| | March 2003: Editor's note: This article was written prior to the launch of STS-107. While data for these experiments was collected during the flight, the loss of the samples precludes any analysis. Hopefully, future mission on the Shuttle or the ISS will allow the important questions raised in the article to be answered. Knowing the answer to that question is fundamental to planning a long-duration mission, such as one to Mars, as well as to understanding more fully the medical effects of prolonged stress on people on Earth. And a partial answer may come from two microbiology/immunology experiments under the direction of Duane L. Pierson, lead microbiologist for crew health and environmental safety at NASA Johnson Space Center in Houston, Texas. Both experiments are scheduled for the upcoming STS-107 space shuttle mission. More modest, narrowly focused immunology experiments have been conducted on astronauts on previous space shuttle flights, but STS-107 is the first mission during which a more comprehensive battery of tests will be run. Historically, more than half the Apollo astronauts reported preflight and in-flight infectious illnesses. The incidence of infectious illnesses fell dramatically after Apollo 13, when the Crew Health Stabilization Program was instituted. The program restricts astronauts from contact with crowds, small children, and anyone showing symptoms of any illness for seven to 10 days before launch. "Even with stringent precautions, however, space shuttle astronauts still report occasional skin cuts and abrasions and note that wounds take longer than usual to heal," Pierson says. Moreover, there's one class of infectious agents against which no quarantine offers protection: latent viruses that — like the proverbial Trojan horse — lie dormant within an astronaut's own body and can reactivate and replicate, perhaps attacking at an unguarded moment. Evidence of any impairment of the immune system's ability to fight infections in space and evidence of stress-related reactivation of latent viruses is what Pierson and his colleagues are seeking through their experiments flying on STS-107. Stress and the Immune System "It's well known that prolonged physiological or psychological stress can diminish the immune capability, resulting in increased risk of illness," Pierson observes. Stress compromises the immune system by acting primarily on three glands: the hypothalamus, the pituitary, and the pair of adrenals. "When the hypothalamus in the brain perceives danger or some other stress requiring the body to be put on high alert, it communicates 'we've got a problem' to the pituitary gland, which regulates the adrenal glands," he explains. "The central nervous system then communicates to the adrenals either through the sympathetic nervous system — the 'hard wiring' of nerves — or through the pituitary by the release of soluble chemical messengers into the blood." Finally, the adrenals release several stress hormones — adrenaline (epinephrine), noradrenaline (norepinephrine), and cortisol (a form of cortisone) being the most familiar — to the entire body, increasing the force of the heartbeat and giving the muscles unusual strength in the classic "fight or flight" response. In marshalling all the body's resources to handle an immediate crisis, however, adrenaline and the other stress hormones "tend to slow down all non-urgent bodily functions, including the immune response," Pierson notes. "Such diminished immunity is supposed to be a temporary thing until the immediate crisis passes. But problems arise if stress is prolonged. Under chronic stress, the immune system can be lowered enough that the body becomes more vulnerable than usual to bacterial or viral infections." Above: Stress compromises the immune system by acting on several glands to release stress hormones such as epinephrine (left) and cortisol (right) into the bloodstream. Remaining in a stressed state for extended periods can suppress the immune system enough to allow latent or new infections to be expressed. Credit: Duane Pierson. Source:
OBPR Space Research Newsletter, September 2002 (Vol. 1, No. 4). What concerns Pierson and his colleagues at Johnson Space Center is that "space is a unique high-stress environment for astronauts." First there is the transient physical stress of several g's of acceleration to get off Earth. There is the psychosocial stress of dangers inherent in launch itself, confinement to a small living space for weeks or months, demands of long work hours or of conducting many experiments and extravehicular activities, not to mention isolation from family, some sleep deprivation, and the shifting dimension of time. At a mission's end, there is the tension of plunging back into Earth's atmosphere in a superheated vehicle. And for the entire duration of being in orbit, there's one ever-present situation never experienced on the ground: microgravity. Significantly, prolonged physical and psychological stresses can diminish or alter the immune response even when people don't perceive them as negative — and clearly, astronauts relish the excitement of going into space. Hence the big question: Can the unique stresses associated with spaceflight have a measurable medical effect on the human immune system? From the results of earthbound studies of people in high-stress professions (law enforcement, firefighting, and the like) as well as in high-stress environments (such as wintering over in Antarctica), Pierson strongly suspects that they can. Instead of relying on subjective questionnaires that ask the astronauts whether or not they feel stressed, Pierson and his colleagues want to obtain independent and objective physiological measurements of stress — such as, say, the levels of stress hormones in the blood. "Before sending people to Mars," Pierson says, "we need to understand the human immune response to spaceflight." Experiment #1: The Body's Defensive Army Pierson's first STS-107 experiment, conducted on blood drawn from astronauts before and after flight, is designed to measure whether the stress of launch, spaceflight, and return to Earth has any effect on the ability of three types of white blood cells to fight infection. To use a military analogy, the human immune system actually consists of two complementary divisions, the adaptive and the innate. The adaptive division creates antibodies to specific microbial invaders (either through previous infection or through vaccination), essentially causing the body to retain a "memory" of a specific invader. In contrast, the innate division of the immune system is the body's first line of defense against all invaders indiscriminately — attacking and destroying all cells recognized as foreign. The soldiers of both divisions are specialized white blood cells.
