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Effects of microgravity and other space stressors in immunosuppression and viral reactivation with potential nervous system involvement
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.259125
Keywords: Astronaut, neurology and microgravity, space like stress, virus reactivation
Short-duration spaceflight onboard the space shuttle has been shown to contribute to dysregulation of the immune and endocrine systems.[1],[2] Astronauts on board the International Space Station (ISS) for a longer duration (≥6 months) have experienced similar stressful situations. Increased levels of plasma and urinary stress hormones (cortisol and catecholamines) have been documented.[3],[4] Virus reactivation has been shown to be associated with stressful conditions associated with spaceflight, including psychosocial factors, such as isolation, confinement, anxiety, sleep deprivation, physical exertion, noise, increased radiation, and microgravity.[5],[6] Reactivation of latent herpes viruses, either directly from radiation of latently infected cells and/or from perturbation of the immune system, increases the risk of astronauts in developing viral diseases. Reactivation of several latent viruses in astronauts is well documented, although the mechanism is unclear.[7] The immune system, with its distinct cell populations, provides resistance to disease. The innate immune system provides first (external body membranes-skin and mucosae) and second (antimicrobial proteins and phagocytes) lines of defense against foreign invaders. The adaptive (specific) immune system is the third line of defense, attacking particularly foreign substances unable to be cleared by first- and second-line defenses. Immunity is markedly translational, operating throughout the body and exchanging information and interfacing with other body systems, including the nervous system [8] and bone (osteoimmunology).[9] It is intensely influenced by stress, nutrition, and exercise.[10] The immune system dysregulation has now been demonstrated to occur during flight and persist throughout a 6-month orbital spaceflight.[11],[12],[13],[14],[15] This phenomenon typically occurs concurrently with persistent reactivation and shedding of latent herpes viruses. As a healthy immune system is necessary to suppress the latent virus reactivation, it is possible that reactivation of these latent herpes viruses could be a “bio-marker” of compromised adaptive immune function, particularly the cytotoxic T-lymphocyte function. Studies have demonstrated altered distribution of peripheral leukocytes, diminished function of specific leukocyte subpopulations, and skewed cytokine profiles in many astronauts. Mehta et al., positively correlated the plasma cytokine alterations with viral shedding in specific crew members and postulated a T-helper (Th2) shift associated with flight.[16] There appears to be a causal relationship between immune dysregulation (particularly cytotoxic function) and viral reactivation in space. Spaceflight poses two unique microbial space-like stresses (SLSs): microgravity (MG) and other low-shear environments, as well as space irradiation. These could be experienced by normal flora microbes (resident flora present on astronauts) or by exogenous, unavoidable sources of contamination. Through SLS-induced responses, resident flora could become opportunistic and function as a pathogen. Opportunistic infection with compromised immune responses could have life-threatening consequences.[17] Studies have demonstrated that microgravity and low fluid shear dynamics associated with microgravity play a role in regulation of microbial gene expression, physiology, and even pathogenesis.[18],[19] Exposure of astronauts to acceleration/deceleration, cosmic radiation, and microgravity results in stressors contributing to the dysregulation of immune and endocrine systems.[2],[20] Other stressors include social separation, confinement, sleep deprivation, circadian rhythm disruption, and anxiety.
