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Project Title:  Effects of Long-Term Exposure to Microgravity on Salivary Markers of Innate Immunity Reduce
Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 11/03/2011  
End Date: 12/14/2018  
Task Last Updated: 01/28/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Simpson, Richard  Ph.D. / University of Arizona 
Address:  College of Agriculture and Life Sciences; College of Medicine 
1177 E. Fourth Street, Room 308, Shantz Building 
Tucson , AZ 85721-0001 
Email: rjsimpson@email.arizona.edu 
Phone: 713-397-0121  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Arizona 
Joint Agency:  
Comments: NOTE: Formerly at University of Houston until September 2017 move to University of Arizona.  
Co-Investigator(s)
Affiliation: 
Clarke, Mark  Ph.D. University of Houston 
Crucian, Brian  Ph.D. Wyle Laboratories, Inc. 
O'Connor, Dan  Ph.D. University of Houston 
Pierson, Duane  Ph.D. NASA Johnson Space Center 
Spielmann, Guillaume  Ph.D. University of Houston 
Mehta, Satish  Ph.D. NASA Johnson Space Center 
Key Personnel Changes / Previous PI: September 2018 report: Dr. Satish Mehta has joined the project as CoInvestigator.
Project Information: Grant/Contract No. NNX12AB48G 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: 2010 Crew Health NNJ10ZSA003N 
Grant/Contract No.: NNX12AB48G 
Project Type: FLIGHT 
Flight Program: ISS 
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Immune:Risk of Adverse Health Event Due to Altered Immune Response (IRP Rev F)
Human Research Program Gaps: (1) IM01:We do not know to what extent spaceflight alters various aspects of human immunity during spaceflight missions up to 6 months (IRP Rev E)
(2) IM02:It is necessary to define a flight standard related to spaceflight-associated immune system dysregulation (IRP Rev E)
Flight Assignment/Project Notes: ISS Flight Definition phase

NOTE: End date changed to 12/14/2018 per NSSC information (Ed., 10/1/18)

NOTE: End date changed to 5/2/2018 per NSSC information (Ed., 11/22/17)

NOTE: End date changed to 11/2/2017 per NSSC information (Ed., 1/23/17)

NOTE: End date changed to 11/2/2016 per NSSC information (Ed., 7/17/15)

NOTE: Gap Immune05 deleted per IRP Rev E (Ed., 3/24/14)

Task Description: Immune system dysregulation has been documented during and after spaceflight, but it is not known if these changes increase infection susceptibility or pose a significant health risk to crewmembers. Inherent problems with current in-flight research are small sample sizes and the difficulty to control for the many confounding factors that impact on the immune system. As such, it is not known if changes in immunity are due to the microgravity environment per se, or to the stressors associated with landing and re-adaptation to the 1G environment. The present project proposes a Flight Definition investigation, utilizing a longitudinal repeated measures design to determine the effects of long-term exposure to microgravity on a host of salivary antimicrobial proteins (AMPs) associated with innate host immune defense, whilst also considering the impact of other acute stressors such as launch, Soyuz landing, and extravehicular activity (EVA). Saliva samples will be collected from crewmembers selected for International Space Station (ISS) mission and ground-based controls at bi-weekly intervals for 6 months prior to flight, during the 6-month period on the ISS, and for 1 month on return to Earth. Saliva sampling was selected because it is an excellent biological fluid with which to detect broad-spectrum biomarkers of front-line host immune defense and is suitable for the spaceflight environment. Attempts will also be made to establish relationships between AMPs and other stressors associated with spaceflight (i.e., mood state disturbances, circadian desynchronization, sleep loss/disruption, stress biomarkers) using serial data.

Finally, blood samples will be collected before and after the mission to determine the impact of spaceflight on cellular aspects of innate immunity. Given the potential of salivary AMPs to serve as an indicator of weakened immunity during spaceflight, this project will serve as a foundation for future countermeasure developments and technological advances to detect real time changes during subsequent lunar or Mars missions.

Research Impact/Earth Benefits: This project will improve our understanding on how acute and long-term stress impacts on multiple aspects of the immune system. These research findings will be useful to determine if any immune related health problems might exist in individuals exposed to stressful environments (i.e., soldiers, caregivers).

Task Progress & Bibliography Information FY2019 
Task Progress: The study was initiated in September 2012 and data collection started in March 2013. We enrolled the required number of subjects giving us a sample size of eight crewmembers and seven ground-based controls including a crewmember who completed a 1-year ISS mission. Baseline blood, urine, and saliva samples were collected from all crewmembers and ground-based control subjects. All crewmembers and ground-based controls successfully completed all experimental procedures, although compliance for the health survey questionnaires, Profile of Mood States (POMS), and Sleep Quality questionnaires was not complete.

We successfully measured NK-cell killing potential against 4 separate tumor target cells in vitro and performed detailed immuophenotyping assays in whole blood samples identifying changes in the frequency of total T-cells, CD4+ T-cells, CD8+ T-cells, NK-cells, B-cells, granulocytes, monocytes, and their subtypes. In addition, interferon-gamma ELISpot assays were used to enumerate viral-specific T-cells against antigens derived from the herpesviruses cytomegalovirus (CMV), Epstein-Barr virus (EBV), Varicella Zoster virus (VZV), and Herpes simplex virus-1 (HSV-1). We also measured multiple analytes in saliva including the stress biomarkers alpha-amylase, cortisol and DHEA, the anti-microbial proteins LL-37, HNP 1-3, lactoferrinandlysozyme, and the systemic inflammatory marker C-reactive protein. We also quantified viral DNA against the latent herpesviruses CMV, EBV, VZV, and HSV-1 using both saliva and urine samples collected from the crew and the ground-based controls and measured IgG antibody titers against each of these viruses in plasma. The major findings from this project have so far been presented in three separate manuscripts. First, the NK-cell phenotypic and functional data was recently published in the Journal of Applied Physiology. The American Physiological Society (APS) selected this paper for a prestigious APS Select Award. Second, a manuscript with the salivary stress and antimicrobial biomarkers was recently submitted to Journal of Applied Physiology and is currently in review (Ed. note January 2020--the paper is published now; see Bibliography section). Third, the B-cell immune phenotyping data was combined with Dr. Guillaume Spielmann’s omnibus project as we felt the story related to B-cell function would be better if it were combined with this data set. This manuscript was recently published in the Journal of Applied Physiology (PMID: 30496712).

[Ed. note: compiled from PI's final report received October 2019]

Bibliography Type: Description: (Last Updated: 08/04/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Spielmann G, Agha NH, Kunz HE, Simpson RJ, Crucian BE, Mehta SK, Laughlin M, Campbell J. "B-cell homeostasis is maintained during long duration spaceflight." J Appl Physiol (1985). 2019 Feb 1;126(2):469-476. Epub 2018 Nov 29. https://doi.org/10.1152/japplphysiol.00789.2018 ; PubMed PMID: 30496712; PubMed Central PMCID: PMC6397409. , Feb-2019
Articles in Peer-reviewed Journals Agha NH, Baker FL, Kunz HE, Spielmann G, Mylabathula PL, Rooney BV, Mehta SK, Pierson DL, Laughlin MS, Markofski MM, Crucian BE, Simpson RJ. "Salivary antimicrobial proteins and stress biomarkers are elevated during a 6-month mission to the International Space Station." J Appl Physiol (1985). 2019 Nov 21. [Epub ahead of print] PubMed PMID: 31751178 ; https://doi.org/10.1152/japplphysiol.00560.2019 , Nov-2019
Articles in Peer-reviewed Journals Bigley AB, Agha NH, Baker FL, Spielmann G, Kunz HE, Mylabathula PL, Rooney B, Laughlin MS, Pierson DL, Mehta SK, Crucian BE, Simpson RJ. "NK-cell function is impaired during long-duration spaceflight." J Appl Physiol (1985). 2019 Apr 1;126(4):842-53. Epub 2018 Nov 1. PubMed PMID: 30382809 ; https://doi.org/10.1152/japplphysiol.00761.2018 , Apr-2019
Articles in Peer-reviewed Journals Agha NH, Mehta SK, Rooney BV, Laughlin MS, Markofski MM, Pierson DL, Katsanis E, Crucian BE, Simpson RJ. "Exercise as a countermeasure for latent viral reactivation during long duration space flight." FASEB J. First published: 03 January 2020. https://doi.org/10.1096/fj.201902327R ; PubMed PMID: 31908052 , Jan-2020
Articles in Peer-reviewed Journals Kunz HE, Agha NH, Hussain M, LaVoy EC, Smith KA, Mylabathula P, Diak D, Baker FL, O'Connor DP, Bond RA, Katsanis E, Bollard CM, Simpson RJ. "The effects of ß1 and ß1+2 adrenergic receptor blockade on the exercise-induced mobilization and ex vivo expansion of virus-specific T cells: Implications for cellular therapy and the anti-viral immune effects of exercise." Cell Stress Chaperones. Published online ahead of print 10 August 2020. https://doi.org/10.1007/s12192-020-01136-7 ; PMID: 32779001 , Aug-2020
Awards Bigley AB, Agha NH, Baker FL, Spielmann G, Kunz HE, Mylabathula PL, Rooney B, Laughlin MS, Pierson DL, Mehta SK, Crucian BE, Simpson RJ. "American Physiological Society (APS) selected this paper for a prestigious APS Select Award, "For distinction in scholarship in the Journal of Applied Physiology for the article 'NK-cell function is impaired during long-duration spaceflight.' " https://doi.org/10.1152/japplphysiol.00761.2018 , January 2019." Jan-2019
Project Title:  Effects of Long-Term Exposure to Microgravity on Salivary Markers of Innate Immunity Reduce
Fiscal Year: FY 2018 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 11/03/2011  
End Date: 12/14/2018  
Task Last Updated: 09/03/2018 
Download report in PDF pdf
Principal Investigator/Affiliation:   Simpson, Richard  Ph.D. / University of Arizona 
Address:  College of Agriculture and Life Sciences; College of Medicine 
1177 E. Fourth Street, Room 308, Shantz Building 
Tucson , AZ 85721-0001 
Email: rjsimpson@email.arizona.edu 
Phone: 713-397-0121  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Arizona 
Joint Agency:  
Comments: NOTE: Formerly at University of Houston until September 2017 move to University of Arizona.  
Co-Investigator(s)
Affiliation: 
Clarke, Mark  Ph.D. University of Houston 
Crucian, Brian  Ph.D. Wyle Laboratories, Inc. 
O'Connor, Dan  Ph.D. University of Houston 
Pierson, Duane  Ph.D. NASA Johnson Space Center 
Spielmann, Guillaume  Ph.D. University of Houston 
Mehta, Satish  Ph.D. NASA Johnson Space Center 
Key Personnel Changes / Previous PI: September 2018 report: Dr. Satish Mehta has joined the project as CoInvestigator.
Project Information: Grant/Contract No. NNX12AB48G 
Responsible Center: NASA JSC 
Grant Monitor: Vos, Jessica  
Center Contact:  
jessica.r.vos@nasa.gov 
Solicitation / Funding Source: 2010 Crew Health NNJ10ZSA003N 
Grant/Contract No.: NNX12AB48G 
Project Type: FLIGHT 
Flight Program: ISS 
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Immune:Risk of Adverse Health Event Due to Altered Immune Response (IRP Rev F)
Human Research Program Gaps: (1) IM01:We do not know to what extent spaceflight alters various aspects of human immunity during spaceflight missions up to 6 months (IRP Rev E)
(2) IM02:It is necessary to define a flight standard related to spaceflight-associated immune system dysregulation (IRP Rev E)
Flight Assignment/Project Notes: ISS Flight Definition phase

