The successful diaspora of humans into deep space requires an understanding of the risk of deep space radiation exposure on short- and long-term health outcomes, including risks to the central nervous system (CNS). Assessing CNS risk must consider the impact of deep space radiation on the behavior of latent neurotropic infectious agents that reside within the human CNS. Herpes simplex virus (HSV) is among the most widespread agent in this category, permanently infecting the nervous systems of more than 80% of the global population. Latent HSV cannot be eliminated from the nervous system and there is no vaccine to prevent infection. Thus for the foreseeable future, humans traveling into deep space will harbor this and other alpha-herpesviruses. While uncontrolled HSV replication in the CNS results in often fatal encephalitis, this virus also has the capacity to promote chronic inflammation and neurodegeneration. Indeed there is substantial evidence that in combination with genetic risk factors, HSV infection in the CNS further increases the probability of developing Alzheimer’s disease. During this study, the effects of simulated deep space radiation on the development of CNS pathology (reactive lesions) and the impact of latent and induced in vivo reactivation of HSV infection on the development of CNS pathology was determined together with the role that human ApoE alleles play in these processes.
Investigators employed their well characterized mouse model of HSV latency and in vivo reactivation in combination with quantitative measures of reactive lesions in the CNS to determine the effect of simulated deep space radiation on HSV mediated CNS damage. The acute stage of infection was monitored using their standard approaches including quantitative evaluation of infectious virus titers. Latent infection in the trigeminal ganglia and brain were quantified at 30-40 days post-infection using their quantitative real time PCR assay for the viral genome. Spontaneous and induced exit from latency was quantified at the single neuron level using their whole TG immunohistochemical assay. This approach permitted investigators to identify even a single positive neuron in groups of ganglia. Viral reactivation (production of infectious virus) was evaluated using their standard assay. Reactivation was induced using their well-established hyperthermic stress procedure (temperature of the mice is raised to 42.5 C for 10 minutes). Investigators have shown and published that this procedure reliably induces viral reactivation and can be repeatedly employed two times per week for periods of up to at least one year post-infection. Investigators have determined the repeated reactivation stress of C57Bl/6 mice results in reactive astrocytic lesions in the CNS of HSV infected but not in uninfected mice. Interestingly this damage is much more extensive in mice that express the human ApoE4 allele or in IL10 knock out mice. This suggests important relevance to human biology since both IL10 polymorphisms and the ApoE4 allele have been shown to be associated with increased risk of acquiring Alzheimer’s disease. The investigators collaborated with radiation biologists at NASA to determine appropriate conditions to simulate deep space radiation and to quantify the effects of such radiation on CNS damage induced by reactivation of HSV latent infections.
The goal of this project was to assess the risk of combined simulated galactic cosmic radiation (sGCR) exposure and the presence of latent HSV in the nervous system. Using a well-characterized model of acute and latent HSV infection in the mouse as the working platform, risk associated with sGCR exposure in the context of the full complexity of host responses in the presence and absence of viral latency was evaluated. Two time frames were investigated: (i) acute effects, i.e., does sGCR cause viral reactivation in the latently infected nervous system, and if so, what is the outcome, and (ii) long term effects, i.e., are long term outcomes of latent virus in the nervous system altered by sGCR exposure.
sGCR exposure of HSV latently infected mice resulted in no widespread lytic activation of latent viral genomes in the nervous system but did result in the highly restricted and temporally limited reactivation associated with terrestrial stimuli (i.e., occurring in 1-3 neurons and resolving in the nervous system within 48 hours). In addition, studies modelling moderate immune suppression (a known space mission risk) combined with HSV reactivation (space mission risk) revealed that moderate immune suppression does not alter the control of HSV spread following a reactivation event. In contrast, this same immune suppression resulted in severe disease outcomes in newly HSV infected hosts. Thus HSV latent infection and commensurate immunity to HSV, even considering the potential for reactivation from latency, may be an advantage to crew unless all crew are uninfected or a vaccine becomes available.
Despite reduced spleen weight in sGCR exposed group, immunity to HSV was fully maintained. Thus reduced spleen weight did not correlate with a detectable defect in long term maintenance of immunologic memory or the downstream ability to mount a protective immune response. Furthermore, long-term HSV latency results in cognitive impairment, a finding observed in three independent groups in both sGCR exposed and unexposed groups. However, these behavioral effects were not significantly exacerbated by radiation exposure. The cognitive impairment was associated with AD like changes in the brain and especially prominent in the huApoE4 targeted replacement mice. This model, combining two known AD risk factors, aging and the ApoE4 allele with a latent viral infection is an important advance. Radiation exposure had some effect independent of infection, but with rare exceptions, did not significantly exacerbate the effects of infection alone.
No datasets exist for this experiment. A final report was archived.