Have you ever wondered why people say to stay in your bed an extra day when you have the flu, even after you start feeling better? The answer lies in small hormonal molecules called glucocorticoids that walk a fine line between health and harm in their role in your body. Dr. Ruslan Medzhitov of the Department of Immunobiology at the Yale School of Medicine recently published a paper in Cell Host and Microbe investigating the role of these molecules upon contraction of the influenza virus.
No matter where we turn, we are constantly exposed to an endless array of pathogens, day in and day out. Most of these pathogens have no significant effect on us, however, because our immune system quickly and successfully destroys these invaders, thus preventing them from harming our fragile bodily systems. Each pathogen that our immune systems face elicits a different immune response, with the mechanisms specific to each pathogen. However, such host-pathogen interactions extend beyond dealing only with one pathogen; ongoing immune responses can influence the body’s response to another pathogen, as well.
Our Bodies’ Response to Coinfection
Medzhitov’s research used mouse coinfection models to explore how the immune response to an influenza virus influences the body’s handling of bacterial infections. His results demonstrated that the influenza virus triggers a bodily response that causes a rise in serum glucocorticoid levels, leading to systemic immunosuppression. Such effects render the body vulnerable to bacterial infections that would otherwise be innocuous. However, the research also showed that artificially decreasing glucocorticoid levels leads to lethal immunopathology due to excessive inflammatory response. Thus, the balance between immune defense and immunopathology in relation to the host’s reaction to coinfection is of utmost importance to gaining a fuller understanding of our body’s handling of viral infections.
When our bodies are subject to infections, our symptoms can be caused by two sources: the particular pathogen we are victim to and our immune response against the pathogen. The specific pathogens that enter our bodies can directly cause damage to our tissues and organs; certain pathogens can even affect various parts of our body, causing systemic infections. Systemic infections are caused by our own immune response, designed to destroy the pathogen. “When our immune system reacts to the presence of the pathogen,” explains Medzhitov, “it induces an inflammatory response that causes collateral damage to our own tissues while it is destroying the pathogen.” The influenza virus is a perfect example of this—the main symptoms that we feel, such as fever, result from the immune response, the main source of the illness. Our symptoms subside and we start feeling better when the inflammatory response is controlled and decreased by an increase in glucocorticoids. Such a decrease in the immune response causes immunosuppression, which then places our bodies at risk for secondary infections, such as bacterial pathogens that normally would have no visible effect on our health.
Influenza as a Pathogen
Past research on the influenza virus focused on studying the effect of the virus on bacteria that caused pneumonia and led to lung infections. The ubiquity of such bacteria lends to easy attack when our bodies are weakened and the immune defenses down. When the influenza virus invades our bodies, it elicits an antiviral response specialized to deal with the specific viral strain using a mechanism different from the immune response to bacterial infections. This response to the influenza virus actually interferes with the normal immune response to bacterial infection, leading to potentially uncontrolled respiratory bacterial infections. The research in this area does not delve into general immunosuppression, but rather focuses on mechanisms that only occur in the lung. Medzhitov is the first to describe the influences of the influenza virus’s expansion to systemic immunosuppression, a condition that can lead to complications from secondary bacterial infections.
The influenza virus is a respiratory infection that enters the body and establishes itself in the lungs. The respiratory tract becomes the main target for secondary infections, especially respiratory bacterial infections that infiltrate the body via inhalation. Dramatic general immunosuppression occurs, during which our immune system becomes temporarily deficient, compromised of its ability to handle problems that would otherwise not cause significant damage. Under normal circumstances without immunosuppression caused by the influenza virus, most bacterial pathogens are quickly destroyed by our immune system. For example, the Listeria strain of bacteria is very common and generally innocuous, omnipresent in poultry and any contaminated and unfresh food. Our immune system can easily kill Listeria to the extent where they only become a problem if consumed in huge quantities.
The Mice Experiment
In Medzhitov’s research, this strain of bacteria was introduced in mice for coinfection with the influenza virus. While normal mice uninfected with the influenza virus handled the bacteria well without showing any signs of damage to their health, mice infected with the virus were severely impaired by the bacteria. Massive growth of the bacteria was observed and the livers of the mice had impaired function. The immune system was rendered deficient, experiencing a severe suppression that lasted for a week.