NOTE: End date changed to 12/14/2018 per NSSC information (Ed., 10/1/18)

NOTE: End date changed to 5/2/2018 per NSSC information (Ed., 11/22/17)

NOTE: End date changed to 11/2/2017 per NSSC information (Ed., 1/23/17)

NOTE: End date changed to 11/2/2016 per NSSC information (Ed., 7/17/15)

NOTE: Gap Immune05 deleted per IRP Rev E (Ed., 3/24/14)

Task Description: Immune system dysregulation has been documented during and after spaceflight, but it is not known if these changes increase infection susceptibility or pose a significant health risk to crewmembers. Inherent problems with current in-flight research are small sample sizes and the difficulty to control for the many confounding factors that impact on the immune system. As such, it is not known if changes in immunity are due to the microgravity environment per se, or to the stressors associated with landing and re-adaptation to the 1G environment. The present project proposes a Flight Definition investigation, utilizing a longitudinal repeated measures design to determine the effects of long-term exposure to microgravity on a host of salivary antimicrobial proteins (AMPs) associated with innate host immune defense, whilst also considering the impact of other acute stressors such as launch, Soyuz landing, and extravehicular activity (EVA). Saliva samples will be collected from crewmembers selected for International Space Station (ISS) mission and ground-based controls at bi-weekly intervals for 6 months prior to flight, during the 6-month period on the ISS, and for 1 month on return to Earth. Saliva sampling was selected because it is an excellent biological fluid with which to detect broad-spectrum biomarkers of front-line host immune defense and is suitable for the spaceflight environment. Attempts will also be made to establish relationships between AMPs and other stressors associated with spaceflight (i.e., mood state disturbances, circadian desynchronization, sleep loss/disruption, stress biomarkers) using serial data.

Finally, blood samples will be collected before and after the mission to determine the impact of spaceflight on cellular aspects of innate immunity. Given the potential of salivary AMPs to serve as an indicator of weakened immunity during spaceflight, this project will serve as a foundation for future countermeasure developments and technological advances to detect real time changes during subsequent lunar or Mars missions.

Research Impact/Earth Benefits: This project will improve our understanding on how acute and long-term stress impacts on multiple aspects of the immune system. These research findings will be useful to determine if any immune related health problems might exist in individuals exposed to stressful environments (i.e., soldiers, caregivers).

Task Progress & Bibliography Information FY2018 
Task Progress: Project objectives for the last reporting period were:

1. Complete all data collection procedures for 8 crewmembers (including 1y mission) and 7 ground-based control subjects.

2. Continue analysis of archived samples for all enrolled subjects.

3. Disseminate research findings to the scientific community.

Overview of Work Completed Study Progress: The study was initiated in September 2012 and data collection started in March 2013. We successfully enrolled the required number of subjects giving us a sample size of eight crewmembers and seven ground-based controls including an additional crewmember who completed a 1-year mission to the ISS. Baseline blood, urine, and saliva samples have been collected from all crewmembers and ground-based control subjects. All crewmembers and ground-based controls have completed all experimental procedures. We have obtained in flight samples and ambient blood returns from all enrolled crewmembers. All baseline and in flight ambient blood samples were processed and analyzed successfully. Frozen saliva, urine, and plasma samples have all been processed and analyzed. The IRB (Institutional Review Board) protocol was renewed in July 2018. During the last reporting period, the project team have been analyzing and interpreting data in preparation for dissemination to the scientific community. Data analysis and write up was somewhat delayed due to the Principal Investigator (PI) Dr. Simpson changing institutions (moving from the University of Houston to the University of Arizona) within the last reporting period. One scientific paper was published during the last reporting period, two others have been submitted for publication, and two others are currently in preparation (details below). One of the recent articles from this work “Long-duration spaceflight impairs NK-cell function” is currently under review with the Journal of Applied Physiology. Publications and Presentations: Our validation work for this project allowed us to assess NK-cell function in the context of latent cytomegalovirus infection, age, and exercise. This led to publications by Bigley et al. (2016) in the journals Cellular Immunology and Clinical and Experimental Immunology, Bigley et al. (2015) in Oxidative Medicine and Cellular Longevity and Brain, Behavior, and Immunity, and Bigley et al. (2018) in Clinical and Experimental Immunology. We also published a manuscript in European Journal of Applied Physiology, which stemmed from the validation work of our saliva assays for this project (Kunz et al., 2015). In addition, Spielmann et al. (2016) and Kunz et al. (2018) used the validation work from the viral T-cell quantification component of the “Salivary Markers” study for a publication in Scientific Reports and Physiology and Behavior, respectively. Furthermore, Graff et al. (2018), Agha et al. (2018), and LaVoy et al. (2017) used the validation work for cellular phenotyping of the “Salivary Markers” study in their recent publications in Brain, Behavior, and Immunity and Physiological Reports. The PI (Dr. Simpson) collaborated with NASA scientists and other space life scientists to generate two review articles pertaining to the effects of space travel on immune function (Crucian et al. 2018; Makedonas et al., 2018). Hematology data from this project was also used in the BMC Hematology publication by Kunz et al. (2017). NASA funding was acknowledged in all of these publications. The work supported by this research grant was presented at the International Society of Exercise and Immunology (ISEI) 2017 Symposium in July 2017, the Human Research Program Investigators' Workshop in January 2017 and February 2018, and the American College of Sports Medicine (ACSM) annual meetings in 2017 and 2018. Current and Future Work

All data has been collected and analyzed. The following papers are a direct result of this project and have been published (See also Cumulative Bibliography): Crucian BE, Chouker A, Simpson RJ, Mehta S, Marshall G, Smith SM, Zwart SR, Heer M, Ponomarev S, Whitmire A, Frippiat JP, Douglas GL, Lorenzi H, Buchheim JI, Makedonas G, Ginsburg GS, Ott CM, Pierson DL, Krieger SS, Baecker N & Sams C (2018). Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions. Frontiers in Immunology, 9, 1437. Crucian, B., Simpson, R.J., Mehta, S., Stowe, R., Chouker, A., Hwang, S., Actor, J.K., Salam, A.P., Pierson, D. and C. Sams. (2014) Terrestrial stress analogs for spaceflight associated immune system dysregulation. Brain, Behavior and Immunity, 39, 23-32.

Kunz H, Quiriarte H, Simpson RJ, Ploutz-Snyder R, McMonigal K, Sams C & Crucian B. (2017). Alterations in hematologic indices during long-duration spaceflight. BMC Hematology, 8, 17-12. Makedonas G, Chouker A, Mehta S, Simpson RJ, Stowe R, Sams C, Pierson DL & Crucian BE (2018). Mechanistic Clues to Overcome Spaceflight-Induced Immune Dysregulation. Current Pathobiology Reports, 6, 185-192. Spielmann, G., Laughlin, M. S., Kunz, H., Crucian, B. E., Quiriarte, H. D., Mehta, S. K., Pierson, D. L. & Simpson, R. J. (2018). Latent viral reactivation is associated with changes in plasma antimicrobial protein concentrations during long-duration spaceflight. Acta Astronautica, 146, 111-116.

The following manuscripts have been submitted for publication or are in preparation:

Bigley, A.B., Agha, N.H., Kunz, H.E., Baker, F.L., Spielmann, G., Rooney, B.V., Mylabathula, P., Laughlin, M. S., Mehta, S. K., Pierson, D. L. Crucian, B. E., & Simpson, R. J. (2018). NK-cell function is impaired during long duration spaceflight. Journal of Applied Physiology (In Review).

Spielmann, G., Simpson, R. J. Laughlin, M. S., Kunz, H., Crucian, B. E., Mehta, S. K. & Campbell, J.C. (2018). B-cell homeostasis is maintained during long-duration spaceflight. Journal of Applied Physiology (In Review).

Agha, N.H., Kunz, H.E., Baker, F.L., Spielmann, G., Rooney, B.V., Mylabathula, P., Bigley, A.B., Laughlin, M. S., Mehta, S. K., Pierson, D. L. Crucian, B. E., & Simpson, R. J. (2018). Long-duration spaceflight alters antimicrobial proteins in astronaut saliva (In preparation).

Agha, N.H., Spielmann, G., Kunz, H.E., Baker, F.L., Rooney, B.V., Mylabathula, P., Bigley, A.B., Laughlin, M. S., Mehta, S. K., Pierson, D. L. Crucian, B. E., & Simpson, R. J. (2018). T-cell and NK-cell responses to latent viral reactivation onboard the International Space Station (In preparation).

Bibliography Type: Description: (Last Updated: 08/04/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Agha NH, Spielmann G, Kunz HE, Baker FL, Rooney BV, Mylabathula P, Bigley AB, Laughlin MS, Mehta SK, Pierson DL, Crucian BE, Simpson RJ. "The impact of a 6-month mission to the International Space Station (ISS) on salivary antimicrobial proteins." 13th International Society for Exercise and Immunology (ISEI) Symposium, Coimbra, Portugal, July 11-14, 2017.

