Herpes Virus Reactivation in Astronauts During Spaceflight and Its Application on Earth

Abstract

Latent herpes virus reactivation has been demonstrated in astronauts during shuttle (10-16 days) and International Space Station (≥180 days) flights. Following reactivation, viruses are shed in the body fluids of astronauts. Typically, shedding of viral DNA is asymptomatic in astronauts regardless of mission duration; however, in some cases, live/infectious virus was recovered by tissue culture that was associated with atopic-dermatitis or skin lesions during and after spaceflight. Hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes activation during spaceflight occurs as indicated by increased levels of stress hormones including cortisol, dehydroepiandrosterone, epinephrine, and norepinephrine. These changes, along with a decreased cell mediated immunity, contribute to the reactivation of latent herpes viruses in astronauts. Currently, 47/89 (53%) astronauts from shuttle-flights and 14/23 (61%) astronauts from ISS missions shed one or more herpes viruses in saliva/urine samples. Astronauts shed Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and herpes-simplex-1 (HSV-1) in saliva and cytomegalovirus (CMV) in urine. Larger quantities and increased frequencies for these viruses were found during spaceflight as compared to before or after flight samples and their matched healthy controls. The shedding did not abate during the longer ISS missions, but rather increased in frequency and amplitude. These findings coincided with the immune system dysregulation observed in astronauts from shuttle and ISS missions. VZV shedding increased from 41% in space shuttle to 65% in ISS missions, EBV increased 82 to 96%, and CMV increased 47 to 61%. In addition, VZV/CMV shed ≤30 days after ISS in contrast to shuttle where VZV/CMV shed up to 5 and 3 days after flight respectively. Continued shedding of infectious-virus post-flight may pose a potential risk for crew who may encounter newborn infants, sero-negative adults or any immunocompromised individuals on Earth. Therefore, developing spaceflight countermeasures to prevent viral reactivation is essential. Our spaceflight-developed technologies for saliva collection/rapid viral detection have been extended to include clinical applications including zoster patients, chicken pox, post-herpetic neuralgia, multiple sclerosis, and various neurological disorders. These protocols are employed in various clinics and hospitals including the CDC and Columbia University in New York, as well as overseas in Switzerland and Israel.

Keywords: herpes; immunity; latency; spaceflight; viral reactivation.

FIGURE 1

Spaceflight is a stressful environment with various stressors acting through the hypothalamus-pituitary-adrenal (HPA)-axis and the sympathetic-adrenal-medullary (SAM)-axis. Increases in stress hormones, such as cortisol from the adrenal glands, result in reductions in cellular immunity which facilitates opportunistic viral reactivation.

FIGURE 2

Cortisol and DHEA were analyzed in saliva from astronauts before, during and after the space flights using a commercially available ELISA assays (Salimetrics, LLC, State College, PA, United States). There was a significant increase in the molar ratio of cortisol to DHEA during the flight phase for both Space Shuttle (N = 17) or ISS (N = 10). The increase in this ratio may be associated with lower cellular immunity and innate immunity; potentially contributing to greater inflammatory cytokines that may affect bone remodeling and bone growth. ^∗ Indicates significance when comparing flight against pre-flight and post-flight. p < 0.01.

FIGURE 3

Percent distribution of astronauts shedding VZV. EBV and CMV before, during the mission at time point early-mission, mid-mission, late-mission, and after either short and long duration space flights. Saliva and urine samples were collected from 112 astronauts (89 short duration and 23 long duration) before, during, and after the spaceflight. Saliva was analyzed for Epstein–Barr virus (EBV) and varicella-zoster virus (VZV), and urine was analyzed for Cytomegalovirus CMV by real time PCR assay using Taqman 7900 (Thermofisher, Inc.). The shedding of EBV. VZV and CMV DNA in body fluids is significantly higher during spaceflight as compared to pre-flight, post-flight, and the control p < 0.01 (Mehta et al., 2014, 2017). However, when comparing these shedding patterns between space shuttle and ISS missions, the differences were not significant.

FIGURE 4

Varicella-zoster virus (VZV) copy number per mL of saliva in Fifty-four zoster patients treated with valacyclovir and 14 healthy subjects. On treatment days 1, 7-, and 14 later, pain was scored (data not given here) and saliva examined for VZV-DNA by real time PCR. Patients were divided into two groups based upon the infected dermatome, Trigeminal Cervical and Thoracic/Lumbar. VZV-DNA was found in every patient the day treatment was started and disappeared in 82% with the treatment. Analysis of human saliva has potential usefulness in diagnosing neurological disease produced by VZV without rash. When comparing patient shedding against normal healthy controls, it was significantly higher, p < 0.01 (Mehta et al., 2008).