That changes in immune status promote viral reactivation have been documented in both terrestrial space-analog [21] and spaceflight studies.[13],[22],[23],[24] Spaceflight studies have demonstrated considerable immune dysregulation and functional changes with significant viral reactivation. Significant changes in cell-mediated immunity occurred in most astronauts when herpes viruses were reactivated.[12],[13] Glaser et al., showed an association of Epstein–Barr Virus (EBV) reactivation and diminished cell-mediated immunity.[24] The hypothalamus-pituitary-adrenal axis along with the sympathetic-adrenal-medullary (SAM) axis partially mediate the stress response where glucocorticoids and catecholamines are secreted in proportionate concentrations relative to the stress stimulus [Figure 1].[25],[26],[27]
Though acute responses to stress can be positive, a long duration or chronically high levels of stress hormones can negatively affect the regulation of the immune system and its individual components.[21] Changes in a variety of immune cells, both in the form (phenotype) and function (killing capacity), result in decreased cell-mediated immunity, which facilitates opportunistic reactivation of latent viruses.[12],[28]
The adrenal gland releases cortisol and dehydroepiandrosterone (DHEA) (glucocorticoid steroid hormones) in response to stress. Cortisol is anti-inflammatory and immunosuppressive, but DHEA is an important antagonist to cortisol. This makes the molar ratio of cortisol to DHEA ([C]/[D]), an important indicator of immune regulation. Regular diurnal release of these hormones in saliva samples are evaluated for changes/trends occurring during launch/preflight, flight, and return.[5] Diurnal patterns of salivary cortisol are significantly higher during flight as opposed to DHEA, which is significantly lower. Such an increased [C]/[D] molar ratio during spaceflight indicates immune challenge and modulation,[29] including the increased inflammatory cytokine response and the Th2 shift observed in earlier spaceflight studies.[16],[21] These stressors amplify the release of stress hormones, negatively affecting the adaptive immune system, thus facilitating latent herpes virus reactivation during and after spaceflight. Increased levels of salivary, plasma, and urinary stress hormones such as cortisol and catecholamines commonly accompany spaceflight.[3] Cytokines analysis (10 days before launch (L − 10), in comparison to their baseline samples taken 180 days before launch (L − 180), and on Earth at landing (R + 0)) Cytokines are small cell-signaling proteins that play a crucial role in the modulation of the human immune response. Inflammatory/Th2 cytokines and chemokines increase immediately upon return to Earth at landing, designated as R + 0. The Th2 cytokine, interleukin (IL-4) was the most sensitive/responsive to the phases of flight with 35- and 21-fold increases from the baseline values at L − 10 and R + 0, respectively. When analyzing plasma cytokine levels in the context of virus shedding, there seems to be a connection between astronauts who shed virus and have significantly elevated levels of cytokines (IL- 1 α, IL-6, IL-8, IFN (interferon) γ, IL-12p70, IL-4, IL-10, IL-13, eotaxin, and interferon gamma-induced protein 10 (IP)-10).[16] Lymphoid and myeloid growth factors are also elevated in virus shedding astronauts by about two-folds.
Alterations in cytokine profile, either independently or in combination with microgravity, cause a variety of immune vulnerabilities by significantly changing numbers, proportions, and functions of leukocytes. monocytes,[30] granulocytes,[31] and lymphocytic functionality [12],[28] is diminished, critically reducing the effectiveness of immune response to pathogens and the ability to prevent viral reactivation. T-cells and natural killer (NK) cells play an important role in attacking and destroying viruses/virus-infected cells, and these functions are substantially reduced during spaceflight. Both CD4+ and CD8+ T-cells taken from astronauts during the flight phase respond ineffectively against a variety of stimuli, which under normal circumstances would have evoked a more profound response by the T-cells. The weakened response can last throughout the duration of the space flight.[12] Additional flight studies focusing on the function of NK-cells have shown decrements in cytotoxicity due to decreased production of the enzymes perforin and granzyme B.[28] Without these enzymes, NK-cells are rendered ineffective against the target cell/pathogen and this impairment may last up to 60 days postflight. In both cases, reductions in T-cell and NK-cell function lead to the inability of the immune system to suppress/sequester/eliminate opportunistic viral reactivation.