Annals of Research in Sport and Physical Activity. 2018;ex2018:97-8. https://doi.org/10.14195/2182-7087_ex2018_26 , Jul-2017

Abstracts for Journals and Proceedings Bigley AB, Mylabathula PL, Agha N, Li L, Mehta S, Crucian B, Pierson D, Laughlin M, Rezvani K, Simpson RJ. "The role of microgravity in dysregulated NK-cell function and CMV-specific T-cell responses during spaceflight." 2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017.

2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017. , Jan-2017

Abstracts for Journals and Proceedings Bigley AB, Agha NH, Kunz HE, Baker FL, Spielmann G, Rooney BV, Mylabathula P, Laughlin MS, Mehta SK, Pierson DL, Crucian BE, Simpson RJ. "Dysregulated NK-cell function during long-duration spaceflight." 13th International Society for Exercise and Immunology (ISEI) Symposium, Coimbra, Portugal, July 11-14, 2017.

Annals of Research in Sport and Physical Activity. 2018;ex2018:99-100. https://doi.org/10.14195/2182-7087_ex2018_25 , Jul-2017

Abstracts for Journals and Proceedings Simpson RJ, Bigley AB, Spielmann G, Kunz H, Agha N, Baker F, Rooney B, Mylabathula PL, Graff R, Laughlin M, Mehta S, Pierson D, Crucian B. "Long duration spaceflight impairs NK-cell function in ISS crewmembers: findings from the ‘Salivary Markers’ project." 2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017.

2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017. , Jan-2017

Abstracts for Journals and Proceedings Bigley AB, Agha NH, Kunz HE, Baker FL, Spielmann G, Rooney BV, Mylabathula P, Laughlin MS, Mehta SK, Pierson DL, Crucian BE, Simpson RJ. "The role of microgravity and stress-related humoral factors in dysregulated NK-cell function during spaceflight." National Space Biomedical Research Institute (NSBRI) Summer Bioastronautics Institute, Houston, TX, USA, May 31-June 3, 2016.

National Space Biomedical Research Institute (NSBRI) Summer Bioastronautics Institute, Houston, TX, USA, May 31-June 3, 2016. , Jun-2016

Abstracts for Journals and Proceedings Bigley AB, Agha NH, Kunz HE, Baker FL, Spielmann G, Mylabathula PL, Bigley AB, Simpson RJ. "Simulated microgravity ‘disarms’ human NK-cells and inhibits cytotoxicity." 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Spielmann G, Campbell J, Crucian BE, Laughlin MS, Simpson RJ. "The impact of long-duration spaceflight on the function of plasma cells." American College of Sports Medicine (ACSM) 65th Annual Meeting, Minneapolis, MN, May 29-June 2, 2018.

Medicine & Science in Sports & Exercise. 2018 May;50(Suppl 1 5S):336. https://doi.org/10.1249/01.mss.0000536188.85345.86 , Jun-2018

Articles in Peer-reviewed Journals Bigley AB, Baker FL, Simpson RJ. "Cytomegalovirus: an unlikely ally in the fight against blood cancers?" Clin Exp Immunol. 2018 Sep;193(3):265-74. https://doi.org/10.1111/cei.13152 ; PubMed PMID: 29737525; PubMed Central PMCID: PMC6150251 , Sep-2018
Articles in Peer-reviewed Journals Simpson RJ, Graham SM, Connaboy C, Clement R, Pollonini L, Florida-James GD. "Blood lactate thresholds and walking/running economy are determinants of backpack-running performance in trained soldiers." Appl Ergon. 2017 Jan;58:566-72. Epub 2016 May 4. https://doi.org/10.1016/j.apergo.2016.04.010 ; PubMed PMID: 27154276 , Jan-2017
Articles in Peer-reviewed Journals Agha NH, Baker FL, Kunz HE, Graff R, Azadan R, Dolan C, Laughlin MS, Hosing C, Markofski MM, Bond RA, Bollard CM, Simpson RJ. "Vigorous exercise mobilizes CD34+ hematopoietic stem cells to peripheral blood via the ß2-adrenergic receptor." Brain Behav Immun. 2018 Feb;68:66-75. Epub 2017 Oct 7. https://doi.org/10.1016/j.bbi.2017.10.001 ; PubMed PMID: 29017969 , Feb-2018
Articles in Peer-reviewed Journals Alfano CA, Bower J, Cowie J, Lau S, Simpson RJ. "Long-duration space exploration and emotional health: Recommendations for conceptualizing and evaluating risk." Acta Astronaut. 2018 Jan;142:289-99. https://doi.org/10.1016/j.actaastro.2017.11.009 , Jan-2018
Articles in Peer-reviewed Journals Crucian BE, Choukèr A, Simpson RJ, Mehta S, Marshall G, Smith SM, Zwart SR, Heer M, Ponomarev S, Whitmire A, Frippiat JP, Douglas GL, Lorenzi H, Buchheim JI, Makedonas G, Ginsburg GS, Ott CM, Pierson DL, Krieger SS, Baecker N, Sams C. "Immune system dysregulation during spaceflight: Potential countermeasures for deep space exploration missions." Front Immunol. 2018 Jun 28;9:1437. Review. https://doi.org/10.3389/fimmu.2018.01437 ; PubMed PMID: 30018614 ; PubMed Central PMCID: PMC6038331 , Jun-2018
Articles in Peer-reviewed Journals Graff RM, Kunz HE, Agha NH, Baker FL, Laughlin M, Bigley AB, Markofski MM, LaVoy EC, Katsanis E, Bond RA, Bollard CM, Simpson RJ. "ß2-adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans." Brain Behav Immun. Available online 30 August 2018, In Press, Corrected Proof. https://doi.org/10.1016/j.bbi.2018.08.017 ; PubMed PMID: 30172948 , Aug-2018
Articles in Peer-reviewed Journals Kunz H, Quiriarte H, Simpson RJ, Ploutz-Snyder R, McMonigal K, Sams C, Crucian B. "Alterations in hematologic indices during long-duration spaceflight." BMC Hematol. 2017 Sep 8;17:12. https://doi.org/10.1186/s12878-017-0083-y ; PubMed PMID: 28904800 ; PubMed Central PMCID: PMC5590186 , Sep-2017
Articles in Peer-reviewed Journals Kunz HE, Spielmann G, Agha NH, O'Connor DP, Bollard CM, Simpson RJ. "A single exercise bout augments adenovirus T-cell mobilization and function." Physiol Behav. 2018 Oct 1;194:56-65. Epub 2018 Apr 30. https://doi.org/10.1016/j.physbeh.2018.04.035 ; PubMed PMID: 29723594 , Oct-2018
Articles in Peer-reviewed Journals LaVoy EC, Hussain M, Reed J, Kunz H, Pistillo M, Bigley AB, Simpson RJ. "T-cell redeployment and intracellular cytokine expression following exercise: Effects of exercise intensity and cytomegalovirus infection." Physiol Rep. 2017 Jan;5(1): e13070. https://doi.org/10.14814/phy2.13070 ; PubMed PMID: 28087817 ; PubMed Central PMCID: PMC5256156 , Jan-2017
Articles in Peer-reviewed Journals Makedonas G, Choukèr A, Mehta S, Simpson RJ, Stowe R, Sams C, Pierson D, Crucian B. "Mechanistic clues to overcome spaceflight-induced immune dysregulation." Curr Pathobiol Rep. 2018 Jul 19;6:185-92. Review. https://doi.org/10.1007/s40139-018-0178-6 , Jul-2018
Articles in Peer-reviewed Journals Rooney BV, Bigley AB, LaVoy EC, Laughlin M, Pedlar C, Simpson RJ. "Lymphocytes and monocytes egress peripheral blood within minutes after cessation of steady state exercise: A detailed temporal analysis of leukocyte extravasation." Physiol Behav. 2018 Oct 1;194:260-7. Epub 2018 Jun 7. https://doi.org/10.1016/j.physbeh.2018.06.008 ; PubMed PMID: 29885920 , Oct-2018
Articles in Peer-reviewed Journals Simpson RJ, Bigley AB, Agha N, Hanley PJ, Bollard CM. "Mobilizing immune cells with exercise for cancer immunotherapy." Exerc Sport Sci Rev. 2017 Jul;45(3):163-72. Review. https://doi.org/10.1249/JES.0000000000000114 ; PubMed PMID: 28418996 , Jul-2017
Articles in Peer-reviewed Journals Spielmann G, Laughlin MS, Kunz H, Crucian BE, Quiriarte HD, Mehta SK, Pierson DL, Simpson RJ. "Latent viral reactivation is associated with changes in plasma antimicrobial protein concentrations during long-duration spaceflight." Acta Astronaut. 2018 May;146:111-6. https://doi.org/10.1016/j.actaastro.2018.02.039 , May-2018
Project Title:  Effects of Long-Term Exposure to Microgravity on Salivary Markers of Innate Immunity Reduce
Fiscal Year: FY 2017 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 11/03/2011  
End Date: 05/02/2018  
Task Last Updated: 06/13/2017 
Download report in PDF pdf
Principal Investigator/Affiliation:   Simpson, Richard  Ph.D. / University of Arizona 
Address:  College of Agriculture and Life Sciences; College of Medicine 
1177 E. Fourth Street, Room 308, Shantz Building 
Tucson , AZ 85721-0001 
Email: rjsimpson@email.arizona.edu 
Phone: 713-397-0121  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Arizona 
Joint Agency:  
Comments: NOTE: Formerly at University of Houston until September 2017 move to University of Arizona.  
Co-Investigator(s)
Affiliation: 
Clarke, Mark  Ph.D. University of Houston 
Crucian, Brian  Ph.D. Wyle Laboratories, Inc. 
O'Connor, Dan  Ph.D. University of Houston 
Pierson, Duane  Ph.D. NASA Johnson Space Center 
Spielmann, Guillaume  Ph.D. University of Houston 
Project Information: Grant/Contract No. NNX12AB48G 
Responsible Center: NASA JSC 
Grant Monitor: Vos, Jessica  
Center Contact:  
jessica.r.vos@nasa.gov 
Solicitation / Funding Source: 2010 Crew Health NNJ10ZSA003N 
Grant/Contract No.: NNX12AB48G 
Project Type: FLIGHT 
Flight Program: ISS 
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Immune:Risk of Adverse Health Event Due to Altered Immune Response (IRP Rev F)
Human Research Program Gaps: (1) IM01:We do not know to what extent spaceflight alters various aspects of human immunity during spaceflight missions up to 6 months (IRP Rev E)
(2) IM02:It is necessary to define a flight standard related to spaceflight-associated immune system dysregulation (IRP Rev E)
Flight Assignment/Project Notes: ISS Flight Definition phase

