could relieve it.

Illness, Social Disadvantage, and Sexual Risk Behavior in Adolescence and the Transition to Adulthood.

This study investigated the influence of illness on sexual risk behavior in adolescence and the transition to adulthood, both directly and through moderation of the impact of social disadvantage. We hypothesized positive effects for social disadvantages and illness on sexual risk behavior, consistent with the development of faster life history strategies among young people facing greater life adversity. Using the first two waves of the National Longitudinal Study of Adolescent to Adult Health, we developed a mixed-effects multinomial logistic regression model predicting sexual risk behavior in three comparisons: risky nonmonogamous sex versus safer nonmonogamous sex, versus monogamous sex, and versus being sexually inactive, by social characteristics, illness, interactions thereof, and control covariates. Multiple imputation was used to address a modest amount of missing data. Subjects reporting higher levels of illness had lower odds of having safer nonmonogamous sex (OR = 0.84, p < .001), monogamous sex (OR = 0.82, p < .001), and being sexually inactive (OR = 0.74, p < .001) versus risky nonmonogamous sex, relative to subjects in better health. Illness significantly moderated the sex (OR = 0.88, p < .01), race/ethnicity (e.g., OR = 1.21, p < .001), and childhood SES (OR = 0.94; p < .01) effects for the sexually inactive versus risky nonmonogamous sex comparison. Substantive findings were generally robust across waves and in sensitivity analyses. These findings offer general support for the predictions of life history theory. Illness and various social disadvantages are associated with increased sexual risk behavior in adolescence and the transition to adulthood. Further, analyses indicate that the buffering effects of several protective social statuses against sexual risk-taking are substantially eroded by illness.

Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats.

BACKGROUND: Production of inflammatory mediators by reactive microglial cells in the brain is generally considered the primary mechanism underlying the development of symptoms of sickness in response to systemic inflammation. METHODS: Depletion of microglia was achieved in C57BL/6 mice by chronic oral administration of PLX5622, a specific antagonist of colony stimulating factor-1 receptor, and in rats by a knock-in model in which the diphtheria toxin receptor was expressed under the control of the endogenous fractalkine receptor (CX3CR1) promoter sequence. After successful microglia depletion, mice and rats were injected with a sickness-inducing dose of lipopolysaccharide according to a 2 (depletion vs. control) × 2 (LPS vs. saline) factorial design. Sickness was measured by body weight loss and decreased locomotor activity in rats and mice, and reduced voluntary wheel running in mice. RESULTS: Chronic administration of PLX5622 in mice and administration of diphtheria toxin to knock-in rats depleted microglia and peripheral tissue macrophages. However, it did not abrogate the inducible expression of proinflammatory cytokines in the brain in response to LPS and even exacerbated it for some of the cytokines. In accordance with these neuroimmune effects, LPS-induced sickness was not abrogated, rather it was exacerbated when measured by running wheel activity in mice. CONCLUSIONS: These findings reveal that the sickness-inducing effects of acute inflammation can develop independently of microglia activation.

Infectious disease and sickness behaviour: tumour progression affects interaction patterns and social network structure in wild Tasmanian devils.

Infectious diseases, including transmissible cancers, can have a broad range of impacts on host behaviour, particularly in the latter stages of disease progression. However, the difficulty of early diagnoses makes the study of behavioural influences of disease in wild animals a challenging task. Tasmanian devils (Sarcophilus harrisii) are affected by a transmissible cancer, devil facial tumour disease (DFTD), in which tumours are externally visible as they progress. Using telemetry and mark-recapture datasets, we quantify the impacts of cancer progression on the behaviour of wild devils by assessing how interaction patterns within the social network of a population change with increasing tumour load. The progression of DFTD negatively influences devils' likelihood of interaction within their network. Infected devils were more active within their network late in the mating season, a pattern with repercussions for DFTD transmission. Our study provides a rare opportunity to quantify and understand the behavioural feedbacks of disease in wildlife and how they may affect transmission and population dynamics in general.

Fear of illness recurrence and mental health anxiety in people recovering from psychosis and common mental health problems.