It is the innate division of the immune system that interests Pierson and his colleagues. Specifically, Pierson wants to investigate the effects of spaceflight and return to Earth on three different types of white blood cells: neutrophils, monocytes, and natural killer (NK) cells. Like a military force on a field of battle, each type of soldier has a different method of attack. Neutrophils are short-lived, relatively small and agile white cells that function as the first wave of the cavalry. Moments after an injury or infection, they rush to the site as part of the inflammatory response and begin destroying foreign bacteria or yeasts by a process called phagocytosis. "A neutrophil sees a microbe and engulfs it, killing it through an oxidating burst with a super oxide or hydrogen peroxide," Pierson explains. "Then internal granules in the neutrophil digest it," at which point the neutrophil dies (pus in a wound is mostly dead neutrophils). Neutrophils are essential in healing ordinary cuts and scratches and repairing worn-out or damaged tissues. Monocytes are long-lived, much larger and somewhat slower-moving white cells that function as the heavy artillery. Once they reach the site of infection, they migrate out of the bloodstream into tissues, where they become potent macrophages — assisting the neutrophils in their job of phagocytosis. "Macrophages do the heavy lifting," Pierson says, engulfing foreign bacteria and yeasts "and even particles of dirt," and breaking them apart. But instead of just digesting the smaller pieces, macrophages present the smaller pieces to other types of white cells (notably T cells); antibodies are produced by plasma cells, thereby interacting with the adaptive division of the immune system. Monocytes and macrophages are particularly important in healing deep puncture wounds. NK cells are special-purpose scouts and mercenaries. There are relatively few of them in the bloodstream compared with neutrophils and monocytes. "They are always on surveillance, not only for bacteria but also for cancerous tumor cells and cells infected with viruses. And when they see 'em, they zap 'em," says Pierson. Above: When an injury or infection occurs (left), chemical signals, such as prostaglandins, are released to alert the immune system to the problem. In response, the blood vessels near the infection site dilate and become more permeable to allow the white blood cells to migrate from the blood into the surrounding tissue (center). Once the neutrophils and monocytes encounter the foreign bodies, they engulf and destroy them (right). Credit: Duane Pierson. Source:
OBPR Space Research Newsletter, September 2002 (Vol. 1, No. 4). The question that intrigues Pierson and his colleagues is this: Could the persistent stress of spaceflight suppress the innate arm of an astronaut's immune system enough that fewer monocytes and NK white blood cells would be produced — or that all the white cells would be somehow impaired in doing their jobs? Experiment #2: Latent Viruses Pierson's other STS-107 experiment is designed to measure whether the stress of spaceflight can trigger the reactivation of latent viruses. Latent viruses are ubiquitous. For example, virtually every adult carries one or more of eight currently recognized human herpesviruses, any one of which can infect its host for a lifetime. Herpesviruses include herpes simplex viruses types 1 and 2 (which cause fever blisters and genital herpes, respectively), Epstein-Barr virus (infectious mononucleosis and a number of cancers), varicella zoster (chicken pox and shingles), and cytomegalovirus (infectious mononucleosis, encephalitis, and other central nervous system diseases). Herpesviruses are also a leading infectious cause of blindness. How do latent viruses differ from other infectious viruses, such as strains of influenza? "With respiratory flu, you feel bad for seven to 10 days while your body's adaptive immune system attacks and kills the virus," Pierson explains. "As the immune system drives the virus out of your body, you feel better. Eventually, the virus is completely gone," he continues. But the immune system usually does not drive a herpesvirus out of your body completely. Instead, as the immune system gains the upper hand, the virus retreats up a nerve to a ganglion (mass of nerve tissue) near your spinal cord. "Symptoms