Raymond P. Stowe

Chronic herpesvirus reactivation occurs in aging.

The aged immune system is characterized by clonal expansions of CD8+ T cells of which a substantial portion are directed against Epstein-Barr virus (EBV) and cytomegalovirus (CMV). It is unknown if these expansions represent increased viral reactivation or simply reflect an accumulation over time. We investigated herpesvirus reactivation in young and old subjects co-infected with CMV and EBV. Using molecular and serological techniques, we found significant increases in both the frequency and magnitude of EBV and CMV reactivation in elderly subjects. CMV DNA was frequently detected in the urine of elderly subjects; EBV load in peripheral blood was also significantly increased. Notably, EBV DNA in plasma was detected in a majority of the elderly subjects which was supported by frequent transcription of late structural genes. Furthermore, CD8+ T cells specific for EBV structural antigens were detected in samples from the elderly. Samples from our younger control group were negative for EBV DNA in plasma, CMV DNA in urine, expression of structural transcripts, and lacked CD8+ T cells specific for EBV structural antigens. These findings indicate that the aged immune system is no longer able to control EBV and CMV reactivation that could now be characterized as chronic instead of latent.

Reactivation and Shedding of Cytomegalovirus in Astronauts during Spaceflight

The reactivation of cytomegalovirus (CMV) in 71 astronauts was investigated, using polymerase chain reaction. A significantly greater (P<.0001) shedding frequency was found in urine samples from astronauts before spaceflight (10.6%) than in urine from the healthy control subject group (1.2%). Two of 4 astronauts studied during spaceflight shed CMV in urine. A significant increase (P<.0001) in CMV antibody titer, compared with baseline values, was also found 10 days before spaceflight. CMV antibody titer was further increased (P<.001) 3 days after landing, compared with 10 days before the mission. Significant increases in stress hormones were also found after landing. These results demonstrate that CMV reactivation occurred in astronauts before spaceflight and indicate that CMV may further reactivate during spaceflight.

Immune system dysregulation following short- vs long-duration spaceflight.

INTRODUCTION Immune system dysregulation has been demonstrated to occur during and immediately following spaceflight. If found to persist during lengthy flights, this phenomenon could be a serious health risk to crewmembers participating in lunar or Mars missions. METHODS A comprehensive postflight immune assessment was performed on 17 short-duration Space Shuttle crewmembers and 8 long-duration International Space Station (ISS) crewmembers. Testing consisted of peripheral leukocyte subset analysis, early T cell activation potential, and intracellular/secreted cytokine profiles. RESULTS For Shuttle crewmembers, the distribution of the peripheral leukocyte subsets was found to be altered postflight. Early T cell activation was elevated postflight; however, the percentage of T cell subsets capable of being stimulated to produce IL-2 and IFN gamma was decreased. The ratio of secreted IFN gamma:IL-10 following T cell stimulation declined after landing, indicating a Th2 shift. For the ISS crewmembers, some alterations in peripheral leukocyte distribution were also detected after landing. In contrast to Shuttle crewmembers, the ISS crewmembers demonstrated a statistically significant reduction in early T cell activation potential immediately postflight. The percentage of T cells capable of producing IL-2 was reduced, but IFN gamma percentages were unchanged. A reduction in the secreted IFN gamma:IL-10 ratio (Th2 shift) was also observed postflight in the ISS crewmembers. CONCLUSION These data indicate that consistent peripheral phenotype changes and altered cytokine production profiles occur following spaceflight of both short and long duration; however, functional immune dysregulation may vary related to mission duration. In addition, a detectable Th2 cytokine shift appears to be associated with spaceflight.

