Immune System - Immune Cell Alterations - Immune System Dysregulation - Microbial Alterations and Vaccine Development - Infection Studies
Immune SystemIn microgravity, immune system alterations were observed such as immune system dysregulation and immune cell alterations1. In terms of the immune cell alterations, the changes happen in cytokine production, proliferation and function of immune cell populations both in adaptive and innate immunity2,3. In terms of immune system dysregulation, changes occur in the balance between the human body, the human microbiome and the virulence of some pathogens can be increased due to the extreme environmental stresses such as microgravity and cosmic radiation1.
Immune Cell AlterationsPrevious studies performed on astronauts during and after short spaceflight missions showed an inhibition of lymphocyte proliferation4 and a decrease in production of interferon-a/b, which is an indicator of decreased immune system response against pathogens5. As a general trend it seems like, T cell and natural killer (NK) cell percentages are commonly reduced, whereas B cell percentages are commonly elevated2. Moreover, the number of lymphocytes, monocytes, their cytokine production and dendritic cell and T-cell activation were reduced1.
However, it is unknown whether, the phenomenon observed during short-duration flights would persist during long-duration spaceflights such as human Mars mission. Therefore, to prevent clinical risks for crew members such as infectious disease, allergies and hypersensitivities, persistent latent herpes virus reactivation, further research has to be done. A very recent research performed by Crucian et al, investigated the alterations in adaptive immune system during long-duration spaceflight using blood of astronauts3. The study found that white blood cell count was elevated and T-cell function (both CD4+ and CD8+) was reduced3. Moreover, the results from long-duration spaceflights indicated elevation of some specific cytokines such as TNFa, IL8, VEGF, which are known to be associated with inflammation and other regulatory processes2. Another research performed by Wei et al, investigated the effect of simulated microgravity on human peripheral blood lymphocytes. As a result, it was found that numerical chromosome instability of human peripheral blood lymphocytes was not affected by microgravity whereas the structural chromosome instability was increased through the inhibition of DNA replication and reduced DNA repair6.
Immune System DysregulationPrevious studies showed that the balance between human body and human microbiome can be disturbed and the virulence of some pathogens could be increased in microgravity. Moreover, spaceflight can induce dysbiosis in the human microflora, which results in reduction of the defense group of microorganisms such as bifidobacteria and lactobacilli and in elevation of opportunistic pathogens such as E.Coli, enterobacteria and clostridia1. Thus, increased susceptibility to infection in astronauts was also observed in terms of bacterial or viral infections2. Herpes virus infections, conjunctivitis, dental infections, upper respiratory infections, influenza, viral gastroenteritis and mild dermatologic problems have been documented during spaceflights1.
Microbial Alterations and Vaccine DevelopmentMicrogravity stress can have a great role in regulating microbial gene expression, physiology, pathogenesis and changes in virulence factors7,8. Thus, researchers have been using microgravity to find therapeutic agents or vaccines against several pathogens, while Salmonella was being the most common one. Earlier, in 1998, microgravity-based vaccine development studies began when NASA funded the research project of Professor Nickerson about the response of Salmonella to microgravity. Later, the commercial corporation Astrogenetix contributed in the project and the research has resulted in the discovery of potential candidate genes for Salmonella vaccine development9. Moreover, methicillin-resistant Staphylococcus aureus was also flown to space to examine the virulence in microgravity. More recently, the research focused on improving the anti-pneumococcal effectiveness of existing orally delivered Recombinant Attenuated Salmonella Vaccine (RASV). For this study, the Salmonella vaccine strain is genetically modified so that it carries an antigenic protein from Streptococcus pneumonia and the aim is to stimulate the protective immune response by mimicking the disease10. Since RASVs can be produced against a wide variety of human pathogens, potentially new vaccines can be developed against many other diseases.