clear up and you feel better, but the virus continues to reside [hide] in your body in a latent stage," Pierson says, "and no further symptoms occur — perhaps for years." Inside your body, the virus lies in wait until it is reactivated by persistent stress, when it may start multiplying. Eventually the virus shows up in bodily fluids such as urine or saliva in a process called "shedding." When a becomes sick or stressed, the numbers of viruses in the body may rise to the point of producing symptoms (such as an outbreak of fever blisters), which completely differ from the symptoms of the initial infection. But viral shedding can also occur without any overt signs of infection. This asymptomatic shedding is of greatest interest to Pierson and his colleagues. Shedding is an early indicator of infection; the body then starts its fight against the virus. Could the shedding pose a risk of infecting other astronauts on the flight?  |
Above: Some viruses, such as the human herpesviruses, can remain dormant in the body for years after the initial, or primary, infection. Although the immune system responds to primary infection by these viruses, some portion of the virus is able to "escape," traveling up peripheral nerves and lying dormant in ganglions near the spinal cord. Prolonged stress, which compromises the immune system, can allow the virus to come out of "hiding" and travel back down the peripheral nerve to cause a recurrent infection. Credit: Duane Pierson. Source:
OBPR Space Research Newsletter, September 2002 (Vol. 1, No. 4). Simple Procedures, High Payoff Ideally, answering the questions in Pierson's two experiments would require astronauts' saliva, urine, and blood to be sampled daily before, during, and after flight to look for the presence or absence of stress hormones and herpesviruses and the concentration of different types of white blood cells. But daily blood testing is impractical. In addition to the annoyance to astronauts of enduring needles every day, "there are lots of technical constraints" to the analysis of fresh blood samples in flight, Pierson notes. For one thing, "the analytical equipment is bulky and will not operate in microgravity." Blood samples could be collected in flight and refrigerated until returned to Earth for later analysis, but that's of no help because "many cells will die or change their functions." So, to measure the action of white blood cells, Pierson and his colleagues are limited to obtaining blood samples from astronauts on the ground — during their flight physicals 10 days before launch, the day of their landing, three days and two weeks after landing, and during their routine annual physicals a year or so after flight. Collecting urine and saliva in flight and preserving them until landing to test for stress hormones and latent viruses, however, is another matter. "The viruses don't die or change, even over 60 days, and they don't have to perform a function. They just need to say 'present' when we call roll," Pierson quips. Thus, once in flight, the STS-107 astronauts will have a small extra task each day right after they wake up: "They'll take a cotton dental roll, put it in their mouth, roll it around to collect saliva, and put it in a Ziploc bag that has a little preservative to keep the bacteria down." The bag doesn't even have to be frozen or refrigerated. Back on Earth, the saliva and urine specimens are analyzed by a process called the polymerase chain reaction for the presence of viral-specific DNA. The concentration of latent viruses in the saliva during flight will be compared with the concentration measured in samples taken six months before flight, three times a week for a month before flight, and every day for two weeks after flight. A similar simple procedure will be followed for urine samples. Although Pierson and his colleagues have conducted various individual blood or saliva tests with space shuttle astronauts on some two dozen previous flights over the past decade, STS-107 will be the first opportunity to comprehensively measure components of the immune system, viral reactivation, and stress hormones simultaneously — and whether the amount of immune-system suppression is medically as well as scientifically significant. "It's a very exciting mission," Pierson says. "This will be our most comprehensive baseline to date." |
