The purpose of this NCRP commentary is to provide the current state of knowledge on the effects of ionizing radiation on the immune system and on latent herpes virus reactivation to the scientific community and government agencies. Its purpose is to better understand radiation-induced latent virus reactivation, which is possibly an underestimated consequence of ionizing radiation exposure. This activity should involve the radiation research community (academia, industry and regulatory agencies) and government agencies (NASA, DOD, CDC)

Crucian, Brian E.

Mehta, Satish

Plante, Ianik

NASA Technical Reports Server

PAC 1 initiated proposal 
Dated: June 30, 2019 
Authors –  Ianik Plante, MD, PhD 
 Satish Mehta, PhD 
 Brian Crucian, PhD 
  
  
  
Proposed Topic - Effects of radiation on immune system and latent virus reactivation 
The purpose of this NCRP commentary is to provide the current state of knowledge on 
the effects of ionizing radiation on the immune system and on latent herpes virus 
reactivation to the scientific community and government agencies. Its purpose is to better 
understand radiation-induced latent virus reactivation, which is possibly an 
underestimated consequence of ionizing radiation exposure. This activity should involve 
the radiation research community (academia, industry and regulatory agencies) and 
government agencies (NASA, DOD, CDC).    
 
Background: 
Ionizing radiation (IR) is known to have several effects on the immune system. While the 
immunosuppressive effects of high-dose ionizing radiation (HD-IR) is well known, the 
effects of low doses (LD-IR) on the immune system are controversial and poorly 
understood (Manda et al., 2012). One consequence of immunosuppression is the 
reactivation of latent viruses. Many of the viruses that cause latent infections are from the 
family of Herpesviridae: herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus 
(VZV), Epstein–Barr virus (EBV), and others (Traylen et al., 2011). The genome of a virus 
that causes latent infection of cells must be transcribed and translated into viral proteins. 
This occurs when the virus is reactivated from a latent stage to a lytic stage. Certain viral 
genes that are specific to each virus initiate this reactivation process. Although some viral 
gene products have been identified, the exact mechanisms behind transcriptional 
activation that determine a virus’ reactivation from latency are not known (Tal-Signer et 
al.,1997).  
 
It is important to understand the effects of LD-IR and HD-IR on the immune system for 
the following reasons. First, its relevance for the medical radiation exposure. Over the last 
years, the rate of diagnostic imaging and associated radiation exposure has increased 
rapidly (Smith-Bindman et al., 2012). The numbers of positron emission tomography 
(PET) scans as well as nuclear diagnostic procedures are also increasing rapidly. 
Furthermore, these sometimes repeated and/or combined examinations might lead to 
radiation doses that are equivalent to or even higher than the yearly average of the 
internationally accepted dose limits for occupational exposure. Another reason to study 
the effects of LD-IR is to understand the influence of the combined effect of the 
https://ntrs.nasa.gov/search.jsp?R=20190029028 2019-09-26T19:41:54+00:00Z
microgravity environment and LD-IR exposure in astronauts. Astronauts demonstrate a 
unique pattern of immune system dysregulation.  Included are alterations in peripheral 
leukocyte distribution, reductions in T and NK cell function, apparently unaltered B cell 
function, and dysregulated cytokine profiles. Causal factors may include radiation 
exposure, radiation associated inflammation or alterations to gut microbiome, stress or 
circadian issues. Although latent virus shedding in astronauts is essentially asymptomatic 
(Mehta et al., 2013), astronauts do experience some level of clinical incidence during 
spaceflight (Crucian et al., 2016a). Some unique crewmembers experience a persistent 
atopic dermatitis which can be serious enough to require topical or oral steroid treatment 
(Crucian et al., 2016b).  The precise relationship between radiation and these clinical 
manifestations is unknown. Regarding HD-IR, a recent study has shown that, compared 
with incidence rates of shingles reported in a general U.S. population, the age- and sex-
standardized rates of shingles were 4.8 times higher (95% confidence interval (CI), 4.0–
5.6) in patients with hematologic malignancies and 1.9 times higher (95% CI, 1.7–2.1) in 
those with solid tumors (Habel et al., 2013). 
 
It is worth mentioning here that the consequences of latent viral reactivation can be very 
serious. For example, the reactivation of latent Varicella Zoster Virus (VZZ) may be 
complicated by post-herpetic neuralgia, zoster paresis, cranial nerve palsies, myelitis, 
meningoencephalitis, vasculopathy, or ocular disorders (Gilden et al, 2000). Similarly, 
reactivation of Epstein-Barr virus (EBV) may lead to lymphoproliferative disease and may 
play a role in Hodgkin’s lymphoma, peripheral B and T cell lymphomas, and 
nasopharyngeal carcinoma (Pizzigalo et al., 2010).  
 
