The environmental conditions that could lead to an increased risk for the development of an infection during prolonged space flight include: microgravity, stress, radiation, disturbance of circadian rhythms, and altered nutritional intake. A large body of literature exists on the impairment of the immune system by space flight. With the advent of missions outside the Earth's magnetic field, the increased risk of adverse effects due to exposure to radiation from a solar particle event (SPE) needs to be considered. Using models of reduced gravity and SPE radiation, we identify that either 2 Gy of radiation or hindlimb suspension alone leads to activation of the innate immune system and the two together are synergistic. The mechanism for the transient systemic immune activation is a reduced ability of the GI tract to contain bacterial products. The identification of mechanisms responsible for immune dysfunction during extended space missions will allow the development of specific countermeasures.
References
[1]
Wang KX, Shi Y, Denhardt DT (2007) Osteopontin regulates hindlimb-unloading-induced lymphoid organ atrophy and weight loss by modulating corticosteroid production. Proc Natl Acad Sci U S A 104: 14777–14782.
[2]
Aponte VM, Finch DS, Klaus DM (2006) Considerations for non-invasive in-flight monitoring of astronaut immune status with potential use of MEMS and NEMS devices. Life Sci 79: 1317–1333.
[3]
Mallis MM, DeRoshia CW (2005) Circadian rhythms, sleep, and performance in space. Aviat Space Environ Med 76: B94–107.
[4]
Cena H, Sculati M, Roggi C (2003) Nutritional concerns and possible countermeasures to nutritional issues related to space flight. Eur J Nutr 42: 99–110.
[5]
Shearer WT, Zhang S, Reuben JM, Lee BN, Butel JS (2005) Effects of radiation and latent virus on immune responses in a space flight model. J Allergy Clin Immunol 115: 1297–1303.
[6]
Uri JJ, Haven CP (2005) Accomplishments in bioastronautics research aboard International Space Station. Acta Astronaut 56: 883–889.
[7]
Pierson DL, Mehta SK, Magee BB, Mishra SK (1995) Person-to-person transfer of Candida albicans in the spacecraft environment. J Med Vet Mycol 33: 145–150.
[8]
Pierson DL, Chidambaram M, Heath JD, Mallary L, Mishra SK, et al. (1996) Epidemiology of Staphylococcus aureus during space flight. FEMS Immunol Med Microbiol 16: 273–281.
[9]
Taylor GR (1974) Recovery of medically important microorganisms from Apollo astronauts. Aerosp Med 45: 824–828.
[10]
Novikova N, De Boever P, Poddubko S, Deshevaya E, Polikarpov N, et al. (2006) Survey of environmental biocontamination on board the International Space Station. Res Microbiol 157: 5–12.
[11]
Pierson DL, Stowe RP, Phillips TM, Lugg DJ, Mehta SK (2005) Epstein-Barr virus shedding by astronauts during space flight. Brain Behav Immun 19: 235–242.
[12]
Klaus DM, Howard HN (2006) Antibiotic efficacy and microbial virulence during space flight. Trends Biotechnol 24: 131–136.
[13]
Sonnenfeld G, Shearer WT (2002) Immune function during space flight. Nutrition 18: 899–903.
[14]
Levine DS, Greenleaf JE (1998) Immunosuppression during spaceflight deconditioning. Aviat Space Environ Med 69: 172–177.
[15]
Crucian BE, Cubbage ML, Sams CF (2000) Altered cytokine production by specific human peripheral blood cell subsets immediately following space flight. J Interferon Cytokine Res 20: 547–556.
[16]
Borchers AT, Keen CL, Gershwin ME (2002) Microgravity and immune responsiveness: implications for space travel. Nutrition 18: 889–898.
[17]
Gueguinou N, Huin-Schohn C, Bascove M, Bueb JL, Tschirhart E, et al. (2009) Could spaceflight-associated immune system weakening preclude the expansion of human presence beyond Earth's orbit? J Leukoc Biol 86: 1027–1038.
