No Gravity? Exhausted Immune System

By: Helen Beilinson

In 1970, astronaut Fred Haise fell ill thousands of miles from home aboard Apollo 13. The culprit? A bacterium that, on Earth, causes no symptoms in healthy individuals. The extended health screens taken before his flight indicated that Haise’s health was in impeccable condition and his doctors had no reason to believe that Haise’s immune system couldn’t battle the bacteria. But, as we have learned over the last fifty years, weak gravity, or microgravity, impairs the immune system. Although Haise survived and returned to Earth safely, his infection was one of the first indications that our immune systems function under different rules in space.

Strengthening weakened immune systems is not an impossible task on Earth, it has been done with everything from battling infections to battling cancer. However, to help individuals’ bodies fight infections in microgravity is still a difficult thing to do because it is still unclear how microgravity changes the way the cells of our immune systems function. Last year, a study published in Life Sciences in Space Research provides a basis for how future astronauts can aid their bodies function at full capacity by finding a unique feature of immune cells in microgravity.

Dr. Jillian Bradley and her colleagues studied an immune cell type called T cells, which are fundamental in fighting infections. When an infection occurs in the body, other immune cells sense the intrusion and signal to the T cells that they need to activate to fight off the infection. T cells are also capable of killing our own cells that aren’t ideal—for example, if they are infected with a virus or if they are cancer cells.

Bradley compared T cells grown in normal gravity conditions and in microgravity, by placing the T cells in a spinning chamber that drops the level of gravity the cells experience. T cells need to be turned on, or activated, to handle invading bacteria or other infectious agents. When Bradley starting the signaling to the T cells in microgravity, they became more active more quickly compared to the T cells receiving the same signals in normal gravity.

However, something surprising happened if she looked at the T cells after a few days of being activated. After three days, these activated T cells lose their muster. The longer duration in microgravity made these T cells activate more sluggishly, as if they couldn’t receive the signals to turn on.

Slow T cell responses are potentially dangerous and could be the reason Haise got sick in space. T cells are activated a few days after an infection starts, giving the bacteria time to multiply before these heavy hitting cells start attacking them. If the activated T cells are slow in their response time to the infection, the bacteria have more opportunity to expand and cause symptoms of being sick. Slow immune responses in space could put astronauts at risk for infections by bacteria that on Earth our immune responses respond rapidly to, like the bacteria Haise was infected with.

When investigating why microgravity is debilitating for T cells, Bradley found that T cells without gravity very quickly make a protein that inhibits their function. This protein is seen in the T cells that enter a state of exhaustion, where they have been told to activate to much that they lose the ability to quickly respond. Typically, this protein is seen when T cells are exposed to very extended periods of activation, however, in microgravity, the amount of time it takes to exhaust a T cell is significantly shorter.

It may not be all bad news, however, because this mark of immune response dampening is infamous in another location where turning T cells back into full swing is already being done—tumors.

In addition to their ability to eliminate infections, T cells are important in battling cancers. However, when tumors are large enough, they exhaust T cells, causing to express the same inhibitory protein as microgravity does. The newest wave of cancer treatments, termed cancer immunotherapies, are focused on eliminating or suppressing the function of the inhibitory proteins, causing the T cells to be more active and able to eliminate the cancer cells more readily.

Could the same technology be applied in space? Scientists don’t know yet. But it could be a potential way that astronauts can utilize existing technology to prevent them from getting sick in space.

With eyes on missions to Mars and beyond, understanding how microgravity affects our bodies is critical to ensure the health of those leaving our stratosphere and defining the changes occurring in our immune cells provides physicians with the information they need to design novel treatments for astronauts dealing with infections in space. Fascinatingly, the parallels between T cells in microgravity and in cancer could provide insights to keeping bugs at bay in space.

Why don’t we kill our microbiota?