Deep space missions beyond the Earth’s protective Geomagnetic field are scheduled to 
begin in 2024, first with lunar orbital and landing missions, to be followed by Mars flyby 
and orbital missions in the 2030s. The astronauts participating in these missions will 
experience persistent elevated radiation, as well as increased magnitude of other 
spaceflight stressors, while (likely) a reduced capacity for exercise and nutritional 
countermeasures support. A central question is whether the detection of increased levels 
of viruses in humans during spaceflight is due to immunosuppression associated with 
travel in space or a direct effect of space environmental factors, such as radiation inducing 
reactivation of the virus from latency. Our recent study (Mehta et al., 2018) has shown 
that latent EBV can be reactivated by radiation exposure alone.    
 
 
Proposal – seek funding to support the issuance of an updated NCRP report to address, 
but not limited to, the following topics: 
 The effects of radiation on the immune system at low and high doses 
 The role of radiation in the reactivation of latent virus 
o LET (radiation type and energy) 
o Dose 
o Dose-rate 
 
Possible funding from Government Agencies (stakeholders and representatives)* 
 
NASA  Jason Weeks 
 
References: 
1. Manda K, Glasow A, Paape D, Hildebrandt G. Effects of ionizing radiation on the 
immune system with special emphasis on the interaction of dendritic and T cells. Frontiers 
in oncology. 2012 Aug 24;2:102. 
2. Traylen CM, Patel HR, Fondaw W, et al. Virus reactivation: a panoramic view in human 
infections. Future Virol. 2011;6(4):451–463. doi:10.2217/fvl.11.21 
3. Tal-Singer, R., Lasner, T.M., Podrzucki, W., Skokotas, A., Leary, J.J., Berger, S.L. and 
Fraser, N.W., 1997. Gene expression during reactivation of herpes simplex virus type 1 
from latency in the peripheral nervous system is different from that during lytic infection 
of tissue cultures. Journal of Virology, 71(7), pp.5268-5276. 
4. Smith-Bindman R, Miglioretti DL, Johnson E, Lee C, Feigelson HS, Flynn M, Greenlee 
RT, Kruger RL, Hornbrook MC, Roblin D, Solberg LI. Use of diagnostic imaging studies 
and associated radiation exposure for patients enrolled in large integrated health care 
systems, 1996-2010. Jama. 2012 Jun 13;307(22):2400-9. 
5. Mehta, S.K.; Crucian, B.E.; Stowe, R.P.; Simpson, R.J.; Ott, C.M.; Sams, C.F.; Pierson, 
D.L. Reactivation of latent viruses is associated with increased plasma cytokines in 
astronauts. Cytokine 2013, 61, 205–209. 
6. Crucian, B., Babiak-Vazquez, A., Johnston, S., Pierson, D.L., Ott, C.M. and Sams, C., 
2016. Incidence of clinical symptoms during long-duration orbital spaceflight. International 
journal of general medicine, 9, p.383. 
7. Crucian, B., Johnston, S., Mehta, S., Stowe, R., Uchakin, P., Quiriarte, H., Pierson, D., 
Laudenslager, M.L. and Sams, C., 2016. A case of persistent skin rash and rhinitis with 
immune system dysregulation onboard the International Space Station. The Journal of 
Allergy and Clinical Immunology: In Practice, 4(4), pp.759-762. 
8. Habel LA, Ray GT, Silverberg MJ, Horberg MA, Yawn BP, Castillo AL, Quesenberry 
CP, Li Y, Sadier P, Tran TN. The epidemiology of herpes zoster in patients with newly 
diagnosed cancer. Cancer Epidemiology and Prevention Biomarkers. 2013 Jan 
1;22(1):82-90. 
9. Gilden, D.H.; Kleinschmidt-DeMasters, B.K.; LaGuardia, J.J.; Mahalingam, R.; Cohrs, 
R.J. Neurologic complications of the reactivation of varicella-zoster virus. N. Engl. J. Med. 
2000, 342, 635–645. 
10. Pizzigalo, E.; Racciatti, D.; Gorgoretti, V. EBV chronic infections. Medierr. J. Hematol. 
Infect. Dis. 2010, 2, e2010022. 
11. Mehta, S., Bloom, D., Plante, I., Stowe, R., Feiveson, A., Renner, A., Dhummakupt, 
A., Markan, D., Zhang, Y., Wu, H. and Scoles, B., 2018. Reactivation of Latent Epstein-
Barr Virus: A Comparison after Exposure to Gamma, Proton, Carbon, and Iron Radiation. 
International journal of molecular sciences, 19(10), p.2961. 
 
 
 
 
 


Effects of radiation on immune system and latent virus reactivation

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