NOTE: End date changed to 5/2/2018 per NSSC information (Ed., 11/22/17)

NOTE: End date changed to 11/2/2017 per NSSC information (Ed., 1/23/17)

NOTE: End date changed to 11/2/2016 per NSSC information (Ed., 7/17/15)

NOTE: Gap Immune05 deleted per IRP Rev E (Ed., 3/24/14)

Task Description: Immune system dysregulation has been documented during and after spaceflight, but it is not known if these changes increase infection susceptibility or pose a significant health risk to crewmembers. Inherent problems with current in-flight research are small sample sizes and the difficulty to control for the many confounding factors that impact on the immune system. As such, it is not known if changes in immunity are due to the microgravity environment per se, or to the stressors associated with landing and re-adaptation to the 1G environment. The present project proposes a Flight Definition investigation, utilizing a longitudinal repeated measures design to determine the effects of long-term exposure to microgravity on a host of salivary antimicrobial proteins (AMPs) associated with innate host immune defense, whilst also considering the impact of other acute stressors such as launch, Soyuz landing, and extravehicular activity (EVA). Saliva samples will be collected from crewmembers selected for International Space Station (ISS) mission and ground-based controls at bi-weekly intervals for 6 months prior to flight, during the 6-month period on the ISS, and for 1 month on return to Earth. Saliva sampling was selected because it is an excellent biological fluid with which to detect broad-spectrum biomarkers of front-line host immune defense and is suitable for the spaceflight environment. Attempts will also be made to establish relationships between AMPs and other stressors associated with spaceflight (i.e., mood state disturbances, circadian desynchronization, sleep loss/disruption, stress biomarkers) using serial data.

Finally, blood samples will be collected before and after the mission to determine the impact of spaceflight on cellular aspects of innate immunity. Given the potential of salivary AMPs to serve as an indicator of weakened immunity during spaceflight, this project will serve as a foundation for future countermeasure developments and technological advances to detect real time changes during subsequent lunar or Mars missions.

Research Impact/Earth Benefits: This project will improve our understanding on how acute and long-term stress impacts on multiple aspects of the immune system. These research findings will be useful to determine if any immune related health problems might exist in individuals exposed to stressful environments (i.e., soldiers, caregivers).

Task Progress & Bibliography Information FY2017 
Task Progress: Study Progress: The study was initiated in September 2012 and data collection started in March 2013. As of November 2016, we have enrolled the required number of subjects giving us a sample size of eight crewmembers and seven ground-based controls including a crewmember who completed a 1-year ISS mission. Baseline blood, urine, and saliva samples have been collected from all crewmembers and ground-based control subjects. All crewmembers and ground-based controls have completed all experimental procedures. We have obtained in flight samples and ambient blood returns from all enrolled crewmembers. All baseline and in flight ambient blood samples were processed and analyzed successfully. Saliva, urine, and blood plasma samples have been stored at -80°C until analysis. Frozen samples are currently being analyzed for all subjects. The IRB (Institutional Review Board) protocol was renewed in July 2014.

Publications and Presentations: Our validation work for this project allowed us to assess NK-cell function in the context of latent cytomegalovirus infection, age, and exercise. This led to publications by Bigley et al. (2016) in the journals Cellular Immunology and Clinical and Experimental Immunology, and Bigley et al. (2015) in Oxidative Medicine and Cellular Longevity and Brain, Behavior, and Immunity. We also published a manuscript in European Journal of Applied Physiology, which stemmed from the validation work of our saliva assays for this project (Kunz et al., 2015). In addition, Spielmann et al. (2016) used the validation work from the viral T-cell quantification component of the ‘Salivary Markers’ study for a publication in the Nature affiliated journal Scientific Reports. NASA funding was acknowledged in all of these publications. The work supported by this research grant was presented at the National Space Biomedical Research Institute (NSBRI) Summer Bioastronautics Institute and American College of Sports Medicine annual meeting in July 2016 and the Human Research Program Investigator’s Workshop in February 2016.

Current and Future Work: The study protocol is ongoing. By the end of year 5, we expect to have all data processed and analyzed for all crewmembers and ground-based controls. The remainder of FY17 will be spent analyzing frozen biological samples, interpreting data, and producing scientific papers.

Applications and Acquisition of Funding: Work on the ‘Salivary Markers’ project has allowed us to apply for further research funding. We have received additional research funding for space life science specific research projects but also from the National Institutes of Health (NIH). The latter project requires us to assess the impact of latent CMV infection on NK-cell phenotype and cytotoxicity in multiple myeloma patients following autologous stem cell transplantation. Our ideas for this project and preliminary data stemmed from the ‘Salivary Markers’ project. We also received a student research grant from the American College of Sports Medicine to analyze archived data related to astronaut fitness levels and latent viral reactivation.

Bibliography

The following are some of the published papers supported by this work (see also Task Book Bibliography below):

Bigley AB, Rezvani K, Shah N, Sekine T, Spielmann G, Pistillo M, Agha N, Kunz H, LaVoy ECP, Bollard CM & R.J. Simpson (2016). Latent CMV infection enhances anti-tumor cytotoxicity through accumulation of NKG2C+ NK-cells in healthy humans. Clinical and Experimental Immunology, 185, 239-251.

Bigley AB, Spielmann G, Agha N, O’Connor, D.P. & R.J. Simpson (2016). Dichotomous effects of latent CMV infection on the phenotype and functional properties of CD8+ T-cells and NK-cells. Cellular Immunology, 300, 26-32.

Bigley, A.B., Spielmann, G., Agha, N., & R.J. Simpson (2015). The effects of age and latent cytomegalovirus infection on NK-cell phenotype and exercise responsiveness in man. Oxidative Medicine & Cellular Longevity, 2015, 979645.

Bigley, A.B. Rezvani, K., Pistillo, M., Reed, J., Kunz, H., Agha, N., Bollard, C.M. & R.J. Simpson (2015). Acute exercise preferentially mobilizes NK-cells with a highly-differentiated phenotype and augments cytotoxicity against lymphoma and multiple myeloma target cells. Part II: Impact of latent cytomegalovirus infection and catecholamine sensitivity. Brain, Behavior and Immunity, 49, 59-65.

Kunz, H. Bishop, N.C., Spielmann, G., Pistillo, M., Reed, J., Ograjsek, T., Park, Y., Mehta, S., Pierson, D.L. & R.J. Simpson (2015) Fitness level impacts salivary antimicrobial responses to a single bout of cycling exercise. European Journal of Applied Physiology, 115, 1015-27.

Spielmann, G., Bollard, C.M., Kunz, H., Hanley, P.J. & R.J. Simpson (2016). A single exercise bout enhances the ex vivo manufacture of viral-specific T-cells from healthy donors: implications for allogeneic adoptive transfer immunotherapy. Scientific Reports, 16; 6:25852.

The following presentations were delivered and supported by this work:

Simpson, R.J., Bigley, A.B., Spielmann, G., Kunz, H.E., Agha, N., Baker, F., Rooney, B., Mylabathula, P.L., Graff, R.M., Crucian, B.E., Laughlin, M., Mehta, S.K., & D.L. Pierson. Long duration spaceflight impairs NK-cell function in astronauts. ACSM Annual Meeting, Boston, MA, USA, May 31st – June 4th, 2016.

Bigley, A.B. The role of microgravity and stress-related humoral factors in dysregulated NK-cell function during spaceflight. NSBRI Summer Bioastronautics Institute, Houston, TX, USA, May 31st – June 3rd, 2016.

Bigley, A.B. The effects of exercise and spaceflight on NK-cells. Invited Presentation at University of Calgary, Human Performance Laboratory Seminar, Sports Medicine Centre, Calgary, AB, Canada, March 30th – March 31st, 2016.

Mylabathula, P.L., Bigley, A.B., & R.J. Simpson. Simulated microgravity ‘disarms’ human NK-cells and inhibits cytotoxicity. HRP Investigators’ Workshop, Galveston, TX, USA, February 8th – February 11th, 2016.

Simpson, R.J. Immune responses to prolonged spaceflight: the ‘Salivary Markers’ study. NASA Human Research Program Investigator’s Workshop, Galveston, TX, USA, Feb 8th – Feb 11th 2016.

Interviews/Press Releases:

Simpson, R.J. interviewed for: Want a stronger immune system? Try hitting the gym. NBC Nightly News with Lester Holt: http://www.nbcnews.com/nightly-news/video/want-a-stronger-immune-system--try-hitting-the-gym-592155715731

Simpson, R.J. interviewed for: After record 340 days in space, Scott Kelly is coming down to Earth by Kim McGuire. Houston Chronicle, February 27, 2016: http://www.houstonchronicle.com/news/houston-texas/houston/article/After-record-340-days-in-space-Scott-Kelly-is-6858657.php

Simpson, R.J. Article in the Houston Chronicle regarding Dr Simpson’s NASA-funded research: http://www.houstonchronicle.com/local/history/city-of-possibilities/article/Trying-to-make-space-exploration-a-healthier-10415337.php?t=cd985e8469438d9cbb&cmpid=email-premium#photo-11641970

Bibliography Type: Description: (Last Updated: 08/04/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Simpson RJ, Bigley AB, Spielmann G, Kunz HE, Agha N, Baker F, Rooney B, Mylabathula PL, Graff RM, Crucian BE, Laughlin M, Mehta SK, Pierson DL. "Long duration spaceflight impairs NK-cell function in astronauts." American College of Sports Medicine 63rd Annual Meeting, Boston, MA, May 31-June 4, 2016.

