Effect of Space Flight on Innate Immunity to Respiratory Viral Infections (Mouse Immunology-2) - 08.03.16
The Effect of Space Flight on Innate Immunity to Respiratory Viral Infections (Mouse Immunology-2) investigates the effects of microgravity on immune function to fight Respiratory Syncytial Virus (RSV). In microgravity, crewmembers experience changes in immune function. These studies will help scientists determine the biological significance of space flight induced changes in immune responses. Science Results for Everyone
From spines to spit, through tissue sharing, this research investigation supported multiple studies. One study found that microgravity has a diminishing effect on biomechanical properties of the cartilage between vertebra, suggesting that limiting spinal movement after return to Earth could allow spine re-acclimation. Another indicated that short-duration flight effected proteins in saliva, but the effect diminished after longer exposure, with no significant tissue damage observed on the oral mucosa. These changes may represent the body's adjustment to the space environment. Other preliminary results contain the first direct evidence of oxidative stress and neuronal damage in the retina and lens, perhaps due to gene expression changes, and mechanical damage to optic nerves. Experiment Details
Roberto P. Garofalo, M.D., The University of Texas Medical Branch, Galveston, Galveston, TX, United States
Antonella Casola, M.D., University of Texas Medical Branch, Galveston, TX, United States
Maria Antonieta Guerrero-Plata, The University of Texas Medical Branch, Galveston, Galveston, TX, United States
Eduardo A. C Almeida, Ph.D., Moffett Field, CA, United States
Richard D. Boyle, Ph.D., Universities Space Research Association, Moffett Field, CA, United States
David Fitzgerald, Ph.D., Oregon Health and Science University, Portland, OR, United States
Larry F. Hoffman, Ph.D., University of California Los Angeles, Los Angeles, CA, United States
Maija Mednieks, Ph.D., University of Connecticut Health Center, Farmington, CT, United States
Joseph S. Tash, Ph.D., University of Kansas Medical Center, Kansas City, KS, United States
Stavros Thomopoulos, Ph.D., Washington University, St. Louis, MO, United States
Alan R. Hargens, Ph.D., University of California San Diego, San Diego, CA, United States
Michael J. Pecaut, Ph.D., Loma Linda University, CA, United States
NASA Ames Research Center, Moffett Field, CA, United States
Sponsoring Space Agency
National Aeronautics and Space Administration (NASA)
Human Exploration and Operations Mission Directorate (HEOMD)
ISS Expedition Duration
September 2010 - March 2011
Increment 25/26 is the first flight for the Mouse Immunology-2 investigation.
- Mouse Immunology-2 characterizes Respiratory Syncytial Virus (RSV) (a highly contagious virus that causes respiratory tract infections) replication in the lung and nasal turbinates (soft bony tissues inside the nose), disease severity, and histopathology (microscopic examination of tissue) of the airways.
- Mouse Immunolgy-2 experiments are conducted on mice flown in the Space Shuttle that will be infected with RSV immediately after their return to Earth.
The most prevalent acute respiratory tract illnesses in the general community are mostly benign, self-limiting events primarily following infections of the upper respiratory tract. The factors that contribute to the progression of upper respiratory tract infection to lower respiratory tract illness are not fully understood, but a robust innate immune response appears to be critical for limiting disease severity, blocking viral shedding (the movement by any route of a virus from an infected host) and person-to-person transmission. Viral lower respiratory tract illness contributes to a large portion of hospital visits in the United States for both adults and children. Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract illness in infants and children worldwide. Since a vaccine has not been developed and immunity is only partial, re-infections with RSV are common throughout life. RSV can also cause life-threatening pulmonary disease in immunocompromised (decreased level of immunity) adults.