[18]
Belay T, Aviles H, Vance M, Fountain K, Sonnenfeld G (2002) Effects of the hindlimb-unloading model of spaceflight conditions on resistance of mice to infection with Klebsiella pneumoniae. J Allergy Clin Immunol 110: 262–268.
[19]
Aviles H, Belay T, Fountain K, Vance M, Sonnenfeld G (2003) Increased susceptibility to Pseudomonas aeruginosa infection under hindlimb-unloading conditions. J Appl Physiol 95: 73–80.
[20]
Durnova GN, Kaplansky AS, Portugalov VV (1976) Effect of a 22-day space flight on the lymphoid organs of rats. Aviation, space, and environmental medicine 47: 588–591.
[21]
Steffen JM, Musacchia XJ (1986) Thymic involution in the suspended rat: adrenal hypertrophy and glucocorticoid receptor content. Aviat Space Environ Med 57: 162–167.
[22]
Berry WD, Murphy JD, Smith BA, Taylor GR, Sonnenfeld G (1991) Effect of microgravity modeling on interferon and interleukin responses in the rat. Journal of interferon research 11: 243–249.
[23]
Gould CL, Lyte M, Williams J, Mandel AD, Sonnenfeld G (1987) Inhibited interferon-gamma but normal interleukin-3 production from rats flown on the space shuttle. Aviation, space, and environmental medicine 58: 983–986.
[24]
Nash PV, Mastro AM (1992) Variable lymphocyte responses in rats after space flight. Experimental cell research 202: 125–131.
[25]
Nash PV, Konstantinova IV, Fuchs BB, Rakhmilevich AL, Lesnyak AT, et al. (1992) Effect of spaceflight on lymphocyte proliferation and interleukin-2 production. Journal of applied physiology 73: 186S–190S.
[26]
Nash PV, Bour BA, Mastro AM (1991) Effect of hindlimb suspension simulation of microgravity on in vitro immunological responses. Experimental cell research 195: 353–360.
[27]
Pecaut MJ, Simske SJ, Fleshner M (2000) Spaceflight induces changes in splenocyte subpopulations: effectiveness of ground-based models. American journal of physiology Regulatory, integrative and comparative physiology 279: R2072–2078.
[28]
Hellweg CE, Baumstark-Khan C (2007) Getting ready for the manned mission to Mars: the astronauts' risk from space radiation. Naturwissenschaften 94: 517–526.
[29]
Wilson JW, Cucinotta FA, Shinn JL, Simonsen LC, Dubey RR, et al. (1999) Shielding from solar particle event exposures in deep space. Radiat Res 30: 361–382.
[30]
Smart DF, Shea MA (2003) The local time dependence of the anisotropic solar cosmic ray flux. Adv Space Res 32: 109–114.
[31]
Kim MH, Hayat MJ, Feiveson AH, Cucinotta FA (2009) Prediction of frequency and exposure level of solar particle events. Health Phys 97: 68–81.
[32]
Hu S, Kim MH, McClellan GE, Cucinotta FA (2009) Modeling the acute health effects of astronauts from exposure to large solar particle events. Health Phys 96: 465–476.
[33]
Ni H, Balint K, Zhou Y, Gridley DS, Maks C, et al. (2011) Effect of solar particle event radiation on gastrointestinal tract bacterial translocation and immune activation. Radiat Res 175: 485–492.
[34]
Chapes SK, Mastro AM, Sonnenfeld G, Berry WD (1993) Antiorthostatic suspension as a model for the effects of spaceflight on the immune system. Journal of leukocyte biology 54: 227–235.
[35]
Musacchia XJ (1985) The use of suspension models and comparison with true weightlessness: “a resume”. Physiologist 28: S237–240.
[36]
Morey-Holton E, Globus RK, Kaplansky A, Durnova G (2005) The hindlimb unloading rat model: literature overview, technique update and comparison with space flight data. Adv Space Biol Med 10: 7–40.
