Immune System Dysregulation and Herpesvirus Reactivation Persist During Long-Duration Spaceflight

Background: Immunity, latent herpesvirus reactivation, physiological stress and circadian rhythms were assessed during six month spaceflight onboard ISS. Blood and saliva samples were collected early, mid and late in-flight and returned for immediate analysis. Mid-point study data (10 of 17 planned subjects) will be presented. Results: Some shifts in leukocyte distribution occurred during flight, including alterations in CD8+ T cell maturation. General T cell function was consistently reduced early in-flight. Levels CD8+/IFNg+ producing T cells were depressed early in-flight, and immediately upon landing. Persistent mitogen-dependant reductions were observed in IFNg, IL-17a, IL-10, TNFa and IL-6 production. Monocyte production of IL-10 was reduced, whereas IL-8 levels were increased. Levels of mRNA for the TNFa, IL-6 and IFNg were transiently elevated early in-flight, and the dynamics of TNF and IL-6 gene expression were somewhat antagonistic to their corresponding receptors during flight. The number of virus-specific CD8+ T-cells was measured using MHC tetramers, while their function was measured using intracellular cytokine analysis following peptide stimulation. Both the number and function of EBV-specific cells decreased during flight as compared to preflight levels. The number of CMV-specific T-cells generally increased as the mission progressed while their function was variable. Viral (EBV) load in blood was elevated postflight. Anti-EBV VCA antibodies were significantly elevated by R+0; anti-EA antibodies were not significantly elevated at landing; and anti-CMV antibodies were somewhat elevated during flight. Higher levels of salivary EBV DNA were found during flight. VZV DNA reactivation occurred in ~50 % of astronauts during flight, continuing for up to 30 days post-flight. CMV was shed in 35 % the in-flight and 30% of postflight urine samples of the crewmembers. There was generally a higher level of cortisol as measured in urine and saliva in the astronauts during flight, but plasma cortisol was relatively unchanged during flight. Circadian rhythm of salivary cortisol was altered during flight. Conclusion. Some alterations in immunity do not resolve during six month spaceflight, consequentially resulting in persistent herpesvirus reactivation. Ongoing immune dysregulation may represent specific clinical risks for exploration-class space missions

Fatigue in Medical Residents Leads to Reactivation of Herpes Virus Latency

The main objective of this study was to detect fatigue-induced clinical symptoms of immune suppression in medical residents. Samples were collected from the subjects at rest, following the first night (low-stress), and the last night (high-stress) of night float. Computerized reaction tests, Epworth Sleepiness Scale, and Wellness Profile questionnaires were used to quantify fatigue level. DNA of human herpes viruses HSV-1, VZV, EBV, as well as cortisol and melatonin concentrations, were measured in saliva. Residents at the high-stress interval reported being sleepier compared to the rest interval. EBV DNA level increased significantly at both stress intervals, while VZV DNA level increased only at low-stress. DNA levels of HSV-1 decreased at low-stress but increased at high-stress. Combined assessment of the viral DNA showed significant effect of stress on herpes virus reactivation at both stress intervals. Cortisol concentrations at both stress intervals were significantly higher than those at rest

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483 phin, and GH were registered after the race (0 and 1 hour). We concluded that marathon-associated stress factors can alter physiologic balance of cell-mediated versus humoral and anti-inflammatory versus proinflammatory cytokines. Results suggest that hypothalamic-pituitary-adrenocortical axis hormones played a significant role in the regulation of the observed changes. This information may be beneficial for development of new stress countermeasures to preserve wellness in subjects undergoing intensive physiological stress. INTRODUCTION A competitive marathon race is a very stressful event and can significantly affect virtually any of the physiologic systems of a runner. Dehydration, weight loss, gastrointestinal problems (bleeding), hypo-or hyperthermia, collapse, muscle damage and microtrauma are often seen after a marathon race. 1-6 Particular interest has been paid to the incidences of upper respiratory infections (URTI) among marathoners. 7-10 A number of epidemiologic studies have shown increased risk of URTI in athletes up to 2 weeks after endurance races. Immune and Neuroendocrine Alterations in Marathon Runners ABSTRACT Marathon running is a stressful event that can significantly affect virtually any of the physiologic systems of a runner. The goal of this study was to investigate effects of marathon running on human immune and neuroendocrine parameters and their interaction. Blood samples were collected from 15 male runners (38.3 ± 6.9 years) 18 hours before finish time, then within 20 minutes (0h), 1 hour, 24 hours, 48 hours, 5 days, and 8 days after the marathon. Complete blood count, secretion of cytokines in mitogenactivated cell culture and plasma, and plasma concentration of β-endorphin, Adrenocorticotropic hormone (ACTH), cortisol, and growth hormone (GH) were analyzed. Significant increase in granulocyte and MID-cell count and lymphopenia were seen immediately after the marathon. Secretion of interleukin (IL)-2 and interferon (IFN)-γ significantly declined at 0 and 1 hour after the marathon. Secretion of TNF-α declined at 0 hours and remained suppressed until 5 days. Suppression in the secretion of IL-1β was observed at 48-hour and 5-day intervals. Activated secretion of IL-6 decreased at 24 and 48 hours. Peak concentrations of ACTH, cortisol, β-endor

Robust gene expression changes in the ganglia following subclinical reactivation in rhesus macaques infected with simian varicella virus

Varicella zoster virus (VZV) causes varicella during acute infection and establishes latency in the sensory ganglia. Reactivation of VZV results in herpes zoster, a debilitating and painful disease. It is believed that VZV reactivates due to a decline in cell-mediated immunity; however, the roles that CD4 versus CD8 T cells play in the prevention of herpes zoster remain poorly understood. To address this question, we used a well-characterized model of VZV infection where rhesus macaques are intrabronchially infected with the homologous simian varicella virus (SVV). Latently infected rhesus macaques were thymectomized and depleted of either CD4 or CD8 T cells to induce selective senescence of each T cell subset. After T cell depletion, the animals were transferred to a new housing room to induce stress. SVV reactivation (viremia in the absence of rash) was detected in three out of six CD8-depleted and two out of six CD4-depleted animals suggesting that both CD4 and CD8 T cells play a critical role in preventing SVV reactivation. Viral loads in multiple ganglia were higher in reactivated animals compared to non-reactivated animals. In addition, reactivation results in sustained transcriptional changes in the ganglia that enriched to gene ontology and diseases terms associated with neuronal function and inflammation indicative of potential damage as a result of viral reactivation. These studies support the critical role of cellular immunity in preventing varicella virus reactivation and indicate that reactivation results in long-lasting remodeling of the ganglia transcriptome