Medicine & Science in Sports & Exercise. 2016 May;48(5 Suppl 1):87 , May-2016

Abstracts for Journals and Proceedings Mylabathula PL, Bigley AB, Simpson RJ. "Simulated microgravity ‘disarms’ human NK-cells and inhibits cytotoxicity." 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Simpson RJ. "Immune responses to prolonged spaceflight: the ‘Salivary Markers’ study." 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Articles in Peer-reviewed Journals Kunz H, Bishop NC, Spielmann G, Pistillo M, Reed J, Ograjsek T, Park Y, Mehta SK, Pierson DL, Simpson RJ. "Fitness level impacts salivary antimicrobial protein responses to a single bout of cycling exercise." Eur J Appl Physiol. 2015 May;115(5):1015-27. Epub 2015 Jan 4. https://doi.org/10.1007/s00421-014-3082-8 ; PubMed PMID: 25557386 , May-2015
Articles in Peer-reviewed Journals Bigley AB, Rezvani K, Pistillo M, Reed J, Agha N, Kunz H, O’Connor DP, Sekine T, Bollard CM, Simpson RJ. "Acute exercise preferentially redeploys NK-cells with a highly-differentiated phenotype and augments cytotoxicity against lymphoma and multiple myeloma target cells. Part II: Impact of latent cytomegalovirus infection and catecholamine sensitivity. " Brain Behav Immun. 2015 Oct;49:59-65. Epub 2015 Jan 9. https://doi.org/10.1016/j.bbi.2014.12.027 ; PubMed PMID: 25578514 , Oct-2015
Articles in Peer-reviewed Journals LaVoy EC, Bollard CM, Hanley PJ, O'Connor DP, Lowder TW, Bosch JA, Simpson RJ. "A single bout of dynamic exercise by healthy adults enhances the generation of monocyte-derived-dendritic cells." Cell Immunol. 2015 May;295(1):52-9. Epub 2015 Feb 25. https://doi.org/10.1016/j.cellimm.2015.02.007 ; PubMed PMID: 25749006 , May-2015
Articles in Peer-reviewed Journals LaVoy EC, Bollard CM, Hanley PJ, Blaney JW, O'Connor DP, Bosch JA, Simpson RJ. "A single bout of dynamic exercise enhances the expansion of MAGE-A4 and PRAME-specific cytotoxic T-cells from healthy adults." Exerc Immunol Rev. 2015;21:144-53. PubMed PMID: 25826370 , Apr-2015
Articles in Peer-reviewed Journals Fiuza-Luces C, Simpson RJ, Ramírez M, Lucia A, Berger NA. "Physical function and quality of life in patients with chronic GvHD: a summary of preclinical and clinical studies and a call for exercise intervention trials in patients." Bone Marrow Transplant. 2016 Jan;51(1):13-26. Epub 2015 Sep 14. Review. https://doi.org/10.1038/bmt.2015.195 ; PubMed PMID: 26367233; PubMed Central PMCID: PMC4703521 , Jan-2016
Articles in Peer-reviewed Journals Bigley AB, Spielmann G, Agha N, Simpson RJ. "The effects of age and latent cytomegalovirus infection on NK-cell phenotype and exercise responsiveness in man." Oxid Med Cell Longev. 2015;2015:979645. Published online 2015 Oct 25. https://doi.org/10.1155/2015/979645 ; PubMed PMID: 26583066; PubMed Central PMCID: PMC4637106 , Oct-2015
Articles in Peer-reviewed Journals Bigley AB, Spielmann G, Agha N, O'Connor DP, Simpson RJ. "Dichotomous effects of latent CMV infection on the phenotype and functional properties of CD8+ T-cells and NK-cells." Cell Immunol. 2016 Feb;300:26-32. Epub 2015 Nov 24. https://doi.org/10.1016/j.cellimm.2015.11.005 ; PubMed PMID: 26651951 , Feb-2016
Articles in Peer-reviewed Journals Simpson RJ, Bigley AB, Spielmann G, LaVoy EC, Kunz H, Bollard CM. "Human cytomegalovirus infection and the immune response to exercise." Exerc Immunol Rev. 2016;22:8-27. PubMed PMID: 26853134 , Feb-2016
Articles in Peer-reviewed Journals Bigley AB, Rezvani K, Shah N, Sekine T, Balneger N, Pistillo M, Agha N, Kunz H, O'Connor DP, Bollard CM, Simpson RJ. "Latent CMV infection enhances anti-tumor cytotoxicity through accumulation of NKG2C+ NK-cells in healthy humans." Clin Exp Immunol. 2016 Aug;185(2):239-51. http://dx.doi.org/10.1111/cei.12785 ; PubMed PMID: 26940026; PubMed Central PMCID: PMC4955006 , Aug-2016
Articles in Peer-reviewed Journals Spielmann G, Bollard CM, Kunz H, Hanley PJ, Simpson RJ. "A single exercise bout enhances the manufacture of viral-specific T-cells from healthy donors: implications for allogeneic adoptive transfer immunotherapy." Sci Rep. 2016 May 16;6:25852. http://dx.doi.org/10.1038/srep25852 ; PubMed PMID: 27181409; PubMed Central PMCID: PMC4867645 , May-2016
Articles in Peer-reviewed Journals Turner JE, Spielmann G, Wadley AJ, Aldred S, Simpson RJ, Campbell JP. "Exercise-induced B cell mobilisation: Preliminary evidence for an influx of immature cells into the bloodstream." Physiol Behav. 2016 Oct 1;164(Pt A):376-82. Epub 2016 Jun 16. https://doi.org/10.1016/j.physbeh.2016.06.023 ; PubMed PMID: 27321758 , Oct-2016
Significant Media Coverage NBC Nightly News with Lester Holt. "PI R.J. Simpson interviewed for segment, 'Want a stronger immune system? Try hitting the gym.' " NBC Nightly News with Lester Holt, December 27, 2016. http://www.nbcnews.com/nightly-news/video/want-a-stronger-immune-system--try-hitting-the-gym-592155715731 , Dec-2016
Significant Media Coverage McGuire K. "PI R.J. Simpson interviewed for 'After record 340 days in space, Scott Kelly is coming down to Earth.' " Houston Chronicle, February 27, 2016. http://www.houstonchronicle.com/news/houston-texas/houston/article/After-record-340-days-in-space-Scott-Kelly-is-6858657.php , Feb-2016
Significant Media Coverage Ellis L. " 'Trying to make space exploration a healthier experience for astronauts.' Article about PI R.J. Simpson's research." Houston Chronicle, October 26, 2016. http://www.houstonchronicle.com/local/history/city-of-possibilities/article/Trying-to-make-space-exploration-a-healthier-10415337.php?t=cd985e8469438d9cbb&cmpid=email-premium#photo-11641970 , Oct-2016
Project Title:  Effects of Long-Term Exposure to Microgravity on Salivary Markers of Innate Immunity Reduce
Fiscal Year: FY 2015 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 11/03/2011  
End Date: 11/02/2017  
Task Last Updated: 10/29/2014 
Download report in PDF pdf
Principal Investigator/Affiliation:   Simpson, Richard  Ph.D. / University of Arizona 
Address:  College of Agriculture and Life Sciences; College of Medicine 
1177 E. Fourth Street, Room 308, Shantz Building 
Tucson , AZ 85721-0001 
Email: rjsimpson@email.arizona.edu 
Phone: 713-397-0121  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Arizona 
Joint Agency:  
Comments: NOTE: Formerly at University of Houston until September 2017 move to University of Arizona.  
Co-Investigator(s)
Affiliation: 
Clarke, Mark  Ph.D. University of Houston 
Crucian, Brian  Ph.D. Wyle Laboratories, Inc. 
Lowder, Thomas  Ph.D. University of Houston 
O'Connor, Dan  Ph.D. University of Houston 
Pierson, Duane  Ph.D. NASA Johnson Space Center 
Spielmann, Guillaume  Ph.D. University of Houston 
Project Information: Grant/Contract No. NNX12AB48G 
Responsible Center: NASA JSC 
Grant Monitor: Vos, Jessica  
Center Contact:  
jessica.r.vos@nasa.gov 
Solicitation / Funding Source: 2010 Crew Health NNJ10ZSA003N 
Grant/Contract No.: NNX12AB48G 
Project Type: FLIGHT 
Flight Program: ISS 
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Immune:Risk of Adverse Health Event Due to Altered Immune Response (IRP Rev F)
Human Research Program Gaps: (1) IM01:We do not know to what extent spaceflight alters various aspects of human immunity during spaceflight missions up to 6 months (IRP Rev E)
(2) IM02:It is necessary to define a flight standard related to spaceflight-associated immune system dysregulation (IRP Rev E)
Flight Assignment/Project Notes: ISS Flight Definition phase

NOTE: End date changed to 11/2/2017 per NSSC information (Ed., 1/23/17)

NOTE: End date changed to 11/2/2016 per NSSC information (Ed., 7/17/15)

NOTE: Gap Immune05 deleted per IRP Rev E (Ed., 3/24/14)

Task Description: Immune system dysregulation has been documented during and after spaceflight, but it is not known if these changes increase infection susceptibility or pose a significant health risk to crewmembers. Inherent problems with current in-flight research are small sample sizes and the difficulty to control for the many confounding factors that impact on the immune system. As such, it is not known if changes in immunity are due to the microgravity environment per se, or to the stressors associated with landing and re-adaptation to the 1G environment. The present project proposes a Flight Definition investigation, utilizing a longitudinal repeated measures design to determine the effects of long-term exposure to microgravity on a host of salivary antimicrobial proteins (AMPs) associated with innate host immune defense, whilst also considering the impact of other acute stressors such as launch, Soyuz landing, and EVA. Saliva samples will be collected from crewmembers selected for ISS mission and ground-based controls at bi-weekly intervals for 6 months prior to flight, during the 6-month period on the ISS, and for 1 month on return to Earth. Saliva sampling was selected because it is an excellent biological fluid with which to detect broad-spectrum biomarkers of front-line host immune defense and is suitable for the spaceflight environment. Attempts will also be made to establish relationships between AMPs and other stressors associated with spaceflight (i.e. mood state disturbances, circadian desynchronization, sleep loss/disruption, stress biomarkers) using serial data.

Finally, blood samples will be collected before and after the mission to determine the impact of spaceflight on cellular aspects of innate immunity. Given the potential of salivary AMPs to serve as an indicator of weakened immunity during spaceflight, this project will serve as a foundation for future countermeasure developments and technological advances to detect real time changes during subsequent lunar or Mars missions.

Research Impact/Earth Benefits: This project will improve our understanding on how acute and long-term stress impacts on multiple aspects of the immune system. These research findings will be useful to determine if any immune related health problems might exist in individuals exposed to stressful environments (i.e. soldiers, caregivers).