Epstein-Barr virus shedding by astronauts during space flight

Patterns of Epstein-Barr virus (EBV) reactivation in 32 astronauts and 18 healthy age-matched control subjects were characterized by quantifying EBV shedding. Saliva samples were collected from astronauts before, during, and after 10 space shuttle missions of 5-14 days duration. At one time point or another, EBV was detected in saliva from each of the astronauts. Of 1398 saliva specimens from 32 astronauts, polymerase chain reaction analysis showed that 314 (23%) were positive for EBV DNA. Examination by flight phase showed that 29% of the saliva specimens collected from 28 astronauts before flight were positive for EBV DNA, as were 16% of those collected from 25 astronauts during flight and 16% of those collected after flight from 23 astronauts. The mean number of EBV copies from samples taken during the flights was 417 per mL, significantly greater (p<.05) than the number of viral copies from the preflight (40) and postflight (44) phases. In contrast, the control subjects shed EBV DNA with a frequency of 3.7% and mean number of EBV copies of 40 per mL of saliva. Ten days before flight and on landing day, titers of antibody to EBV viral capsid antigen were significantly (p<.05) greater than baseline levels. On landing day, urinary levels of cortisol and catecholamines were greater than their preflight values. In a limited study (n=5), plasma levels of substance P and other neuropeptides were also greater on landing day. Increases in the number of viral copies and in the amount of EBV-specific antibody were consistent with EBV reactivation before, during, and after space flight.

Leukocyte subsets and neutrophil function after short-term spaceflight.

Changes in leukocyte subpopulations and function after spaceflight have been observed but the mechanisms underlying these changes are not well defined. This study investigated the effects of short‐term spaceflight (8–15 days) on circulating leukocyte subsets, stress hormones, immunoglobulin levels, and neutrophil function. At landing, a 1.5‐fold increase in neutrophils was observed compared with preflight values; lymphocytes were slightly decreased, whereas the results were variable for monocytes. No significant changes were observed in plasma levels of immunoglobulins, cortisol, or adrenocorticotropic hormone. In contrast, urinary epinephrine, norepinephrine, and cortisol were significantly elevated at landing. Band neutrophils were observed in 9 of 16 astronauts. Neutrophil chemotactic assays showed a 10‐fold decrease in the optimal dose response after landing. Neutrophil adhesion to endothelial cells was increased both before and after spaceflight. At landing, the expression of MAC‐1 was significantly decreased while L‐selectin was significantly increased. These functional alterations may be of clinical significance on long‐duration space missions. J. Leukoc. Biol. 65: 179–186; 1999.

Elevated stress hormone levels relate to Epstein-Barr virus reactivation in astronauts

Objective The objective of this study was to determine the effects of stress and spaceflight on levels of neuroendocrine hormones and Epstein-Barr virus (EBV)–specific antibodies in astronauts. Methods Antiviral antibody titers and stress hormones were measured in plasma samples collected from 28 astronauts at their annual medical exam (baseline), 10 days before launch (L−10), landing day (R+0), and 3 days after landing (R+3). Urinary stress hormones were also measured at L−10 and R+0. Results Significant increases (p < .01) in EBV virus capsid antigen antibodies were found at all three time points (L−10, R+0, and R+3) as compared with baseline samples. Anti-EBV nuclear antigen antibodies were significantly decreased at L−10 (p < .05) and continued to decrease after spaceflight (R+0 and R+3, p < .01). No changes were found in antibodies to the nonlatent measles virus. The 11 astronauts who showed evidence of EBV reactivation had significant increases in urinary epinephrine and norepinephrine as compared with astronauts without EBV reactivation. Conclusion These findings indicate that physical and psychological stresses associated with spaceflight resulted in decreased virus-specific T-cell immunity and reactivation of EBV.

Allostatic Load Among Non-Hispanic Whites, Non-Hispanic Blacks, and People of Mexican Origin: Effects of Ethnicity, Nativity, and Acculturation

OBJECTIVES We investigated ethnic differences in allostatic load in a population-based sample of adults living in Texas City, TX, and assessed the effects of nativity and acculturation status on allostatic load among people of Mexican origin. METHODS We used logistic regression models to examine ethnic variations in allostatic load scores among non-Hispanic Whites, non-Hispanic Blacks, and people of Mexican origin. We also examined associations between measures of acculturation and allostatic load scores among people of Mexican origin only. RESULTS Foreign-born Mexicans were the least likely group to score in the higher allostatic load categories. Among individuals of Mexican origin, US-born Mexican Americans had higher allostatic load scores than foreign-born Mexicans, and acculturation measures did not account for the difference. CONCLUSIONS Our findings expand on recent research from the National Health and Nutrition Examination Survey with respect to ethnicity and allostatic load. Our results are consistent with the healthy immigrant hypothesis (i.e., newer immigrants are healthier) and the acculturation hypothesis, according to which the longer Mexican immigrants reside in the United States, the greater their likelihood of potentially losing culture-related health-protective effects.