A strong and prolonged production of the stress hormones was also observed to be highly prevalent. Glucocorticoids are normally released under conditions of stress when the body is subject to the fight-or-flight response. Under extreme stress, when the body is fighting for survival, a high level of glucocorticoids allows it to orchestrate the stress response. This hormone has an immunosuppressive function; people who have inflammatory problems use corticoids, a medicinal derivative of glucocorticoids, to depress the excessive immune response. This suppression also occurs following the flu and compromises the immune system for several days, even after visible bodily symptoms disappear. Thus, even normally innocuous bacteria can become a huge problem at this point given the defunct state of the immune system.
If the mice in Medzhitov’s research were subject to experimentally lowered production of glucocorticoids, they could then easily destroy the bacteria. Immunosuppression was prevented as the level of glucocorticoids dropped to normal levels. The bacteria no longer displayed excessive growth either, especially in the liver. The twist, however, appeared a few days later when the mice began to suffer dramatic setbacks in their health. Eventually, most of the mice died due to an excessive inflammatory response—a part of the immune response to defeat the bacterial pathogens. Since the glucocorticoids were no longer present to generate immunosuppression, the inflammatory response was too strong and thus led to severe health damage in the mice.
Our Bodies’ Response
Our bodies end up at a crossroads: “We must choose between two evils,” says Medzhitov. The first option is to have control over the inflammatory response via the presence of glucocorticoids, but that renders us vulnerable to the second option. Our bodies must select between two mutually exclusive alternatives, a situation that is actually very common in evolution. When we are faced with two contrasting needs, we must compromise one if we select the other, ending up with evolutionary trade-offs in which we gain benefits at a cost. Throughout evolution, such trade-offs are optimized to maximize survival, and in this case, our bodies produce glucocorticoids to prevent inflammatory damage at the cost of leaving us susceptible to secondary infections. Excessive inflammation, however, turns out to be more costly and dangerous than transient immunosuppression and thus, our body chooses the route with the less threatening evil.
Following the influenza virus infection, our bodies face a multitude of secondary bacterial infections that pose potential complications. Our glucocorticoids set up a mechanism for systemic immunosuppression, spanning our entire bodies and covering all major organs. This leaves our bodies in a period of vulnerability that lasts for five to seven days following a flu infection. Usually, we start recovering from flu symptoms after five days, but due to the sustained high level of glucocorticoids, our immune systems are still suppressed and our bodies still susceptible to a plethora of pathogens. Thus, the old folk wisdom that we should stay in bed that extra day makes complete sense, as we are protecting our weakened defenses from threatening opportunistic pathogens. This is particularly important for immunocompromised individuals.
On the topic of potential treatments to deal with the consequences of immunosuppression, Medzhitov comments that although excessive production of glucocorticoids may cause the problem, the presence of the stress hormones is highly beneficial to our bodies and interference with that response mechanism would not be a good idea. Instead, we should be aware that we are immunosuppressed and take measures to reduce the threat of secondary infections. Thus, that extra day in bed is not only to regain strength but also to minimize one’s chances of exposure to opportunistic pathogens.
When asked about future goals in his lab, Medzhitov pointed out the pathogen-dependent effect of the flu infection on the immune response to secondary infections. Previous research on the flu virus, including his own, covers only two of the potentially many mechanisms that vary depending on the secondary pathogen. Many profound effects of the flu extend beyond just the flu virus itself, as seen in the body’s reaction to coinfection with bacterial pathogens. Much work remains to be done in exploring how flu infections affect defense against other mundane pathogens and aspects of normal physiology. Ultimately, Medzhitov seeks to understand the rules of engagement when our bodies deal with multiple infections simultaneously.
The reality is that we are never only subject to one pathogen at a time, which is the situation most immunologists have been studying. “Coinfections are probably more of a rule than an exception,” states Medzhitov. “We are always exposed to many pathogens at the same time, and our immune system deals with them, even if there are no symptoms because our immune response is not strong enough to produce damage.” A lot of unknowns still exist in the field, and a whole new layer of immunology awaits further exploration. For now, just listen to your elders when they tell you to stay in bed that extra day.
About the Author:
Jenny Mei is a freshman in Berkeley College. She is a Molecular, Cellular, and Developmental Biology major under the Neurobiology track and is working in Dr. Amy Arnsten’s lab on the effects of various drugs on the prefrontal cortex. She loves pandas, skiing, and spending time with friends.
Jenny would like to sincerely thank Dr. Medzhitov for his generous time and support, especially given his very busy schedule following such a successful publication.
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