Task Progress & Bibliography Information FY2015 
Task Progress: Project Summary

Immune system dysregulation has been documented during and after spaceflight, but it is not known if these changes increase infection susceptibility or pose a significant health risk to crewmembers. Inherent problems with current in-flight research are small sample sizes and the difficulty to control for the many confounding factors that impact on the immune system. As such, it is not known if changes in immunity are due to the microgravity environment per se, or to the stressors associated with landing and re-adaptation to the 1G environment. The present Flight Definition investigation will utilize a longitudinal repeated measures design to determine the effects of long-term exposure to microgravity on a host of salivary antimicrobial proteins (AMPs), latent viral reactivation, antibacterial properties of saliva, and blood markers associated with innate host immune defense, whilst also considering the impact of other acute stressors such as Soyuz landing. Saliva, urine, and blood samples will be collected from crewmembers selected for ISS mission and ground-based controls pre-flight (L-180-L-45), At “early”, “mid,” and “late” phases during the 6-month period on the ISS, and up to R+63 on return to Earth. Saliva sampling was selected as the primary source because it is an excellent biological fluid with which to detect broad-spectrum biomarkers of front-line host immune defense and is suitable for the spaceflight environment. Attempts will also be made to establish relationships between salivary and cellular immune markers, viral reactivation and other stressors associated with spaceflight (i.e. mood state disturbances, circadian desynchronization, sleep loss/disruption, stress biomarkers) using serial data. Blood samples will be used for monocyte, NK-cell, and neutrophil phenotype and functional assays. This project will help to establish if spaceflight alters innate immune function, which is important to determine if altered immunity poses a significant risk of an adverse health event among crewmembers. Moreover, these data will serve as a foundation for future countermeasure developments and technological advances to detect real time changes in immune function during subsequent lunar or Mars missions.

Task Objective/Description

Year 3 objectives for this project were:

1. Continue test subject recruitment and complete all data collection procedures for 1 crewmember and 1 ground-based control subject; 2. Continue experimental procedures for all enrolled subjects; 3. Disseminate research findings to the scientific community.

Overview of Work Completed in Year 3

Study Progress: The study was initiated in September 2012 and data collection started in March 2013. As of October 2014, we have enrolled the required number of subjects giving us a sample size of six crewmembers and six ground-based controls. We also recruited a crewmember on the 1-year ISS mission and will continue to obtain samples from this subject into FY16. Baseline blood, urine, and saliva samples have been collected from all crewmembers and ground-based control subjects. One crewmember has completed all experimental procedures and a second crewmember has one remaining sample to provide before completing the entire protocol (this is currently scheduled for November 2014). We have obtained in flight samples and ambient blood returns from a total of three crewmembers to date. All baseline and in flight ambient blood samples were processed and analyzed successfully. Saliva, urine, and blood plasma samples have been stored at -80°C until analysis. Frozen samples will be analyzed on completion of the study protocol. The IRB protocol was renewed in July 2014.

Publications and Presentations:

Dr. Crucian and Dr. Simpson took the lead on compiling a review article focused on terrestrial analogs of spaceflight-induced immune system dysregulation. The manuscript entitled: “Terrestrial Stress Analogs for Spaceflight Associated Immune System Dysregulation” was published in Brain, Behavior and Immunity in July 2014 (Crucian, Simpson et al. 2014). The paper by Bigley et al. in which we developed the NK-cell functional assay for use in this study, was also published in Brain, Behavior and Immunity in July 2014 (Bigley, Rezvani et al. 2014). Our validation work for this project also allowed us to assess NK-cell function in the context of latent cytomegalovirus infection. This led to a submitted manuscript that is currently under review with the Journal of Immunology. We also submitted a manuscript to European Journal of Applied Physiology, which stemmed from the validation work of our saliva assays for this project (Kunz et al). This paper has been accepted subject to minor revisions. NASA funding was acknowledged in all of these publications. The work supported by this research grant was presented at the Human Research Program Investigator’s Workshop in February 2014 and the Psychoneuroimmunology Research Society Symposium in July 2014.

Current and Future Work

The study protocol is ongoing. By the end of year 4 we expect to have 4 crewmembers complete the entire experimental protocol. The current Soyuz schedule for our enrolled subjects means we will have to extend the project into a fifth year. This is required not only to complete the experimental procedures for the ‘Salivary Markers’ subjects, but also for the subject on the 1-year ISS mission. The 1-year mission subject is currently scheduled to return in March 2016 and our protocol requirements include the collection of biological samples up to 66 days after landing. Based on the current ‘Salivary Markers’ crewmember enrollment and Soyuz schedule, we expect to collect our final samples by May 2016 (45S). The remainder of FY16 will be spent analyzing frozen biological samples, interpreting data and producing scientific papers.

Bibliography

The following published papers (and papers in revision) were supported by this work:

Bigley, A. B., K. Rezvani, C. Chew, T. Sekine, M. Pistillo, B. Crucian, C. M. Bollard and R. J. Simpson (2014). "Acute exercise preferentially redeploys NK-cells with a highly-differentiated phenotype and augments cytotoxicity against lymphoma and multiple myeloma target cells." Brain Behav Immun 39: 160-171.

Bigley A.B., Rezvani K., Shah N., Sekine T., Spielmann G., Pistillo M., Agha N., Kunz H., LaVoy E.C.P., Bollard C.M., Simpson R.J. "Latent CMV infection enhances anti-tumor cytotoxicity through accumulation of NKG2C+ NK-cells in healthy humans". J Immunol (In Review, submitted September 2014).

Crucian, B., R. J. Simpson, S. Mehta, R. Stowe, A. Chouker, S. A. Hwang, J. K. Actor, A. P. Salam, D. Pierson and C. Sams (2014). "Terrestrial stress analogs for spaceflight associated immune system dysregulation." Brain Behav Immun 39: 23-32.

Kunz, H. Bishop, N.C., Spielmann, G., Pistillo, M., Reed, J., Ograjsek, T., Park, Y., Mehta, S., Pierson, D.L. and R.J. Simpson. “Fitness level impacts salivary antimicrobial responses to a single bout of cycling exercise”. Eur J Appl Physiol (In Revision, submitted July 2014)

The following presentations were delivered and supported by this work:

Bigley, A.B., G. Spielmann, E. C. LaVoy, M. Pistillo, H. Kunz, N. Agha, R. J. Simpson. “Latent cytomegalovirus infection enhances baseline anti-tumor cytotoxicity but impairs NK-cell responses to acute exercise through preferential expansion of NKG2C+ NK-cells in healthy humans”. Psychoneuroimmunology Research Society Annual Meeting, Philadelphia, PA, USA, May 28th -31st 2014.

Kunz, H., G. Spielmann, M. Pistillo, J. Reed, T. Ograjsek, R. J. Simpson. “The impact of workload and training status on salivary antimicrobial proteins following acute exercise”. Psychoneuroimmunology Research Society Annual Meeting, Philadelphia, PA, USA, May 28th -31st 2014.

Spielmann, G., A. B. Bigley, B. E. Crucian, S. Mehta, D. Pierson, H. Kunz, N. Agha, E. C. LaVoy and R. J. Simpson. “Immune cell phenotypes and NK-cell function in astronauts and controls 5 months before a 6-month mission to the International Space Station”. Psychoneuroimmunology Research Society Annual Meeting, Philadelphia, PA, USA, May 28th -31st 2014.

Spielmann, G. B. E. Crucian, S. Mehta, H. Kunz, D. Pierson, and R. J. Simpson. “The impact of long-duration spaceflight on plasma antimicrobial proteins”. NASA Human Research Program Investigator’s Workshop, Galveston, TX, USA, Feb 12th - 13th 2013.

Bibliography Type: Description: (Last Updated: 08/04/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Bigley AB, Spielmann G, LaVoy EC, Pistillo M, Kunz H, Agha N, Simpson RJ. "Latent cytomegalovirus infection enhances baseline anti-tumor cytotoxicity but impairs NK-cell responses to acute exercise through preferential expansion of NKG2C+ NK-cells in healthy humans." 2014 Psychoneuroimmunology Research Society Annual Meeting, Philadelphia, PA, May 28t-31, 2014.

Brain, Behavior, and Immunity. 2014 Sep;40 Suppl:e44. http://dx.doi.org/10.1016/j.bbi.2014.06.173 , Sep-2014

Abstracts for Journals and Proceedings Kunz H, Spielmann G, Pistillo M, Reed J, Ograjsek T, Simpson RJ. "The impact of workload and training status on salivary antimicrobial proteins following acute exercise." 2014 Psychoneuroimmunology Research Society Annual Meeting, Philadelphia, PA, May 28t-31, 2014.

Brain, Behavior, and Immunity. 2014 Sep;40 Suppl:e26. http://dx.doi.org/10.1016/j.bbi.2014.06.108 , Sep-2014

Abstracts for Journals and Proceedings Spielmann G, Bigley AB, Crucian B, Mehta S, Pierson D, Kunz S, Agha N, LaVoy C, Simpson RJ. "Immune cell phenotypes and NK-cell function in astronauts and controls 5 months before a 6-month mission to the International Space Station." 2014 Psychoneuroimmunology Research Society Annual Meeting, Philadelphia, PA, May 28t-31, 2014.

Brain, Behavior, and Immunity. 2014 Sep;40 Suppl:e51. http://dx.doi.org/10.1016/j.bbi.2014.06.196 , Sep-2014

Abstracts for Journals and Proceedings Spielmann G, Crucian B, Mehta S, Kunz S, Pierson D, Simpson RJ. "The impact of long-duration spaceflight on plasma antimicrobial proteins." 2014 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-13, 2014.