Mouse Immunology-2 aims to determine the profile of IFN-a/ß (Type I Interferon Receptor - proteins made and released in response to the presence of viruses) and innate cytokine response to viral infection in bronchoalveolar lavage (BAL) (a diagnostic procedure whereby a visual instrument is passed through the mouth or nose into the lung where fluid is inserted into the lung and recollected for examination) and nasal tissue, as well as other proteins by 2-DE gel electrophoresis (two-dimensional gel electrophoresis technique used to analyze proteins) and Matrix-Assisted Laser Desorption/Ionization-Time Of Flight (MALDI-TOF - a soft ionization technique used in mass spectrometry that allows). Ribonucleic acid (RNA) will be extracted from lung tissue for genomics studies (studies of an organism’s complete genetic information). BAL cells are characterized by flow cytometry (technique used to sort and classify cells by using a fluorescent dye). These studies are conducted in mice as in Aim1 (Absent in melanoma 1 - a protein required for cell division). Mouse Immunology-2 profiles IFN-a/ß and innate cytokine response (a natural function involving chemical communication between cells) to infection in BAL and nasal tissue, and characterizes dendritic (having a branching structure similar to that of a tree) cell migration and function in the lung and nasal tissue. These studies are conducted on mice in the hind limb unloading model (a well-accepted ground-based model used to simulate some of the conditions of space flight and reproduce its effects on the immune system).
Investigators use both RSV and hMPV (Human metapneumovirus - common respiratory infection among children) infection models to characterize viral replication in the lung and nasal tissues, disease severity, airway hyperresponsiveness and histopathology of the airways. Results of human and rodent studies on the effects of space flight on the immune system are limited, but they suggest that space flight has some detrimental effect on the response to infections, although little to no research has been conducted in the area of respiratory pathogens.
Mouse Immunology-2 investigators hypothesize the following: space flight alters host response to respiratory viral pathogens; the deficient antiviral response is characterized by defect(s) in the innate immune response; and the central events are IFN-producing cells (Interferon-Producing Cells) and their impaired function as APC (Antigen Presenting Cells) or trafficking to the lung.
The investigations resulting from the Mouse Immunology-2 tissue sharing program are as follows:
- The Role of the p53 Pathway in Spaceflight-Induced Tissue Degeneration
- Inner Ear Otoconia Response to Microgravity
- Effects of Microgravity on Regional Arterial Remodeling
- The response of articular cartilage to microgravity
- Rodent Spine Deconditioning after 15 Days of Microgravity
- Synaptic Plasticity in Mammalian Utricular Macula
- Protein Expression In Salivary Glands:Effects of Extended Space Flight
- Long Term Space Flight Impacts on Female Reproductive Health (short name: REPRO2)
- The Effect of Weightlessness on the Tendon-to-Bone Insertion
Eduardo Almeida, Ph.D., Ames Research Center, Moffett Field, CA
Spaceflight exposes living beings to microgravity and increased radiation. These two key features of spaceflight are thought to be responsible for physiological degenerative conditions including bone loss, muscle loss, loss of cardiovascular capacity, defects in wound and bone fracture healing, and impaired immune function. In this study scientists hypothesize that spaceflight factors affect tissue growth and regenerative health via the p53/p21-signaling pathway that controls cell growth and differentiation in tissues. Scientists will test their hypothesis using bone tissue from mice flow in space, and various cell and molecular approaches to study the activation of the p53/p21-signaling pathway.
Richard Boyle, Ph.D., Ames Research Center, Moffett Field, CA
Vertebrates sense gravity and acceleration from inner ear otolith organs containing biomineral crystalline deposits of calcium carbonate called otoconia. A widely considered mechanism by which the nervous system responds to change in amplitude of gravity vector is a change in weight-lending otoconia. In this study, scientists apply electron microscopic techniques to image the otoconia mass of mice subjected to microgravity in the Mouse Immunology II mission and the corresponding ground control mice.
