NASA Advanced Capabilities Division Research and Technology Task Book

Task Description: Space flight has been found to affect immune responses, and alterations in a normal immune response often have a major impact on the host’s ability to control infections. A question being explored is whether infectious diseases pose a medical risk to the success of long-duration space journeys. All humans are infected for life with latent and persistent viruses, and it is well-known that suppression of the immune system allows latent viruses to reactivate and multiply, which may cause disease in the person undergoing reactivation or in contacts to whom the virus is transmitted. The general hypothesis is that conditions of long-duration space flight, including radiation, stress, isolation, containment, and sleep deprivation, will alter human immune responses, leading to reactivation of latent viruses, increased viral infections and viral disease, and possible development of malignancies.

We focused on reactivation and shedding of human herpesvirus EBV and human polyomaviruses, agents known to establish persistent infections and to undergo reactivation and cause disease, including cancer, when the host immune system is compromised. Animal models were used to study radiation effects on viral infections and host responses to those infections.

The specific aims of the project were: (1) To determine the effects of space radiation and hind limb unloading (HLU) on host control of virus infections and virus-induced cancers in a mouse model; and (2) To characterize direct effects of radiation on viruses and virus-infected cells.

Key findings of the project were from the mouse polyoma virus space radiation model we developed. A quantitative real-time polymerase chain reaction (RQ-PCR) assay was developed to measure murine polyoma virus (MuPyV) genome copies in infected animal tissues. This model showed that gamma-irradiation leads to immunosuppression, delayed clearance of primary virus infection, and reactivated latent viral infections. Both single high-dose and multiple low doses of gamma-irradiation cause virus reactivation. HLU, which simulates aspects of weightlessness, was applied to the mouse model. HLU results in loss of control of virus infection in a tissue-specific manner. Another finding was the identification of a herpesvirus EBV latent protein that might modulate the development of EBV-associated disease. In collaboration with Dr. G. Sonnenfeld we carried out measurements of virus reactivations in volunteers participating in the NASA-sponsored Bed Rest Study, a model for the effects of space flight conditions on human physiology.

Research Impact/Earth Benefits: This NSBRI-funded research addressed space flight-induced alterations in the immune system and their effects on host control of microbial infections. We have shown in several ground-based human models of space flight that even modest depressions in immune function correlate with virus reactivation and shedding. Using a mouse model, we have evidence of radiation-induced reactivation of viral infections and depression of host immune function. New information from these studies are applicable to the analysis of risks that may affect long-duration space travel. The knowledge gained from studies of virus infections in these test models will be applicable to earth-bound individuals at risk of suffering similar virus reactivations and serious, sometimes life-threatening, consequences due to immunosuppression following organ transplantation or cancer chemotherapy and during pregnancy, old age, and AIDS. Studies of the role of herpesvirus EBV latent genes in human disease may lead to the development of novel antiviral drugs of benefit to individuals on earth experiencing virus reactivations.

Task Progress: Key findings of the project this year were from the mouse polyoma virus space radiation model we developed. This model showed that gamma-irradiation leads to immunosuppression, delayed clearance of primary virus infection, and reactivated latent viral infections. Both single high-dose and multiple low doses of gamma-irradiation cause virus reactivation. Hind limb unloading (HLU), that simulates aspects of weightlessness, was applied to the mouse model and resulted in loss of control of virus infection in a tissue-specific manner. These findings show the deleterious effect of multiple low-dose exposures to irradiation on host control of infections and the added adverse effect of HLU. Significant efforts were made this past reporting period to develop conditions for microarray analyses of immune response gene expression in mice under conditions of virus infection and/or irradiation. This approach will allow an understanding of the mechanisms underlying deleterious effects of space flight conditions on host control of infections.

Bibliography Type: Description: (Last Updated: 10/03/2007) Show Cumulative Bibliography Listing

Abstracts for Journals and Proceedings Ling PD, Lednicky JA, Keitel WA, White ZS, Peng R, Lewis DE, Kozinetz CA, Butel JS. "Virus reactivation and shedding in healthy and immunocompromised humans: importance to space travel." Bioastronautics Investigators' Workshop, Galveston, TX, January 2005.

