Effect of Space Flight on Innate Immunity to Respiratory Viral Infections (Mouse Immunology-2) - 06.01.16

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Science Objectives for Everyone
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.

The following content was provided by Roberto P. Garofalo, M.D., and is maintained in a database by the ISS Program Science Office.
Experiment Details

OpNom:

Principal Investigator(s)
Roberto P. Garofalo, M.D., The University of Texas Medical Branch, Galveston, Galveston, TX, United States

Co-Investigator(s)/Collaborator(s)
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

Developer(s)
NASA Ames Research Center, Moffett Field, CA, United States

Sponsoring Space Agency
National Aeronautics and Space Administration (NASA)

Sponsoring Organization
Human Exploration and Operations Mission Directorate (HEOMD)

Research Benefits
Information Pending

ISS Expedition Duration 1
September 2010 - March 2011

Expeditions Assigned
25/26

Previous Missions
Increment 25/26 is the first flight for the Mouse Immunology-2 investigation.

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Experiment Description

Research Overview

  • 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.

Description
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

  • 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.

  • Inner Ear Otoconia Response to Microgravity

  • 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.

  • Effects of Microgravity on Regional Arterial Remodeling

  • 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.

  • The response of articular cartilage to microgravity

  • 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.

  • Rodent Spine Deconditioning after 15 Days of Microgravity

  • 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.

  • Synaptic Plasticity in Mammalian Utricular Macula

  • 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.

  • Protein Expression In Salivary Glands:Effects of Extended Space Flight

  • 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.

  • Long Term Space Flight Impacts on Female Reproductive Health (short name: REPRO2)

  • 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.

  • The Effect of Weightlessness on the Tendon-to-Bone Insertion

  • 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.

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Applications

Space Applications
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.

Earth Applications
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.

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Operations

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.

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Decadal Survey Recommendations

Information Pending

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Results/More Information

• Rodent Spine Deconditioning after 15 Days of Microgravity
Alan Hargens Ph.D., University of California San Diego, La Jolla, CA  
 
Astronauts are known to experience low back pain during spaceflight and increased incidence of post-spaceflight slipped disc.  Scientists performed compressive creep tests and physical measurements of the spine of mice flown on short-duration spaceflight to see the effect of microgravity on the biomechanical properties of the spinal discs.    For caudal (near the tail) discs, the spaceflight group exhibited 32% lower physiological disc height (PDH), 70% lower nuclear swelling pressure strain dependence (D) and crept more compared to the ground control mice suggesting prolonged microgravity effectively diminished biomechanical properties of caudal discs.  For lumbar discs, neither PDH nor D was significantly different between the two groups. Initial elasticity, fluid pressure, end plate (top and bottom surfaces of the disc) permeability (k) and annular (ring part of disc surrounding the soft nucleus) viscoelasticity (G) for lumbar and caudal discs did not appear influenced by microgravity.  The study concludes that microgravity has a diminishing effect on the biomechanical properties of intervertebral discs, and that this effect is enhanced in discs which have the greatest range of movement.   This potentially deleterious interaction between prolonged weightlessness and differential ranges of motion along the spine may underlie the increased cervical versus lumbar disc herniation rates observed among astronauts.  Results suggest that, after returning to normal gravity, spinal movement should be limited during recovery while the spine re-acclimates to terrestrial conditions and disc swelling  subsides.  Future studies should explore the rate and effect of recovery (post-landing) on the disc to determine if the degenerative effect that microgravity poses on the disc is truly reversible.
 
• Protein Expression In Salivary Glands:Effects of Extended Space Flight
Maija Mednieks Ph.D., University of Connecticut Health Center, Farmington, CT  
 
So far, very little is known about how microgravity affects the oral cavity. Production and secretion of saliva are essential for oral health and comfortable, daily function.  The cleansing, buffering, and anti-microbial activities of saliva help to protect the teeth and the oral mucosa. Talking, chewing and swallowing would become difficult without the mucous and serous secretions. The three major salivary glands, the parotid, submandibular and sublingual glands, are accompanied by numerous minor glands dispersed throughout most regions of the oral mucosa. Some of the major proteins in human saliva are amylase, lysozyme, peroxidase, prolinerich proteins, histatins, mucins and IgA. Hundreds of others oral proteins have been identified through comprehensive protein analysis, and while some of the secretory proteins have specific function in the mouth, others can be indicators of systemic physiology or diagnostic of disease status.  The rodent model is useful for study in that their salivary gland is similar to that of humans.  Results indicated short-duration flight showed an effect on the major salivary proteins that appeared to be diminished after longer exposure to microgravity.  No significant tissue damage was observed, therefore the molecular level differences initially seen may be homeostatic responses, adjustment to the space environment.  The findings are potentially applicable to designing a biochemical test system whereby specific salivary proteins can be biomarkers for stress associated with travel in space and eventually for monitoring responses to conditions on earth.
 
• Spaceflight Effects and Molecular Responses in the Mouse Eye
Susana B. Zanello, Ph.D., Division of Space Life Sciences, Universities Space Research Association, Houston, TX  
 
Recent medical data of astronauts report the development of optic disc edema, choroidal folds, posterior eye globe flattening, and resulting nearsightedness in a fraction of the crew members upon return from missions longer than 30 days.  No clear cause(s) has yet been established, but it is hypothesized that microgravity, subsequent shifting of bodily fluids to the head, and high hydrostatic pressure within the skull and spinal cavities are imposing physical changes (damage) to the eye.  Thus, it is of critical occupational health importance to determine the risk factors microgravity poses on the eye.  Female 10-12 week-old mice were assigned to a flight (FLT) group flown on a shuttle mission, Animal Enclosure Module (AEM) ground control group, or vivarium-housed (VIV) ground controls.  Eyes were collected at 1, 5, and 7 days after landing for tissue studies.  Preliminary results show, for the first time, direct evidence suggesting that oxidative stress, neuronal damage, and mechanical injury take place in the retina, lens, and optic nerve of rodents flown in low-Earth orbit for a period under two weeks.  Moreover, the optic nerve findings suggest that the lesion may be mechanical in nature and that does not resolve after return to Earth, at least in the animals studied.   Investigating the molecular changes occurring in the retina identified 139 genes behaving differently in the flight group compared to the ground control samples. The genes affected were mainly involved in pathways and processes of endoplasmic reticulum (ER) stress, inflammation, neuronal and glial cell loss, axonal degeneration, and herpes virus activation.  The collective change in gene expression in the retina of mice flown in space, possibly led to retinal damage, degeneration, and remodeling.   Research data provide a catalog of differentially expressed genes that can be used to explore various hypotheses of spaceflight’s effects on the eye and the implications for human crews in long-duration space exploration missions.  Further work is needed to discern the contribution of the various spaceflight factors (microgravity, radiation) and to evaluate the impact of the stress response on retinal and optic nerve health.

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Results Publications

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Ground Based Results Publications

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ISS Patents

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Related 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.

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Related Websites
Flight Systems Implementation

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Imagery

image Electron micrograph image of an RSV virion budding from an infected cell. Courtesy of Dr. Roberto Garofalo, UTMB, Galveston.
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