Michael Delp, Ph.D, University of Florida, Gainesville, FL
After return to Earth, crewmembers often develop orthostatic intolerance, which means they become dizzy or faint when standing upright. Unfortunately, this dizziness usually persists for some time, making routine activities difficult. Evidence from crewmembers indicates that this problem is related to abnormal regulation of blood pressure due to impairments in the ability of arterial blood vessels to constrict properly. The purpose of this study is to determine the effects of microgravity on the structure and function of arteries and whether their ability to constrict is altered by spaceflight.
David Fitzgerald Ph.D., Oregon Health and Science University, Portland, OR
The normal forces of everyday life, such as walking, running and jumping, are very important for keeping knees healthy. Without these forces, the knee cartilage may break down leading to painful knee joint disease. Scientists are interested in finding out whether the knee cartilage of humans that fly in space will be damaged by the reduced forces due to lack of gravity acting on the joint.
Alan Hargens Ph.D., University of California San Diego, La Jolla, CA
Scientists are testing the mechanical behavior of spinal discs to test whether the weightlessness in space leads to harmful effects and increases risk for back injury in crewmembers. Results have shown that after 15 days in space, mouse spinal discs demonstrated evidence of degeneration. Also, scientists are testing if the expression of genes is affected by microgravity exposure.
Larry F. Hoffman, Ph.D., University of California Los Angeles, Los Angeles, CA
Cells within the inner ear vestibular system, which senses head movements and the surrounding gravitational field contributing to our ability to maintain a sense of balance, communicate with neurons that project into the central nervous system. Scientists are studying how this communication may be altered during spaceflight, which changes the conditions under which the system must operate. This will provide scientists with an understanding of the capabilities of these sensory cells, which may provide them with clues as to how humans might rehabilitate a damaged inner ear.
Maija Mednieks Ph.D., University of Connecticut Health Center, Farmington, CT
Saliva contains substances that change at zero gravity during travel in space. Using a microscope and biochemical tests to look at cells that produce saliva from mice that were flown on the Space Shuttle Discovery, scientists could tell which substances had been changed. The goal is to devise a clinical test for stress disorders in space and on Earth.
It is important to study the effects of travel in space and to measure reactions to the stress of weightlessness in zero gravity. Stress changes hormone action that is reflected in different body parts/organs and in glands that produce saliva. Collecting saliva during space flight will make it possible to study hormone changes in zero gravity experienced by Astronauts and Cosmonauts. Understanding the effect of stress, e.g. zero gravity, could then be adapted to devising tests using saliva for general clinical applications concerning medicines in both space and on Earth.
Joseph S. Tash, Ph.D., University of Kansas Medical Center, Kansas City, KS
The overall hypothesis driving the research is that long term space flight has a negative impact on female reproductive health. Based on researchers flight results from STS-131, a secondary hypothesis is that: space flight causes downregulation of estrogen hormone receptors (ERa) in both reproductive and non-reproductive tissues, and is a common mechanism underlying space flight degradation of those organ systems in which ERa is down-regulated, such as bone, muscle, immune, and wound healing. Experiments on both STS-131 and STS-133 are expected to determine the changes in key endocrine hormone receptors and related genes in ovaries, uterine horns and several non-reproductive tissues that are known to be critical for reproductive health; but also, important modulators of normal physiology in tissues known to be degraded in space flight. Understanding the mechanism underlying the changes in the receptors and their signalling will provide clues to developing countermeasures to space flight and provide improved quality of life treatments for similar changes that occur during the normal aging process on Earth.
Stavros Thomopoulos Ph.D., Washington University, St. Louis, MO
The overall objective of this experiment is to examine the effect of prolonged weightlessness on the biology and strength of tendons and their insertions into bone. Researchers will study the tendon-to bone insertions of animals subjected to weightlessness on Shuttle missions STS-131 and STS-133.
These investigations are expected to generate new scientific evidence of the immune pathways that are affected in antiviral host response during space flight and possible preventive or therapeutic approaches applicable to future space missions.