[37]
Andra J, Gutsmann T, Muller M, Schromm AB (2010) Interactions between Lipid A and Serum Proteins. Adv Exp Med Biol 667: 39–51.
[38]
Wurfel MM, Hailman E, Wright SD (1995) Soluble CD14 acts as a shuttle in the neutralization of lipopolysaccharide (LPS) by LPS-binding protein and reconstituted high density lipoprotein. J Exp Med 181: 1743–1754.
[39]
Wurfel MM, Kunitake ST, Lichenstein H, Kane JP, Wright SD (1994) Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med 180: 1025–1035.
[40]
Gioannini TL, Weiss JP (2007) Regulation of interactions of Gram-negative bacterial endotoxins with mammalian cells. Immunol Res 39: 249–260.
[41]
Sandler NG, Wand H, Roque A, Law M, Nason MC, et al. (2011) Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 203: 780–790.
[42]
Cano R, Llanos L, Zapater P, Pascual S, Bellot P, et al. (2010) Proteomic evidence of bacterial peptide translocation in afebrile patients with cirrhosis and ascites. J Mol Med 88: 487–495.
[43]
Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, et al. (2009) Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 199: 1177–1185.
[44]
Huang H, Liu T, Rose JL, Stevens RL, Hoyt DG (2007) Sensitivity of mice to lipopolysaccharide is increased by a high saturated fat and cholesterol diet. Journal of inflammation 4: 22.
[45]
Bolke E, Jehle PM, Storck M, Nothnagel B, Stanescu A, et al. (2001) Endotoxin release and endotoxin neutralizing capacity during colonoscopy. Clinica chimica acta; international journal of clinical chemistry 303: 49–53.
[46]
Paulos CM, Wrzesinski C, Kaiser A, Hinrichs CS, Chieppa M, et al. (2007) Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J Clin Invest 117: 2197–2204.
[47]
Palmer JL, Deburghgraeve CR, Bird MD, Hauer-Jensen M, Kovacs EJ (2011) Development of a combined radiation and burn injury model. Journal of burn care & research : official publication of the American Burn Association 32: 317–323.
[48]
Budagov RS, Ul'ianova LP (2000) Comparative analysis of proinflammatory cytokines in plasma of mice exposed to radiation or in combined radiation injury. Radiatsionnaia biologiia, radioecologiia/Rossiiskaia akademiia nauk 40: 188–191.
[49]
Ran XZ, Su YP, Zong ZW, Guo CH, Zheng HE, et al. (2007) Effects of serum from rats with combined radiation-burn injury on the growth of hematopoietic progenitor cells. The Journal of trauma 62: 193–198.
[50]
Kiang JG, Jiao W, Cary LH, Mog SR, Elliott TB, et al. (2010) Wound trauma increases radiation-induced mortality by activation of iNOS pathway and elevation of cytokine concentrations and bacterial infection. Radiation research 173: 319–332.
[51]
Shi CM, Su YP, Cheng TM (2006) Recent advances in the pathological basis and experimental management of impaired wound healing due to total-body irradiation. Medical science monitor : international medical journal of experimental and clinical research 12: RA1–4.
[52]
Schaffer M, Weimer W, Wider S, Stulten C, Bongartz M, et al. (2002) Differential expression of inflammatory mediators in radiation-impaired wound healing. The Journal of surgical research 107: 93–100.
[53]
Sonnenfeld G (2003) Animal models for the study of the effects of spaceflight on the immune system. Adv Space Res 32: 1473–1476.
[54]
Aviles H, Belay T, Vance M, Sonnenfeld G (2005) Effects of space flight conditions on the function of the immune system and catecholamine production simulated in a rodent model of hindlimb unloading. Neuroimmunomodulation 12: 173–181.
[55]
Yin D, Tuthill D, Mufson RA, Shi Y (2000) Chronic restraint stress promotes lymphocyte apoptosis by modulating CD95 expression. J Exp Med 191: 1423–1428.