Bioastronautics Investigators' Workshop, Poster #90, 2005. , Jan-2005

Abstracts for Journals and Proceedings Shearer WT, Zhang S, Reuben JM, Lee BN, Butel JS. "Effects of radiation and latent virus on immune responses in a space flight model. " Bioastronautics Investigators' Workshop, Galveston, TX, Jan. 10-12, 2005.

Bioastronautics Investigators' Workshop, Poster #91, 2005. , Jan-2005

Articles in Peer-reviewed Journals Sonnenfeld G, Aviles H, Butel JS, Shearer WT, Niesel D, Pandya U, Allen C, Ochs HD, Blancher A, Abbal M. "Bed rest and immunity." Acta Astronaut. 2007 Feb-Apr;60(4-7):234-6. http://dx.doi.org/10.1016/j.actaastro.2006.08.004 , Feb-2007

Articles in Peer-reviewed Journals Shearer WT, Zhang S, Reuben JM, Lee BN, Butel JS. "Predictors of immune function in space flight." Acta Astronaut. 2007 Feb-Apr;60(4-7):247-53. http://dx.doi.org/10.1016/j.actaastro.2006.08.005 , Feb-2007

Articles in Peer-reviewed Journals Zhang S, McNees AL, Butel JS. "Quantification of vertical transmission of Murine polyoma virus by real-time quantitative PCR." J Gen Virol. 2005 Oct;86(Pt 10):2721-9. PMID: 16186225 , Oct-2005

Articles in Peer-reviewed Journals Shearer WT, Zhang S, Reuben JM, Lee BN, Butel JS. "Effects of radiation and latent virus on immune responses in a space flight model." J Allergy Clin Immunol. 2005 Jun;115(6):1297-303. PMID: 15940150 , Jun-2005

Articles in Peer-reviewed Journals Walling DM, Ling PD, Gordadze AV, Montes-Walters M, Flaitz CM, Nichols CM. "Expression of Epstein-Barr virus latent genes in oral epithelium: determinants of the pathogenesis of oral hairy leukoplakia." J Infect Dis. 2004 Jul 15;190(2):396-9. Epub 2004 Jun 11. PMID: 15216478 , Jul-2004

Fiscal Year: FY 2006 Task Last Updated: 01/08/2007

PI Name: Butel, Janet S.

Project Title: Biology of Virus Infections: Radiation and Immunity

Division Name: Human Research

Program/Discipline: NSBRI Teams

Element/Subdiscipline: Radiation Effects Team

Joint Agency Name:

Human Research Program Elements: None

Human Research Program Risks:: None

Human Research Program Gaps: None

PI Email: jbutel@bcm.tmc.edu Fax: 713-798-5019

PI Organization Type: UNIVERSITY Phone: 713-798-3003

Organization Name: Baylor College of Medicine

PI Address 1: One Baylor Plaza, 737E

PI Address 2: Department of Molecular Virology and Microbiology

PI Web Page: http://www.bcm.edu/cmb/?pmid=2046

City: Houston State: TX

Zip Code: 77030-3411 Congressional District: 25

Comments: Address updated 9/2008

Project Type: GROUND Solicitation: 2003 Biomedical Research & Countermeasures 03-OBPR-04

Start Date: 04/01/2004 End Date: 12/31/2006

No. of Post Docs: 1 No. of PhD Degrees: 0

No. of PhD Candidates: 0 No. of Master' Degrees: 0

No. of Master's Candidates: 0 No. of Bachelor's Degrees: 1

No. of Bachelor's Candidates: 1 Monitoring Center: NSBRI

Contact Monitor: Contact Phone:

Contact Email:

Flight Program:

Flight Assignment:

Key Personnel Changes/Previous PI:

COI Name (Institution): Conner, Margaret  ( Baylor College of Medicine )
Ling, Paul  ( Baylor College of Medicine )
Zhang, Shaojie  ( Baylor College of Medicine )

Grant/Contract No.: NCC 9-58-IIH00403

Performance Goal No.:

Performance Goal Text:

The general hypothesis being addressed is that conditions of long-duration space flight, including radiation, stress, isolation, containment, and sleep deprivation will alter human immune responses, leading to reactivation of latent viruses, increased viral infections and viral disease, and possible development of malignancies. We are focusing on reactivation and shedding of human herpesvirus EBV and human polyomaviruses, agents known to establish persistent infections and to undergo reactivation and cause disease, including cancer, when the host immune system is compromised. Animal models are being used to study radiation effects on viral infections and host responses to those infections.