OBJECTIVES: It is well known that mental health problems can recur even after effective treatment, leading to an understandable fear of illness recurrence (FIR) and mental health anxiety (MHA). These may themselves contribute to the process of relapse. This study aims to examine whether people recovering from psychosis have greater FIR than those recovering from common mental health problems or healthy controls. The study also hypothesized that there will be a relationship between FIR and MHA and that both these constructs will be associated with maladaptive coping behaviours. Finally, the relationship between mental defeat with FIR and psychological distress (anxiety and depression) will be examined. METHOD: A cross-sectional questionnaire design was employed. Thirty-nine participants in recovery from psychosis, eighty-two in recovery from other mental health difficulties, and sixty-one healthy controls aged 18-73 were recruited from NHS services and via social media. Self-report questionnaires measured mental defeat, mental health anxiety, fear of illness recurrence, maladaptive coping behaviours, and psychological distress. RESULTS: Those recovering from psychosis were found to more negatively evaluate the likely consequences of relapse than those recovering from common mental health problems or healthy controls. However, the levels of FIR in common mental health problems were also significantly elevated when compared to healthy controls. There were no other differences between these groups (in terms of mental defeat, anxiety, depression, social functioning, and maladaptive coping behaviours). The hypothesized relationship between FIR and MHA was also found, and both were associated with maladaptive coping behaviours. Mental defeat was associated with FIR and psychological distress (anxiety and depression). CONCLUSIONS: This study found that those with psychosis experienced higher FIR than those with common mental health problems. Furthermore, people defining themselves as in recovery are worried about relapse and the extent of this is linked to mental health anxiety. Given that such responses may contribute to actual relapse, it is important that these issues are better understood and interventions developed to ameliorate them. PRACTITIONER POINTS: Following recovery, fear of relapse may be particularly high in those with experience of psychosis; it is also present in those with common mental health problems The importance of this observation lies in the issue that anxiety about relapse may initiate a self-fulfilling process, with increased anxiety worsening symptoms and vice versa. Cognitive-behavioural therapy for health anxiety may be beneficial to those experiencing high levels of mental health anxiety. Cognitions related to relapse need to be explored and addressed both in further research and, when clearly identified, may be a target during relapse-prevention planning.

Presence of mother prompts dissociation of sickness behavior, fever, and hypothalamic gene expression in lipopolysaccharide-injected guinea pig pups.

During infection, sickness behaviors, such as a hunched stance with piloerection, can facilitate host resistance by supporting the generation and maintenance of fever. Fever, in turn, is mediated by hypothalamic neuroimmune signaling. Sickness behaviors, however, can also be influenced by social stimuli. In this study, guinea pig pups were injected with lipopolysaccharide to simulate a bacterial infection and then exposed to a novel, threatening environment while either with their mother or alone. We found that the presence of the mother suppressed sickness behavior, but enhanced fever, and had no measureable effect on gene expression of hypothalamic mediators of fever. This 3-way dissociation induced by the mother's presence is interpreted in terms of the differential adaptive consequences of behavioral and febrile responses for pups in this situation. The results contribute to a growing literature linking immunological and social processes.

Early life stress sensitizes individuals to the psychological correlates of mild fluctuations in inflammation.

BACKGROUND: Early life stress (ELS) has been linked to health disparities across the human lifespan, particularly increased risk for depression and its recurrence. In this study we explore two plausible and competing pathways through which ELS may lead to depression via inflammation. METHODS: Participants (ages 18-22; n = 41) completed the Early Trauma Inventory as a measure of ELS. Participants then completed consecutive daily diaries of mood and other sickness behavior for the 7 days prior to and 7 days after receiving the annual influenza vaccine. Circulating concentrations of plasma interleukin-6 (IL-6) were measured immediately before and 24 hr after vaccination. RESULTS: ELS was not associated with the magnitude of change in IL-6 from pre- to post-vaccine, however, exposure to ELS moderated the association between change in IL-6 from pre- to post-vaccine and changes in both cognitive difficulty and depressed mood. Individuals exposed to greater ELS showed greater psychological sensitivity to increases in IL-6. CONCLUSIONS: Exposure to ELS may increase sensitivity to peripheral inflammation in the central nervous system. Future studies elaborating on the impact of ELS on the sensitivity of specific neural circuits and cells to inflammation are needed.