Infection StudiesThere has been various infection studies performed on simulated microgravity including pathogens such as Salmonella typhimurium, Pseudomonas aeruginosa, human cytomegalovirus, Norwalk virus, human norovirus and Mycobacterium tuberculosis11. Based on the work of Nickerson lab, 3D microgravity models can be used to represent in vivo infection with bacterial and viral pathogens, even those that are difficult or not possible to culture using conventional methods11. In this case, microgravity cultures are beneficial for assessment of infection in 3-D tissues examining pathogen variants, for understanding the role of viral proteins and drugs on host cells and the efficacy of candidate drugs11. The research performed by Hwang et al, performed in simulated microgravity using mouse splenocytes and mycobacterium tuberculosis, showed that immune responses of lymphocytes and macrophages were decreased12. Moreover splenocytes could not function normally when immune stimulatory antigen Concanavalin was introduced12. Furthermore, microgravity conditions seemed to generate an immune environment that is more suitable for propagation of intracellular Mycobacterium tuberculosis12. A research performed by Yang et al, studied the factors that affect Salmonella Typhimurium infection under simulated microgravity. According to the study it is found that the 50% lethal dose values were not significantly different for microgravity and normal gravity, however in mice injected with S.Typhimurium cultured in normal gravity, the disease progression was more rapid and resulted in earlier death of mice13. Likewise the study performed by Hammond lab found that Salmonella grew significantly better in spaceflight. It was less virulent in spaceflight but become more virulent when returned to ground and injected into mice14.
1. Cervantes, J. L., & Hong, B. Y. (2016) Dysbiosis and Immune Dysregulation in Outer Space. International reviews of immunology, 35(1), 67-82.
2. Yi, B., Crucian, B., Tauber, S., Ullrich, O., & Choukèr, A. (2016) Immune Dysfunction in Spaceflight: An Integrative View. Effect of Spaceflight and Spaceflight Analogue Culture on Human and Microbial Cells (pp. 61-79). Springer New York.
3. Crucian, B., Stowe, R. P., Mehta, S., Quiriarte, H., Pierson, D., & Sams, C. (2015) Alterations in adaptive immunity persist during long-duration spaceflight. npj Microgravity, 1, 15013.
4. Gueguinou, N., Huin-Schohn, C., Bascove, M., Bueb, J. L., Tschirhart, E., Legrand-Frossi, C., et al. (2009) Could spaceflight-associated immune system weakening preclude the expansion of human presence beyond Earth’s orbit? Journal of Leukocyte Biology, 86(5), 1027–1038.
5. Talas, M., Batkai, L., Stoger, I., Nagy, L., Hiros, L., Konstantinova, I., et al. (1983) Results of space experiment program “Interferon”. I. Production of interferon in vitro by human lymphocytes aboard space laboratory Solyut-6 (“Interferon I”) and influence of space flight on lymphocyte functions of cosmonauts (“Interferon III”). Acta Microbiologica Hungarica, 30(1), 53–61.
6. Wei, L., Liu, C., Kang, L., Liu, Y., Shi, S., Wu, Q., & Li, Y. (2014) Experimental study on effect of simulated microgravity on structural chromosome instability of human peripheral blood lymphocytes. PloS one, 9(6), e100595.
7. Klaus DM. (2002) Space microbiology: microgravity and microorganisms. New York, NY: John Wiley; 2002.
8. Nickerson CA, Ott CM, Wilson JW, et al. (2003) Low-shear modeled microgravity: a global environmental regulatory signal affecting bacterial gene expression, physiology, and pathogenesis. J Microbiol Methods 2003;54(1):1–11.
9. Ruttley, T. (2012) International Space Station Plays Role in Vaccine Development. NASA. Retrieved 22 August 2016, from http://www.nasa.gov/mission_pages/station/research/benefits/vaccine_development.html
10. Nimon, J. (2011) NASA - Voyage to Vaccine Discovery Continues with Space Station Salmonella Study. Nasa.gov. Retrieved 22 August 2016, from http://www.nasa.gov/mission_pages/station/research/news/RASV.html
11. Nickerson, C. A., Richter, E. G., & Ott, C. M. (2007) Studying host–pathogen interactions in 3-D: organotypic models for infectious disease and drug development. Journal of Neuroimmune Pharmacology, 2(1), 26-31.
12. Hwang, S. A., Pan, C., Boyd, S., Pellis, N. R., & Actor, J. K. (2012) Modeled microgravity conditions suppress innate macrophage and lymphocytic responses to common mitogens and Mycobacterium tuberculosis infection. Gravitational and Space Research, 26(1).
13. Yang, J., Barrila, J., Roland, K. L., Ott, C. M., & Nickerson, C. A. (2016) Physiological fluid shear alters the virulence potential of invasive multidrug-resistant non-typhoidal Salmonella Typhimurium D23580. npj Microgravity, 2, 16021.