The specific aims of the project are: (1) To determine the effects of space radiation and hind limb unloading (HLU) on host control of virus infections and virus-induced cancers; and (2) To characterize direct effects of radiation on viruses and virus-infected cells.

Key findings of the project this year were from the mouse polyoma virus space radiation model we developed. This model showed that gamma-irradiation leads to immunosuppression, delayed clearance of primary virus infection, and reactivated latent viral infections. Both single high-dose and multiple low doses of gamma-irradiation cause virus reactivation. HLU, that simulates aspects of weightlessness, was applied to the mouse model. HLU results in loss of control of virus infection in a tissue-specific manner. Combined effects of HLU and virus infection resulted in increased mortality.

Plans for the coming year include experiments to further examine the effect of multiple, low-dose radiation exposures on host control of viral infections; expanded analysis of the effects of HLU and irradiation on control of polyoma virus infection, reactivation, and immune impairment; determination of cytokine and chemokine mRNA levels in tissues from HLU studies; measurements of virus reactivations in volunteers participating in the NASA-sponsored Bed Rest Study, a model for the effects of space flight conditions on human physiology, in collaboration with Dr. G. Sonnenfeld; and studies of radiation-induced signals that cause EBV reactivation from latency in cultured cells.

Research Impact/Earth Benefits: The mouse model we developed here involving polyoma virus infection and radiation will allow targeted studies of the effects of irradiation on host immune function, virus infection, and tumor development. Such data will define the risk of these combined factors to long-duration space flight and will allow tests of countermeasures. We have shown that radiation can cause reactivation of latent viral infections and depress host immune function. The evidence for viral reactivations highlights the need to understand synergistic effects of radiation and space flight conditions that may result in more deleterious effects on immune function and control of microbial infections and disease. The knowledge gained from studies of virus reactivations in these test models will be applicable to earth-bound individuals at risk of suffering similar virus reactivations and serious, sometimes life-threatening, consequences due to immunosuppression following organ transplantation or cancer chemotherapy and during pregnancy, old age, and AIDS. Studies of the role of EBV latent genes in human disease may lead to the development of novel antiviral drugs.

Task Progress: Key findings of the project this year were from the mouse polyoma virus space radiation model we developed. This model showed that gamma-irradiation leads to immunosuppression, delayed clearance of primary virus infection, and reactivated latent viral infections. Both single high-dose and multiple low doses of gamma-irradiation cause virus reactivation. Hind limb unloading (HLU), that simulates aspects of weightlessness, was applied to the mouse model. HLU results in loss of control of virus infection in a tissue-specific manner. Combined effects of HLU and virus infection resulted in increased mortality. These findings show the deleterious effect of multiple low-dose exposures to irradiation on host control of infections and the added adverse effect of HLU. This mouse model is proven useful to define the risk of combined factors that affect the immune system to long duration space flight.

Bibliography Type: Description: (Last Updated: 10/03/2007) Show Cumulative Bibliography Listing

Articles in Peer-reviewed Journals Sonnenfeld G, Aviles H, Butel J S, Shearer W T, Niesel D, Pandya U, Allen C, Ochs H D, Blancher A, Abbal, M. "Bed rest and immunity." Acta Astronautica. In Press, 2006. Expected publication Feb 2007. , Apr-2006

Fiscal Year: FY 2005 Task Last Updated: 12/02/2005

PI Name: Butel, Janet S.

Project Title: Biology of Virus Infections: Radiation and Immunity

Division Name: Human Research

Program/Discipline: NSBRI Teams

Element/Subdiscipline: Immunology, Infection and Hematology Team

Joint Agency Name:

Human Research Program Elements: None

Human Research Program Risks:: None

Human Research Program Gaps: None

PI Email: jbutel@bcm.tmc.edu Fax: 713-798-5019

PI Organization Type: UNIVERSITY Phone: 713-798-3003

Organization Name: Baylor College of Medicine

PI Address 1: One Baylor Plaza, 737E

PI Address 2: Department of Molecular Virology and Microbiology

PI Web Page: http://www.bcm.edu/cmb/?pmid=2046

City: Houston State: TX

Zip Code: 77030-3411 Congressional District: 25

Comments: Address updated 9/2008

Project Type: GROUND Solicitation: 2003 Biomedical Research & Countermeasures 03-OBPR-04