Understanding the function of the immune system during space flight may have great relevance to our understanding of the process of aging and/or stress-related immunomodulation (adjustments in the level of an immune response) on Earth. In particular, studying the innate host response against pathogens during/after space flight will provide novel data on the function of the respiratory mucosal response to viral pathogens.
Operational Requirements and Protocols
Mouse Immunology-2 has a requirement for Late Load upmass and Early Retrieval.
Crewmembers will perform hardware and animal health checks daily.
Decadal Survey Recommendations
Animal and Human Biology AH12
Animal and Human Biology AH14
Animal and Human Biology AH15
Theriot CA, Zanello SB. Molecular effects of spaceflight in the mouse eye after space shuttle mission STS-135. Gravitational and Space Research. 2014 August; 2(1): 3-24.
Mednieks M, Khatri A, Hand AR. Salivary gland protein expression after Bion-M1 and Space Shuttle STS-135 missions. Gravitational and Space Research. 2015 July; 3(1): 18 pp.
Zanello SB, Theriot CA, Prospero-Ponce CM, Chevez_Barrios P. Spaceflight effects and molecular responses in the mouse eye: Observations after Shuttle Mission STS-133. Gravitational and Space Research. 2013 October; 1(1): 29-46.
Bailey JF, Hargens AR, Cheng KK, Lotz JC. Effect of microgravity on the biomechanical properties of lumbar and caudal intervertebral discs in mice. Journal of Biomechanics. 2014 September 22; 47(12): 2983-2988. DOI: 10.1016/j.jbiomech.2014.07.005. PMID: 25085756.
Ground Based Results Publications
Spetch L, Bowlin TL, Casola A. Effect of NMSO3 treatment in a murine model of human metapneumovirus infection. Journal of Virology. 2008; 89: 2709-2712.
Hosakote YM, Liu T, Castro SM, Garofalo RP, Casola A. Respiratory syncytial virus induces oxidative stress by modulating antioxidant enzymes. American Journal of Respiratory Cell and Molecular Biology. 2009; 41(3): 348-357.
Guerrero-Plata MA, Casola A, Garofalo RP. Human metapneumovirus induces a profile of lung cytokines distinct from that of respiratory syncytial virus. Journal of Virology. 2005; 79(23): 14992-14997.
Sonnenfeld G. Animal models for the study of the effects of spaceflight on the immune system. Advances in Space Research. 2003; 32(8): 1473-1476.
Sonnenfeld G, Aviles H, Belay T, Vance M, Fountain K. Stress, suspension and resistance to infection. Journal of Gravitational Physiology. 2002; 9(1): 199-200.
Kolli D, Bataki EL, Spetch L, Guerrero-Plata MA, Jewell AM, Piedra PA, Milligan GN, Garofalo RP, Casola A. T lymphocytes contribute to antiviral immunity and pathogenesis in experimental human metapneumovirus infection. Journal of Virology. 2008; 82(17): 8560-8569.
Guerrero-Plata MA, Casola A, Suarez G, Yu X, Spetch L, Peeples ME, Garofalo RP. Differential response of dendritic cells to human metapneumovirus and respiratory syncytial virus. American Journal of Respiratory Cell and Molecular Biology. 2006; 34(5): 643.
Blutt SE, Conner ME. Kinetics of Rotavirus Infection In Mice Are Not Altered In A Ground-Based Model of Spaceflight. Aviation, Space, and Environmental Medicine. 2004; 75(3): 215-219.
Castro SM, Guerrero-Plata MA, Suarez-Real G, Adegboyega PA, Colasurdo GN, Khan AM, Garofalo RP, Casola A. Antioxidant treatment ameliorates respiratory syncytial virus-induced disease and lung inflammation. American Journal of Respiratory and Critical Care Medicine. 2006; 174(12): 1361-1369.
Flight Systems Implementation
Electron micrograph image of an RSV virion budding from an infected cell. Courtesy of Dr. Roberto Garofalo, UTMB, Galveston.
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