[56]
Blanc S, Geloen A, Normand S, Gharib C, Somody L (2001) Simulated weightlessness alters the nycthemeral distribution of energy expenditure in rats. J Exp Biol 204: 4107–4113.
[57]
Crucian B, Sams C (2009) Immune system dysregulation during spaceflight: clinical risk for exploration-class missions. J Leukoc Biol 86: 1017–1018.
[58]
Morukov VB, Rykova MP, Antropova EN, Berendeeva TA, Ponomarev SA, et al. (2010) Indicators of innate and adaptive immunity of cosmonauts after long-term space flight to international space station. Fiziol Cheloveka 36: 19–30.
[59]
Stowe RP, Sams CF, Pierson DL (2011) Adrenocortical and immune responses following short- and long-duration spaceflight. Aviat Space Environ Med 82: 627–634.
[60]
Baqai FP, Gridley DS, Slater JM, Luo-Owen X, Stodieck LS, et al. (2009) Effects of spaceflight on innate immune function and antioxidant gene expression. J Appl Physiol 106: 1935–1942.
[61]
Srinivasan A, McSorley SJ (2007) Pivotal advance: exposure to LPS suppresses CD4+ T cell cytokine production in Salmonella-infected mice and exacerbates murine typhoid. J Leukoc Biol 81: 403–411.
[62]
Bukh AR, Melchjorsen J, Offersen R, Jensen JM, Toft L, et al. (2011) Endotoxemia Is Associated with Altered Innate and Adaptive Immune Responses in Untreated HIV-1 Infected Individuals. PLoS One 6: e21275.
[63]
Lee PI, Ciccone EJ, Read SW, Asher A, Pitts R, et al. (2009) Evidence for translocation of microbial products in patients with idiopathic CD4 lymphocytopenia. J Infect Dis 199: 1664–1670.
[64]
Jagannathan M, Hasturk H, Liang Y, Shin H, Hetzel JT, et al. (2009) TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients. J Immunol 183: 7461–7470.
[65]
Schnare M, Barton GM, Holt AC, Takeda K, Akira S, et al. (2001) Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2: 947–950.
[66]
Medvedev AE, Sabroe I, Hasday JD, Vogel SN (2006) Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease. Journal of endotoxin research 12: 133–150.
[67]
Kaur I, Simons ER, Kapadia AS, Ott CM, Pierson DL (2008) Effect of spaceflight on ability of monocytes to respond to endotoxins of gram-negative bacteria. Clinical and vaccine immunology : CVI 15: 1523–1528.
[68]
Holub M, Lawrence DA, Mondal TK (2006) Effects of murine endotoxemia on lymphocyte subsets and clearance of staphylococcal pulmonary infection. Folia microbiologica 51: 469–472.
[69]
Kariko K, Weissman D, Welsh FA (2004) Inhibition of toll-like receptor and cytokine signaling–a unifying theme in ischemic tolerance. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 24: 1288–1304.
[70]
Elson CO, Cong Y, McCracken VJ, Dimmitt RA, Lorenz RG, et al. (2005) Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunological reviews 206: 260–276.
[71]
Obermeier F, Dunger N, Strauch UG, Hofmann C, Bleich A, et al. (2005) CpG motifs of bacterial DNA essentially contribute to the perpetuation of chronic intestinal inflammation. Gastroenterology 129: 913–927.
[72]
Caradonna L, Mastronardi ML, Magrone T, Cozzolongo R, Cuppone R, et al. (2002) Biological and clinical significance of endotoxemia in the course of hepatitis C virus infection. Current pharmaceutical design 8: 995–1005.
[73]
Schafer C, Parlesak A, Schutt C, Bode JC, Bode C (2002) Concentrations of lipopolysaccharide-binding protein, bactericidal/permeability-increasing protein, soluble CD14 and plasma lipids in relation to endotoxaemia in patients with alcoholic liver disease. Alcohol and alcoholism 37: 81–86.