Start Date: 04/01/2004 End Date: 12/31/2006

No. of Post Docs: 1 No. of PhD Degrees: 0

No. of PhD Candidates: 0 No. of Master' Degrees: 0

No. of Master's Candidates: 0 No. of Bachelor's Degrees: 0

No. of Bachelor's Candidates: 0 Monitoring Center: NSBRI

Contact Monitor: Contact Phone:

Contact Email:

Flight Program:

Flight Assignment: Changed end date of3/31/2008.

Key Personnel Changes/Previous PI: 0

COI Name (Institution): Conner, Margaret  ( Baylor College of Medicine )
Ling, Paul  ( Baylor College of Medicine )
Zhang, Shaojie  ( Baylor College of Medicine )

Grant/Contract No.: NCC 9-58-IIH00403

Performance Goal No.:

Performance Goal Text:

Task Description: Space flight has been found to affect immune responses, although the underlying mechanisms have not been established. Alterations in a normal immune response could have a major impact on the host’s ability to control infections. An important question being explored is whether infectious diseases will pose a medical risk to the success of long-duration space journeys. All humans are infected for life with latent and persistent viruses, and it is well-known that suppression of the immune system allows latent viruses to reactivate and multiply, which may cause disease in the person undergoing reactivation or in contacts to whom the virus is transmitted. The general hypothesis being addressed is that conditions of long-duration space flight, including stress, isolation, containment, microbial contamination, and solar radiation, will alter human immune responses, leading to reactivation of latent viruses, increased viral infections and viral disease, and possible development of malignancies. We are focusing on reactivation and shedding of human herpesvirus EBV and human polyomaviruses, agents known to establish persistent infections and to undergo reactivation and cause disease, including cancer, when the host immune system is compromised. Animal models are being used to study radiation effects on viral infections and host responses to those infections. The specific aims of the project are: (1) To determine the effects of space radiation and hind limb unloading (HLU) on host control of virus infections and virus-induced cancers; and (2) To characterize direct effects of radiation on viruses and virus-infected cells. Key findings of the project this year were from the mouse polyoma virus space radiation model we developed. A quantitative real-time polymerase chain reaction assay was developed to measure murine polyoma virus genome copies in infected animal tissues. Preliminary studies suggest that combined effects of radiation and virus infection on experimental animals lead to immunosuppression and enhanced virus replication. Another key finding was the identification of a herpesvirus EBV latent protein that might modulate the development of EBV-associated disease. These findings may allow new approaches, such as novel drugs, to prevent and treat virus reactivation and virus-associated diseases that arise against an immunosuppressed host background. Plans for the coming year include experiments to determine the effect of multiple, low-dose radiation exposures on host control of viral infections; measurements of virus reactivations in volunteers participating in the NASA-sponsored Bed Rest Study, a model for the effects of space flight conditions on human physiology, in collaboration with Dr. G. Sonnenfeld; studies of radiation-induced signals that cause EBV reactivation from latency in cultured cells; tests of whether the effects of HLU and irradiation synergistically affect control of polyoma virus infections (reactivation) and immune impairment; and determination by flow cytometry of whether virus infection, irradiation, and HLU of mice results in altered distribution and numbers of individual leukocyte cell subsets.

Task Progress: Key findings of the project this year were from the mouse polyoma virus space radiation model we developed. A quantitative real-time polymerase chain reaction assay was developed to measure murine polyoma virus genome copies in infected animal tissues. Preliminary studies suggest that combined effects of radiation and virus infection on experimental animals lead to immunosuppression and enhanced virus replication. Another key finding was the identification of a herpesvirus EBV latent protein that might modulate the development of EBV-associated disease. These findings may allow approaches, such as novel drugs, to prevent and treat virus reactivation and virus-associated diseases that arise against an immunosuppressed host background.