Viral reactivation and shedding of latent herpes viruses have been reported in astronauts during space shuttle Russian Soyuz and ISS missions.[5],[13],[32],[33],[34] This reactivation phenomenon has also been observed in ground-based models of spaceflight including Antarctica, undersea habitat, artificial gravity, and bed rest studies (though not to the extent seen during spaceflight studies). About 47 out of 89 (53%) astronauts from short-duration space shuttle flights and 14 out of 23 (61%) from long-duration ISS spaceflight missions shed at least one or more herpes viruses in their saliva or urine samples. Significant reactivations of EBV, cytomegalovirus (CMV), and Varicella-Zoster virus (VZV) occurred during the flight phase and the magnitude and frequency of viral shedding during spaceflight directly correlates with the duration of spaceflight. VZV shedding increased from 41% in space shuttle to 65% in ISS missions, and in a similar fashion, EBV increased from 82% in space shuttle to 96% in ISS missions, and CMV increased from 47% in space shuttle to 61% in ISS missions. In addition, VZV and CMV shed up to a month post long-duration flight. Percent distribution of these viruses during the shuttle and ISS missions is depicted in [Figure 2]. These viruses can reactivate in concert or independent of other viruses. Reactivation of latent viruses during long-duration spaceflight could increase the risk for adverse medical events during exploration-class deep space missions.[2]
To date, there have been six instances of astronauts with complaints of symptoms, such as skin rash possibly dermatitis, rhinitis symptoms primarily sneezing, and itchy, watery eyes related to herpes viral reactivation.[35] VZV is an important health risk factor to crew members (several have experienced shingles during flight). Furthermore, CMV can be immunosuppressive and may play a role in the well-documented immune dysfunction observed in crew members. The shedding of EBV, VZV, and CMV DNA in body fluids is significantly higher during the spaceflight as compared with the preflight, postflight, and the control (P < 0.01) samples.[5],[13] Saliva and urine samples were collected from 112 astronauts (89 on short duration and 23 on long duration flights) before, during, and after the spaceflight. Saliva was analyzed for EBV and VZV, and urine was analyzed for CMV by real-time polymerase chain reaction (PCR) assay using Taqman 7900 (Thermo Fisher, Inc.). The shedding of EBV, VZV, and CMV DNA in body fluids is significantly higher during the spaceflight as compared with preflight, postflight, and the control samples with a statistical significance of P < 0.01.[5],[13]
Herpes virus is widespread in humans and affects >90% of adults in the United States. It is associated with several types of recurring diseases, including cold sores, genital herpes, chicken pox, and shingles. The virus can occasionally turn deadly, resulting in encephalitis in some. Herpes viruses have co-evolved with humans for millennia and subsequently employ sophisticated strategies to evade the host immune response. Consequently, after a primary infection, they persist lifelong in a latent or dormant phase and are generally asymptomatic in immunocompetent individuals. However, they may reactivate during periods of increased stress, isolation, and during times of immune challenge. Eight major herpes viruses parasitize humans with worldwide infection rates of 70%–95%. Four of the eight were shed in the body fluids of NASA astronauts during both short- and long-duration spaceflight. Though the viral load (virus detected in the body fluids) can be high, these astronauts often have no clinical symptoms associated with reactivation.[36] Postreactivation, replication of the virus may also be enhanced, which could account for the significant increase in viral shedding during spaceflight.
EBV, also known as human herpes virus 4, is one of the most common human viruses and can be found in humans worldwide. EBV is responsible for infectious mononucleosis and is associated with several malignancies.[37],[38],[39] It is a highly infectious DNA virus transmitted by aerosolized microdroplets and by direct contact with saliva. It has a 95% infection rate among adults worldwide, which makes it an ideal target for investigation among a limited and unique astronaut population. Early flight studies from the shuttle missions were the first to demonstrate that EBV DNA was shed in astronaut saliva samples taken before, during, and after space flight.[5],[22],[32] These studies highlighted a 10-fold increase in viral load during the flight phase in comparison to samples taken before or after flight. Additionally, EBV copies shed during space flight seemed to increase as a function of time in space, and as a result of diminished cell immunity.[40] These early findings have been repeatedly corroborated in longer duration ISS missions.[13],[24] Altogether, flight studies have illustrated that approximately 90% of astronauts, regardless of their mission duration, shed EBV during spaceflight. With respect to space travel, latent virus reactivation may be a note-worthy threat to crew health during longer missions, especially if those missions are far from Earth's protective atmosphere. Increased reactivation of latent herpes viruses such as EBV was previously shown in astronauts during short-term space shuttle flights.[5] EBV DNA copies were elevated during flight as compared with pre- and postflight levels. Whereas there are several factors that may have influenced this, including stress from the journey, immunosuppression, and microgravity, increased exposure to cosmic radiation while in space probably had a crucial role in this reactivation.