2014 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-13, 2014. http://www.hou.usra.edu/meetings/hrp2014/pdf/3170.pdf , Feb-2014

Articles in Peer-reviewed Journals Bigley AB, Rezvani K, Chew C, Sekine T, Pistillo M, Crucian B, Bollard CM, Simpson RJ. "Acute exercise preferentially redeploys NK-cells with a highly-differentiated phenotype and augments cytotoxicity against lymphoma and multiple myeloma target cells." Brain Behav Immun. 2014 Jul;39:160-71. Epub 2013 Nov 5. http://dx.doi.org/10.1016/j.bbi.2013.10.030 ; PubMed PMID: 24200514 , Jul-2014
Articles in Peer-reviewed Journals Crucian B, Simpson RJ, Mehta S, Stowe R, Chouker A, Hwang SA, Actor JK, Salam AP, Pierson D, Sams C. "Terrestrial stress analogs for spaceflight associated immune system dysregulation." Brain Behav Immun. 2014 Jul;39:23-32. Epub 2014 Jan 24. http://dx.doi.org/10.1016/j.bbi.2014.01.011 ; PubMed PMID: 24462949 , Jul-2014
Project Title:  Effects of Long-Term Exposure to Microgravity on Salivary Markers of Innate Immunity Reduce
Fiscal Year: FY 2014 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 11/03/2011  
End Date: 11/02/2015  
Task Last Updated: 10/02/2013 
Download report in PDF pdf
Principal Investigator/Affiliation:   Simpson, Richard  Ph.D. / University of Arizona 
Address:  College of Agriculture and Life Sciences; College of Medicine 
1177 E. Fourth Street, Room 308, Shantz Building 
Tucson , AZ 85721-0001 
Email: rjsimpson@email.arizona.edu 
Phone: 713-397-0121  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Arizona 
Joint Agency:  
Comments: NOTE: Formerly at University of Houston until September 2017 move to University of Arizona.  
Co-Investigator(s)
Affiliation: 
Clarke, Mark  Ph.D. University of Houston 
Crucian, Brian  Ph.D. Wyle Laboratories, Inc. 
Lowder, Thomas  Ph.D. University of Houston 
O'Connor, Dan  Ph.D. University of Houston 
Pierson, Duane  Ph.D. NASA Johnson Space Center 
Spielmann, Guillaume  Ph.D. University of Houston 
Project Information: Grant/Contract No. NNX12AB48G 
Responsible Center: NASA JSC 
Grant Monitor: Vos, Jessica  
Center Contact:  
jessica.r.vos@nasa.gov 
Solicitation / Funding Source: 2010 Crew Health NNJ10ZSA003N 
Grant/Contract No.: NNX12AB48G 
Project Type: FLIGHT 
Flight Program: ISS 
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Immune:Risk of Adverse Health Event Due to Altered Immune Response (IRP Rev F)
Human Research Program Gaps: (1) IM01:We do not know to what extent spaceflight alters various aspects of human immunity during spaceflight missions up to 6 months (IRP Rev E)
(2) IM02:It is necessary to define a flight standard related to spaceflight-associated immune system dysregulation (IRP Rev E)
Flight Assignment/Project Notes: ISS Flight Definition phase

NOTE: Gap Immune05 deleted per IRP Rev E (Ed., 3/24/14)

Task Description: Immune system dysregulation has been documented during and after spaceflight, but it is not known if these changes increase infection susceptibility or pose a significant health risk to crewmembers. Inherent problems with current in-flight research are small sample sizes and the difficulty to control for the many confounding factors that impact on the immune system. As such, it is not known if changes in immunity are due to the microgravity environment per se, or to the stressors associated with landing and re-adaptation to the 1G environment. The present project proposes a Flight Definition investigation, utilizing a longitudinal repeated measures design to determine the effects of long-term exposure to microgravity on a host of salivary antimicrobial proteins (AMPs) associated with innate host immune defense, whilst also considering the impact of other acute stressors such as launch, Soyuz landing, and EVA. Saliva samples will be collected from crewmembers selected for ISS mission and ground-based controls at bi-weekly intervals for 6 months prior to flight, during the 6-month period on the ISS, and for 1 month on return to Earth. Saliva sampling was selected because it is an excellent biological fluid with which to detect broad-spectrum biomarkers of front-line host immune defense and is suitable for the spaceflight environment. Attempts will also be made to establish relationships between AMPs and other stressors associated with spaceflight (i.e. mood state disturbances, circadian desynchronization, sleep loss/disruption, stress biomarkers) using serial data.

Finally, blood samples will be collected before and after the mission to determine the impact of spaceflight on cellular aspects of innate immunity. Given the potential of salivary AMPs to serve as an indicator of weakened immunity during spaceflight, this project will serve as a foundation for future countermeasure developments and technological advances to detect real time changes during subsequent lunar or Mars missions.

Research Impact/Earth Benefits: This project will improve our understanding on how acute and long-term stress impacts on multiple aspects of the immune system. These research findings will be useful to determine if any immune related health problems might exist in individuals exposed to stressful environments (i.e. soldiers, caregivers).

Task Progress & Bibliography Information FY2014 
Task Progress: The study was initiated in September 2012 and data collection started in March 2013. We continued to develop our assays for NK-cell function and the detection of viral specific T-cells. Our validation/feasibility work, using exercise as a stress analog, contributed to the publication of two peer-reviewed publications (Spielmann et al., 2013; LaVoy et al., 2013) with another in revision (Bigley et al. In Revision). NASA funding was acknowledged in all of these publications.

CPHS approval for the study was renewed in July 2013.

To date, 4 crewmembers and 2 backup crewmembers have agreed to participate in the study and have provided informed consent. Baseline blood, urine, and saliva samples have been collected from 4 crewmembers and 4 ground-based control subjects. All cellular blood products have been processed and analyzed. Saliva, urine, and blood plasma samples have been stored at -80°C until analysis.

Archived plasma samples from 20 crewmembers that participated in the ‘Integrated Immune’ study were analyzed for a range of antimicrobial proteins. A scientific manuscript is currently being prepared with these data. We expect to submit the paper to a scientific journal by the end of the 2013 calendar year. Dr. Guillaume Spielmann presented the work at the International Society of Exercise Immunology (ISEI) meeting in Newcastle, Australia in poster form. For this work he was awarded the New Investigator prize for best presentation. He also presented work on the effects of latent viral infections, age, and acute stress on immune cell distribution. This work was supported by our validation experiments and Dr. Spielmann was also awarded the New Investigator prize for best oral presentation. It was first time in ISEI history that a single investigator was awarded both prizes.

Bibliography Type: Description: (Last Updated: 08/04/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Spielmann G, Crucian BE, Mehta SK, Kunz H, Pierson DL, Simpson RJ. "The impact of long duration spaceflight on plasma Antimicrobial Proteins." Presented at the International Society of Exercise Immunology Symposium, Newcastle, Australia, September 9-12, 2013.

International Society of Exercise Immunology Symposium, Newcastle, Australia, September 9-12, 2013. International Journal of Exercise Science. , Sep-2013

Abstracts for Journals and Proceedings Spielmann G, Bollard CM, Bigley AB, Hanley PJ, Blaney JWw, Lavoy ECP, Pircher H, Simpson RJ. "CMV-specific T-cells mobilized with exercise have broad epitope specificity and a high-differentiated effector memory phenotype." Presented at the International Society of Exercise Immunology Symposium, Newcastle, Australia, September 9-12, 2013.

International Society of Exercise Immunology Symposium, Newcastle, Australia, September 9-12, 2013. International Journal of Exercise Science , Sep-2013

Articles in Peer-reviewed Journals Lavoy EC, Bigley AB, Spielmann G, Rector JL, Morrison MR, O'Connor DP, Simpson RJ. "CMV amplifies T-cell redeployment to acute exercise independently of HSV-1 serostatus." Medicine and Science in Sports and Exercise. 2014 Feb;46(2):257-67. http://dx.doi.org/10.1249/MSS.0b013e3182a5a0fb ; PubMed PMID: 23877375 (Originally reported as Epub ahead of print. July 19, 2013.) , Feb-2014
Articles in Peer-reviewed Journals Spielmann G, Bollard CM, Bigley AB, Hanley PJ, Blaney JW, Lavoy EC, Pircher H, Simpson RJ. "The effects of age and latent cytomegalovirus infection on the redeployment of CD8+ T cell subsets in response to acute exercise in humans." Brain, Behavior and Immunity. 2014 Jul;39:142-51. Epub 2013 May 15. http://dx.doi.org/10.1016/j.bbi.2013.05.003 ; PubMed PMID: 23684819 (Originally reported as Epub ahead of print--May 15, 2013) , Jul-2014
Articles in Peer-reviewed Journals Mehta SK, Crucian BE, Stowe RP, Simpson RJ, Ott CM, Sams CF, Pierson DL. "Reactivation of latent viruses is associated with increased plasma cytokines in astronauts." Cytokine. 2013 Jan;61(1):205-9. Epub 2012 Oct 26. http://dx.doi.org/10.1016/j.cyto.2012.09.019 ; PubMed PMID: 23107825 , Jan-2013
Awards Spielmann G, Crucian BE, Mehta SK, Kunz H, Pierson DL, Simpson RJ. "Guillaume Spielmann wins New Investigator Award for best poster presentation: 'The impact of long duration spaceflight on plasma Antimicrobial Proteins' at the International Society for Exercise Immunology Symposium, Newcastle, Australia, September 2013." Sep-2013
Awards Spielmann G, Bollard CM, Bigley AB, Hanley PJ, Blaney JW, Lavoy EC, Pircher H, Simpson RJ. "Dr Spielmann wins the New Investigator Award for best oral presentation at the International Society of Exercise Immunology Symposium, Newcastle, Australia, September 2013: 'CMV-specific T-cells mobilized with exercise have broad epitope specificity and a high-differentiated effector memory phenotype.' " Sep-2013
Significant Media Coverage RIA Novosti. "Simpson, R.J. Article entitled: 'Space weakens human immune system – study' in the Russian press features Dr. Simpson’s work." RIA Novosti, April 2013. http://en.ria.ru/science/20130424/180828103.html , Apr-2013
Significant Media Coverage Mulvaney E. "UH study aims to find out why astronauts get sick. Article on Dr. Simpson's flight experiment appears in the Houston Chronicle." Houston Chronicle, April 24, 2013. http://www.chron.com/default/article/UH-study-aims-to-find-out-why-astronauts-get-sick-4460457.php , Apr-2013
Significant Media Coverage Ramirez M. "Student Martin Castaneda's PURS research project featured in UH moment: 'Undergraduate research (PURS)' . " University of Houston's online info, January 23, 2013. http://app1.kuhf.org/articles/1358944298-UH-Moment-Undergraduate-Research-PURS.html , Jan-2013
Project Title:  Effects of Long-Term Exposure to Microgravity on Salivary Markers of Innate Immunity Reduce
Fiscal Year: FY 2013 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 11/03/2011  
End Date: 11/02/2015  
Task Last Updated: 09/28/2012 
Download report in PDF pdf
Principal Investigator/Affiliation:   Simpson, Richard  Ph.D. / University of Arizona 
Address:  College of Agriculture and Life Sciences; College of Medicine 
1177 E. Fourth Street, Room 308, Shantz Building 
Tucson , AZ 85721-0001 
Email: rjsimpson@email.arizona.edu 
Phone: 713-397-0121  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Arizona 
Joint Agency:  
Comments: NOTE: Formerly at University of Houston until September 2017 move to University of Arizona.  
Co-Investigator(s)
Affiliation: 
Clarke, Mark  Ph.D. University of Houston 
Crucian, Brian  Ph.D. Wyle Laboratories, Inc. 
Lowder, Thomas  Ph.D. University of Houston 
O'Connor, Dan  Ph.D. University of Houston 
Pierson, Duane  Ph.D. NASA Johnson Space Center 
Spielmann, Guillaume  University of Houston 
Project Information: Grant/Contract No. NNX12AB48G 
Responsible Center: NASA JSC 
Grant Monitor: Vos, Jessica  
Center Contact:  
jessica.r.vos@nasa.gov 
Solicitation / Funding Source: 2010 Crew Health NNJ10ZSA003N 
Grant/Contract No.: NNX12AB48G 
Project Type: FLIGHT 
Flight Program: ISS 
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Immune:Risk of Adverse Health Event Due to Altered Immune Response (IRP Rev F)
Human Research Program Gaps: (1) IM01:We do not know to what extent spaceflight alters various aspects of human immunity during spaceflight missions up to 6 months (IRP Rev E)
(2) IM02:It is necessary to define a flight standard related to spaceflight-associated immune system dysregulation (IRP Rev E)
Flight Assignment/Project Notes: ISS Flight Definition phase

