This project will study the effects of simulated microgravity and ionizing radiation on the complex process of virus reactivation that is intimately associated with the way cells respond to external stress. Specifically, this proposal aims to increase understanding of mechanisms of Epstein-Barr Virus (EBV) reactivation and has the potential to discover new therapeutic targets for diseases caused in the general population by EBV. The reactivation of all herpesviruses is known to involve 2 components or stages: the initial initiating molecular events that cause reactivation of the latent genomes to progress to the production of reactivating virus, and then the propagation of these reactivating viruses to produce clinical disease. The second part of this process involves overcoming components of the acquired immune response if clinical disease is to result. In order to understand reactivation from a mechanistic point of view, these two processes need to be examined independently. The proposed studies will focus on the initial events that microgravity and ionizing radiation initiate in latent cells to induce the first stage of (molecular) reactivation.
EBV reactivation may not be completely homologous to varicella-zoster virus (VZV) and cytomegalovirus (CMV) reactivation. By focusing on EBV, which has a well-established cell culture system of latency, the mechanistic effects of microgravity and ionizing radiation in inducing EBV reactivation can be studied. This will provide critical and important information regarding the effects of these inducers on EBV reactivation in humans. After these molecular events are established in EBV, possible parallel mechanisms in VZV and CMV can be investigated in future studies.
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To study the effect of radiations, human EBV infected B-lymphocytes will be exposed to various dosages radiations (Protons) at Brookhaven National Lab, New York, to mimic space radiation exposure to crewmembers. Assays will be performed to study the phenotypic changes and EBV load before and after the radiation exposure. Tools to evaluate the effects of radiation and simulated microgravity will include: both viral and cellular gene expression, viral infectivity and viral titer, and DNA methylation.
This experiment is currently in progress. Results will be available at the conclusion of the study.
Mehta SK, Bloom DC, Plante I, Stowe R, Feiveson AH, Renner A, Dhummakupt A, Markan D, Zhang Y, Wu H, Scoles B, Cohen JI, Crucian B, Pierson DL. Reactivation of latent Epstein-Barr virus: A comparison after exposure to gamma, proton, carbon, and iron radiation. Int J Mol Sci. 2018 Sep 28;19(10):2961. [DOI]