Plasma Cytokine Levels in a Population-Based Study: Relation to Age and Ethnicity

BACKGROUND Aging is one factor believed to contribute to processes that underlie chronic low-grade inflammation in older adults. Moreover, more recent studies have suggested that cytokine levels are influenced by ethnicity. METHODS In this study, we determined plasma cytokine profiles in a population-based sample (n = 1,411; aged 25-91 years) to determine the relationship between circulating cytokine levels, aging, and ethnicity. We measured interleukin-1 receptor antagonist (IL-1ra), interleukin (IL)-6, -10, C-reactive protein (CRP), and tumor necrosis factor-receptor 1 (TNF-r1). RESULTS IL-6 and TNF-r1 significantly increased with age, whereas IL-1ra, IL-10, and CRP did not significantly increase with age. After adjusting for age, non-Hispanic whites had significantly higher levels of IL-1ra than Mexican Americans, whereas non-Hispanic blacks had significantly higher levels of IL-6 and CRP than Mexican Americans as well as non-Hispanic whites. CRP levels in non-Hispanic blacks were no longer significantly higher after adjusting for body mass index (BMI), indicating that BMI is an important predictor of this inflammatory marker. CONCLUSIONS These results demonstrate that cytokine levels are influenced by both age and ethnicity. Furthermore, these results show that inflammatory profiles for Mexican Americans are lower than non-Hispanic whites and non-Hispanic blacks.

Stress-Induced Reactivation of Epstein-Barr Virus in Astronauts

Herpesviruses are leading causes of infectious blindness and death in immunocompromised individuals. Impaired cellular immunity, which is known to result in increased frequency and severity of herpesvirus infections, has been demonstrated both during and after spaceflight. Therefore, we examined whether Epstein-Barr virus (EBV), a well-characterized latent herpesvirus, undergoes reactivation in astronauts. Sera from Shuttle astronauts, taken before and after spaceflight, were examined for evidence of EBV reactivation. The geometric mean antibody titer to EBV viral capsid antigen (VCA) was significantly increased prior to flight compared to baseline (p = 0.0001). After spaceflight, evidence of acute lytic replication was found in which 8- to 64-fold increases in EBV early antigen (EA) antibodies occurred without significant increases in antibodies to measles virus. Additionally, stress-induced shifts in circulating leukocytes and elevated levels of urinary cortisol and epinephrine were found. Overall, significant increases in EA or high VCA/EA antibody titers were found in 8 of 23 (35%) male astronauts and 3 of 5 (60%) female astronauts. These results indicate that stress reactivates EBV prior to flight and suggest that acute lytic replication of EBV occurs during spaceflight.

Reactivation of herpes simplex virus type 1 is associated with cytomegalovirus and age

Recent studies have shown that cytomegalovirus (CMV) may be an emerging marker of immunosenescence. CMV can affect the immune system by directly infecting leukocytes and hematopoietic cells or by eliciting an expansion of oligoclonal CD8+ T cells/contraction of the naïve T cell compartment that may reduce the hosts ability to fight other pathogens. To investigate further CMV‐associated changes in immunity, a study was conducted with 1,454 adults (ages 25–91) to determine the association between CMV and reactivation of another latent herpesvirus, Herpes simplex virus type 1 (HSV‐1), as indexed by antibody titers. Elevated antibody titers to latent HSV‐1 were significantly associated with both CMV seropositivity and high CMV antibody levels. Evaluation by specific age groups (<45, 45–64, and 65+ years old) revealed that this association was detectable early in life (<45 years of age). Increases in HSV‐1 antibodies by age occurred in CMV seropositive individuals but not CMV seronegative subjects. Within CMV seropositive subjects, increases in HSV‐1 antibodies by age were only found in individuals with low CMV antibody levels as those with high CMV antibodies already exhibited elevated HSV‐1 antibodies. These associations remained significant after accounting for body mass index, gender, and socioeconomic status. These results suggest that CMV can influence the immune response to another pathogen and support the concept that CMV may accelerate immunosenescence. J. Med. Virol. 84:1797–1802, 2012.