Task Description: Immune system dysregulation has been documented during and after spaceflight, but it is not known if these changes increase infection susceptibility or pose a significant health risk to crewmembers. Inherent problems with current in-flight research are small sample sizes and the difficulty to control for the many confounding factors that impact on the immune system. As such, it is not known if changes in immunity are due to the microgravity environment per se, or to the stressors associated with landing and re-adaptation to the 1G environment. The present project proposes a Flight Definition investigation, utilizing a longitudinal repeated measures design to determine the effects of long-term exposure to microgravity on a host of salivary antimicrobial proteins (AMPs) associated with innate host immune defense, whilst also considering the impact of other acute stressors such as launch, Soyuz landing, and EVA. Saliva samples will be collected from crewmembers selected for ISS mission and ground-based controls at bi-weekly intervals for 6 months prior to flight, during the 6-month period on the ISS, and for 1 month on return to Earth. Saliva sampling was selected because it is an excellent biological fluid with which to detect broad-spectrum biomarkers of front-line host immune defense and is suitable for the spaceflight environment. Attempts will also be made to establish relationships between AMPs and other stressors associated with spaceflight (i.e. mood state disturbances, circadian desynchronization, sleep loss/disruption, stress biomarkers) using serial data.

Finally, blood samples will be collected before and after the mission to determine the impact of spaceflight on cellular aspects of innate immunity. Given the potential of salivary AMPs to serve as an indicator of weakened immunity during spaceflight, this project will serve as a foundation for future countermeasure developments and technological advances to detect real time changes during subsequent lunar or Mars missions.

Research Impact/Earth Benefits: This project will improve our understanding on how acute and long-term stress impacts on multiple aspects of the immune system. These research findings will be useful to determine if any immune related health problems might exist in individuals exposed to stressful environments (i.e. soldiers, caregivers).

Task Progress & Bibliography Information FY2013 
Task Progress: Year 1 objectives for this project were:

1. Determine the salivary antimicrobial proteins that can be accurately measured in saliva obtained using collection devices suitable for spaceflight and the microgravity environment

2. Determine the stability of all immune system biomarkers measured in both blood and saliva for up to 72h post collection

Funding for this project began on November 3rd 2011. This allowed us to start the hiring process for a postdoctoral research fellow (Dr Guillaume Spielmann) who was appointed in March 2012.

Objective #1 Summary

Our goal was to identify a saliva collection method that would be accurate for detecting a number of key project biomarkers and would also be suitable for implementation on the International Space Station (ISS). Although whole saliva would be considered the gold standard, our attempts to collect whole saliva samples in a microgravity environment using the saliva collection aid (SCA) and a C9 parabolic flight were not successful. We therefore attempted to validate our assays with saliva collected using the Salivette and salimetrics oral swab (SOS) technologies. It became apparent that the Salivette method (which uses a cotton roll to collect saliva) would not be suitable as analyte recovery was extremely low and was not related to pair-wise concentrations determined in whole saliva. On the other hand, the SOS technology, although not resulting in complete analyte recovery, was significantly associated with concentrations determined in whole saliva and was sensitive enough to detect within-subject changes following a bout of acute physical stress. Moreover, the relative change to acute stress for all saliva biomarkers measured was not different between the passive drool and SOS collection methods. These data indicate that the SOS method, in addition to its suitability to be implemented on the ISS, is capable of accurately measuring a wide range of salivary biomarkers to detect changes within subjects over time. Dr. Pierson and Dr. Mehta’s laboratory also attempted to recover viral DNA from SOS versus salivette and found that 10x more DNA could be recovered from the SOS.

Objective #2 Summary

Our goal was to determine the stability of the salivary and blood biomarkers and assays for up to 72h post thaw/collection to meet mission operational constraints for returning samples to Earth. Proportions of lymphocyte and monocyte subtypes appear to be stable in whole blood samples up to 48h post draw in either EDTA or ACD treated blood tubes. T-cell populations also appear to be stable up to 72h post draw. NK-cell function can be measured in both EDTA and ACD treated blood tubes and is stable for up to 48h post draw in ACD tubes. However, 48h stability was demonstrated in only 2 out of 4 samples so there is a need to increase the sample size here to determine the likelihood of NK-cell function being assessed on blood samples collected in-flight. The saliva biomarkers measured appear to be stable for up to 72h post thaw and are impervious to multiple repeat freeze-thaw cycles.

Current and Future Work

We are currently assessing the suitability of the SOS technology to measure additional biomarkers in saliva, including histatins, ß-defensins, lactoperoxidase, and C-reactive protein. We recently completed the analysis of 5 antimicrobial proteins in plasma samples obtained from 12 ISS astronauts from the previous “Integrated Immune” study. Analyses of these data are still ongoing. We are also in the process of optimizing assays to determine the antimicrobial capacity of saliva and neutrophil/monocyte oxidative burst and degranulation. Our first informed consent briefing to ISS crewmembers will take place in September 2012, with the first test subjects being recruited in March 2013. We anticipate that all feasibility work will be completed by January 31st 2013.

Bibliography Type: Description: (Last Updated: 08/04/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Simpson RJ, Crucian BE, Lowder TW, Clarke MS, Mehta SK, O'Connor DP, Pierson DL. "The Effects of Long-term Exposure to Microgravity on Salivary Markers of Innate Immunity." 2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012.

2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012. , Feb-2012

Project Title:  Effects of Long-Term Exposure to Microgravity on Salivary Markers of Innate Immunity Reduce
Fiscal Year: FY 2012 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 11/03/2011  
End Date: 11/02/2015  
Task Last Updated: 12/14/2011 
Download report in PDF pdf
Principal Investigator/Affiliation:   Simpson, Richard  Ph.D. / University of Arizona 
Address:  College of Agriculture and Life Sciences; College of Medicine 
1177 E. Fourth Street, Room 308, Shantz Building 
Tucson , AZ 85721-0001 
Email: rjsimpson@email.arizona.edu 
Phone: 713-397-0121  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Arizona 
Joint Agency:  
Comments: NOTE: Formerly at University of Houston until September 2017 move to University of Arizona.  
Co-Investigator(s)
Affiliation: 
Clarke, Mark  University of Houston 
Crucian, Brian  Wyle Laboratories, Inc. 
Lowder, Thomas  University of Houston 
O'Connor, Dan  University of Houston 
Pierson, Duane  NASA Johnson Space Center 
Project Information: Grant/Contract No. NNX12AB48G 
Responsible Center: NASA JSC 
Grant Monitor: Baumann, David  
Center Contact:  
david.k.baumann@nasa.gov 
Solicitation / Funding Source: 2010 Crew Health NNJ10ZSA003N 
Grant/Contract No.: NNX12AB48G 
Project Type: GROUND 
Flight Program: ISS 
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Immune:Risk of Adverse Health Event Due to Altered Immune Response (IRP Rev F)
Human Research Program Gaps: (1) IM01:We do not know to what extent spaceflight alters various aspects of human immunity during spaceflight missions up to 6 months (IRP Rev E)
(2) IM02:It is necessary to define a flight standard related to spaceflight-associated immune system dysregulation (IRP Rev E)
Flight Assignment/Project Notes: ISS Flight Definition phase

Task Description: Immune system dysregulation has been documented during and after spaceflight, but it is not known if these changes increase infection susceptibility or pose a significant health risk to crewmembers. Inherent problems with current in-flight research are small sample sizes and the difficulty to control for the many confounding factors that impact on the immune system. As such, it is not known if changes in immunity are due to the microgravity environment per se, or to the stressors associated with landing and re-adaptation to the 1G environment. The present project proposes a Flight Definition investigation, utilizing a longitudinal repeated measures design to determine the effects of long-term exposure to microgravity on a host of salivary antimicrobial proteins (AMPs) associated with innate host immune defense, whilst also considering the impact of other acute stressors such as launch, Soyuz landing and EVA. Saliva samples will be collected from crewmembers selected for ISS mission and ground-based controls at bi-weekly intervals for 6 months prior to flight, during the 6-month period on the ISS and for 1 month on return to Earth. Saliva sampling was selected because it is an excellent biological fluid with which to detect broad-spectrum biomarkers of front-line host immune defense and is suitable for the spaceflight environment. Attempts will also be made to establish relationships between AMPs and other stressors associated with spaceflight (i.e. mood state disturbances, circadian desynchronization, sleep loss/disruption, stress biomarkers) using serial data. Finally, blood samples will be collected before and after the mission to determine the impact of spaceflight on cellular aspects of innate immunity. Given the potential of salivary AMPs to serve as an indicator of weakened immunity during spaceflight, this project will serve as a foundation for future countermeasure developments and technological advances to detect real time changes during subsequent lunar or Mars missions.

Research Impact/Earth Benefits: 0

Task Progress & Bibliography Information FY2012 
Task Progress: New project for FY2012.

Bibliography Type: Description: (Last Updated: 08/04/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2012