Bibliography Type: Description: (Last Updated: 10/03/2007) Show Cumulative Bibliography Listing

Articles in Peer-reviewed Journals Forsman ZH, Lednicky JA, Fox GE, Willson RC, White ZS, Halvorson SJ, Wong C, Lewis AM Jr, Butel JS. "Phylogenetic analysis of polyomavirus simian virus 40 from monkeys and humans." J Virol. 2004 Sep;78(17):9306-16. PMID: 15308725 , Sep-2004

Articles in Peer-reviewed Journals Gordadze AV, Onunwor CW, Peng R, Poston D, Kremmer E, Ling PD. "EBNA2 amino acids 3 to 30 are required for induction of LMP-1 and immortalization maintenance." J Virol. 2004 Apr;78(8):3919-29. PMID: 15047808 , Apr-2004

Fiscal Year: FY 2004 Task Last Updated: 03/20/2006

PI Name: Butel, Janet S.

Project Title: Biology of Virus Infections: Radiation and Immunity

Division Name: Human Research

Program/Discipline: NSBRI Teams

Element/Subdiscipline: Immunology, Infection and Hematology Team

Joint Agency Name:

Human Research Program Elements: None

Human Research Program Risks:: None

Human Research Program Gaps: None

PI Email: jbutel@bcm.tmc.edu Fax: 713-798-5019

PI Organization Type: UNIVERSITY Phone: 713-798-3003

Organization Name: Baylor College of Medicine

PI Address 1: One Baylor Plaza, 737E

PI Address 2: Department of Molecular Virology and Microbiology

PI Web Page: http://www.bcm.edu/cmb/?pmid=2046

City: Houston State: TX

Zip Code: 77030-3411 Congressional District: 25

Comments: Address updated 9/2008

Project Type: GROUND Solicitation: 2003 Biomedical Research & Countermeasures 03-OBPR-04

Start Date: 04/01/2004 End Date: 12/31/2006

No. of Post Docs: No. of PhD Degrees:

No. of PhD Candidates: No. of Master' Degrees:

No. of Master's Candidates: No. of Bachelor's Degrees:

No. of Bachelor's Candidates: Monitoring Center: NSBRI

Contact Monitor: Contact Phone:

Contact Email:

Flight Program:

Flight Assignment: Original end date was 3/31/2008.

Key Personnel Changes/Previous PI:

COI Name (Institution):

Grant/Contract No.: NCC 9-58-IIH00403

Performance Goal No.:

Performance Goal Text:

Task Description: The general hypothesis being addressed in this project is that conditions of space flight, including solar radiation, will damage the human immune system, leading to reactivation of latent viruses, increased viral infections and disease, and possible development of cancer. We will continue to focus on human herpesviruses and polyomaviruses; we established in the previous funding period that these viruses, known to cause human disease, are reactivated and undergo increased replication in humans under space flight conditions. We will extend our studies to address the synergistic effects of space radiation and hind limb unloading on viral pathogenesis and host control of infections. Mouse models we have developed involving murine polyoma virus will be used to delineate mechanisms underlying space flight-induced immune changes and infectious disease processes and to test countermeasures. The specific aims of the proposed study are: (1) Determine the effects of space radiation and hind limb unloading on host control of virus infections and virus-induced cancers and develop countermeasures to minimize adverse effects of virus infections. The model system is polyoma virus infections in mice. Gamma radiation effects on virus clearance, virus reactivation, and virus-induced tumor development will be determined. Antiviral drugs and a potential virus vaccine will be tested as candidate countermeasures. (2) Characterize direct effects of radiation on viruses and virus-infected cells. Radiation-induced changes in expression of herpesvirus EBV latent and lytic genes will be determined using cell-based assays in vitro, as well as effects of polyomavirus regulatory region variations on viral responses to radiation. (3) Collaboration to develop a virus detection and quantification method for in-flight monitoring. A molecular beacon-based assay targeted to herpesviruses will be developed. This application is appropriate for the NSBRI Immunology, Infection and Hematology Team. The project will provide new insights into the effects of space radiation and space flight conditions on infectious disease processes and will help develop facile, spacecraft-compatible methods for detection and monitoring of virus reactivation. Collaborators on proposed studies include current NSBRI Team members Drs. Shearer and Fox.

Research Impact/Earth Benefits:

Task Progress: New project for FY2004; no progress report for this reporting period.

Bibliography Type: Description: (Last Updated: 10/03/2007) Show Cumulative Bibliography Listing

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