VZV is a human neurotropic alpha herpes virus. Primary infection usually results in varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. As cellular immunity to VZV wanes with age or immunosuppression, virus reactivates to produce herpes zoster (shingles), which is often complicated by postherpetic neuralgia, zoster paresis, cranial nerve palsies, myelitis, meningoencephalitis, vasculopathy, and multiple serious ocular disorders.[41] The virus is transmitted via saliva and can be aerosolized by sneezing and coughing. After the primary infection, VZV becomes latent in various nerve ganglia [42] (cranial, dorsal root, autonomic) along the entire length of the neuroaxis, and reactivation often results in characteristic skin lesions that range from aggravating to painful. Astronauts do not often develop symptoms or rash, although flight studies from both shuttle and ISS missions have shown reactivation of VZV, where viral DNA was found in the saliva of astronauts.[36],[43] Additionally, it has been found that saliva samples taken 2–6 days following landing were infectious by culturing that saliva with human fetal lung (HFL) cells. Infectious VZV was present and has been confirmed by visual inspection of the culture where viral plaques were obvious, as well as by antibody staining and real-time polymerase chain reaction (PCR) DNA analysis. This poses a risk to the welfare of both astronauts and their seronegative contacts back on Earth, as VZV viral load also increases with time in space and is present in saliva of about 60% of astronauts from combined shuttle and ISS missions.[44]
Cytomegalovirus is the only beta-herpes virus known to reactivate in astronauts. It is typically acquired asymptomatically during childhood and has a worldwide prevalence of 75%–90%. Though it remains asymptomatic in immunocompetent people, it may reactivate in individuals whose immune systems are either immature or immunocompromised, causing multiple diseases such as encephalitis, gastroenteritis, pneumonia, and chorioretinitis.[45] Furthermore, multiple studies have suggested that CMV infection is immunosuppressive, because it directly infects leukocytes as well as hematopoietic cells.[46],[47],[48] Additionally, CMV has been uniquely linked to early immune senescence.[49],[50] Spaceflight studies have shown that 27% of the astronauts from short-term space missions shed CMV DNA in either pre- or postflight urine samples, and that anti-CMV IgG antibody titers increased significantly for all shedders from each time point compared with their baseline values.[51] In long-duration spaceflight, 61% of astronauts shed CMV. DNA in their urine during and after spaceflight are infected with CMV, in stark contrast to the absence of CMV DNA in urine samples taken 180 days before flight. These findings demonstrate that CMV reactivation occurs in astronauts regardless of the mission duration, and this may pose additional threats to the health of crew members during longer-duration mission.[5],[16]
During space flight, typically minor illnesses have been reported till date, and there is no evidence that illnesses are unusually severe or longer lasting in space. Whether the findings demonstrate changes related to microgravity, or merely stress-related effects on the immune system remain unclear. Crews spending the winter in Antarctica often display latent viral reactivation, so long-duration space flights may be no exception. Other than ensuring that space travelers are in good health and have had all standard vaccinations, no countermeasure program is currently in place. The crew healthcare systems of the shuttle and ISS contain medications, including antibiotics and antivirals, for the treatment of disease, and “health stabilization program” (or quarantine period) immediately before launch to further diminish the likelihood of developing a communicable disease during a mission. The aerospace physician must assume that immunocompromise, if present in-flight, may persist in the postflight period. Space travelers should be cautioned about the risks of exposure to infectious diseases and the importance of seeking medical help promptly, should symptoms develop.
With the advent of prolonged manned space missions as well as future planned travel to Mars, space microbiology is important. Eventually, standard air travel will involve planes leaving the Earth's atmosphere and reentering the atmosphere cutting flight times by half. Passengers and the normal flora they carry will be exposed to space like stress. Reactivation of latent viruses (especially herpes viruses) is a powerful biomarker of the immune status for astronauts. Understanding mechanics of viral reactivation outside the Earth's atmosphere will benefit both astronauts and those on earth. Effective countermeasures for astronauts and immunocompromised individuals will be essential as space and air travel continue to develop/be explored. As an astronaut's saliva may contain increasingly significant viral DNA both during and after spaceflight that can be infectious, prophylactics (vaccines) may be necessary. Partial gravity environments, e.g., on Mars, might be sufficient to curtail serious viral reactivation and warrants further investigation. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2]
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