By: Zuri Sullivan

If you didn’t already know that humans are colonized by trillions of bacteria, that these bacteria make up much more of our bodies than our own cells, and that they play an important role in our physiology, health, and disease, then you probably didn’t read Helen’s piece about the microbiota and defense against viruses. The “microbiota” refers to the collection of microorganisms that live in and on our bodies. A search for “microbiota” returns close to 14,000 academic papers. To call this a current hot topic would be a massive understatement. Why are scientists so excited about the microbiota? First, major technological advances have allowed scientists to begin unraveling the complex community of bacteria, fungi, and viruses that colonize our bodies. Additionally, mounting evidence suggests that the microbiota can influence nearly every aspect of our physiology, which raises important questions about its interactions with other cells and tissues in our bodies. 

There’s a lot to be learned about the microbiota and its functions, but one of the biggest unanswered questions in the field is why all of these bacteria are overlooked by our immune system. Most of us know the immune system as the mechanism by which our body eliminates disease-causing agents, or pathogens. These pathogens are bacteria, viruses, and fungi—the same organisms that make up the microbiota. One of the biggest unanswered questions regarding the microbiota is why our immune system doesn’t eliminate our own microbial population, but does eliminate those microbes that are pathogenic. The initiation of an immune response against an invading species relies on the detection of pathogen associated molecular patterns (PAMPs). PAMPs are molecular structures that are present in microorganisms, but not in host cells. For example, a particular sugar-like molecule, lipopolysaccharide (LPS) is present on the surface of some bacteria, but absent from mammalian cells. Thus, by targeting attacks against cells that have LPS, the immune system can efficiently target a wide array of bacteria without risking damage to host cells. In addition to being distinctly non-mammalian, another critical feature of PAMPs is that they are conserved amongst microbes. This means that PAMPs tend to be molecules that serve critical functions for microbial survival, and thus they are seen in an array of microbial species, including pathogens (microbes that make us sick) and commensals (microbes that have neutral or beneficial effects on our health). This raises an important conundrum: if the immune system recognizes PAMPs that are common to all microbes, why don’t we attack commensals?

A paper published last week in Science provides an exciting clue to how our commensal bacteria survive some of the host’s innate defenses. They looked at antimicrobial peptides, which are chemicals made by immune cells that can directly kill bacteria. They’re like antibiotics made by your own body, and they are an important innate defense mechanism against bacterial infection. The team of researchers asked whether commensal bacteria might be resistant to antimicrobial peptides, which would allow them to survive in the host. Their hypothesis was that commensal bacteria that are adapted to live in our bodies might have evolved mechanisms to tolerate antimicrobial peptides, while pathogens have not.

They found that a common commensal species, Bacteroidetes thetaiotamicron  (B. theta) was more resistant to a particular antimicrobial peptide than pathogenic bacteria. Next, they identified the B. theta gene that was responsible for antimicrobial peptide resistance, a gene called LpxF. They then asked what role this gene played in the ability of this commensal organism to survive the host immune response to a pathogenic bacteria.

This was an important question, because it illustrates an important principle about how the microbiota helps us protect ourselves from pathogenic bacteria. When we’re infected with an intestinal pathogen, gut immune cells detect the infection and induce many defense mechanisms, one of which is the secretion of antimicrobial peptides. These antimicrobial peptides need to be able to target the pathogen, while sparing the commensals that provides other benefits to the host. Thus, by having a gene that confers resistance to antimicrobial peptides, the commensal has an advantage over the pathogen in the context of an immune response.

This was borne out in an experiment wherein the researchers added two different bacterial strains to the intestines of germ-free mice (mice who are raised to not have their own microbiota): wild-type (normal) B. theta or B. theta that were lacking LpxF (a mutant strain), and therefore lacked resistance to antimicrobial peptides. They then infected these mice with a known pathogen, Citerobacter rodentium. They found that while the LpxF mutant strain of B. theta was outcompeted by the pathogen, the wild-type B. theta survived the immune response.  

The findings of this study illustrate two important principles. First, they provide a mechanism that explains how a commensal bacterium survives a host defense mechanism that is directed against all bacteria. Second, they show that this survival mechanism helps commensal microbes compete with pathogens for colonization of the gut. These principles are relevant to both the continued understanding of the role of the microbiota in host defense, and in understanding the co-evolution of the immune system and commensal microbes. This co-evolutionary relationship, whereby our evolved mechanisms for eliminating bacteria are resisted by commensals that have evolved to live in our bodies, is important for the continued study of the microbiota and its impacts on our health.