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.

Sex against parasites

Image acquired from  Flickr  under a Creative Commons 2.0  license .

Image acquired from Flickr under a Creative Commons 2.0 license.

Sex may seem like all fun and games, but evolutionarily speaking, sexual reproduction has perplexed biologists for decades. It’s a question of math—why have a population in which only 50% of people can reproduce? In other words, why do men exist? Other than killing bugs and lifting heavy things that you could probably lift yourself, men, and sexual reproduction, confers an important evolutionary advantage: protection from pathogens.

The generation time of a human, other animal, or even a plant, is far greater than that of a bacterium. Think years, versus hours (or even minutes). Bacteria, and other pathogens, also acquire mutations at a much higher rate than humans per generation. Although mutating doesn’t sound like a benefit, it actually allows the bacteria to evolve as it is able to find mutations that better suit the particular environment in which it finds itself.

With bacteria acquiring new mutations so often, and evolving so rapidly, how are we humans supposed to keep up? This is where sex comes in. While we aren’t able to reproduce every hour, sexual reproduction allows us, as a species, to be constantly mixing our genetic material. Asexual reproduction, as occurs in bacteria, involves a single organism making an almost exact copy of itself. Any mutations that arise are random, and useful ones are just lucky. Sexual reproduction, on the other hand, always involves mixing information of two parents, so each generation is an opportunity for the acquisition of lots of new traits.

The idea that sexual reproduction might provide protection from pathogens is not a new one. This theory has its roots in a set of ideas known as the Red Queen Hypothesis. In Lewis Carroll’s Through the Looking Glass, the Red Queen says: “Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!” In evolutionary biology, this translates to the idea that pathogens (e.g. viruses, bacteria, fungi, and parasites) and their hosts are engaged in a constant race against one another where the pathogens want to remain in their hosts and hosts want to eliminate them. Fortunately for the pathogens, they’re able to reproduce and evolve more rapidly than complex multicellular organisms like us. Each new generation, which occurs on the scale of hours, is an opportunity for a species of bacteria to acquire new mutations that could fortuitously render it less susceptible to attack from an animal’s immune system.

Multicellular organisms cannot mutate themselves on a per infection basis, so we depend on other mechanisms of battling quickly mutating bugs. The genetic variation that we, as a species, get from sexual reproduction is particularly important for the ability of our immune system to fight pathogens. In fact, the most variable set of genes in the human genome encode proteins that determine what kinds of pathogens an individual is best at fighting. This variation affords our species widespread protection from pathogens in general—even if one person is particularly susceptible to a certain viral infection, for example, the likelihood of everyone being susceptible to this virus is made extremely low by our extraordinary genetic diversity. This diversity is afforded by sexual selection that allows humans to acquire new traits with every generation.

There’s no guarantee that newly acquired traits will be useful, and many of them can be neutral, like eye color, or detrimental, like genetic diseases. Over evolutionary time, however, sexual reproduction is hypothesized to give organisms a leg up in the arms race with pathogens. So in addition to allowing you to make babies and enjoy yourself at the same time, sex may also play an important role in protecting species from extinction.

The Extinction of Tasmanian Devils: Sometimes It's Better to be Different

By: Helen Beilinson

Australia has an incredibly unique list of animal inhabitants. From massive pythons to flying foxes (the largest bat species in the world) to ridiculous spiders and centipedes to some of the largest, smallest, and most poisonous jellyfish, Australians definitely have more interesting backyard fauna than I do here in New Haven (although the black squirrels are pretty cute).

Aside from its slightly more terrifying creatures, Australia is home to a huge amount of marsupials. Marsupials are mammals, meaning they feed their young with milk, like humans do. Unlike humans, however, mother marsupials do not carry their young in their uteri until birth. Instead, after a certain time of developing in utero (meaning, in the uterus), marsupial young will climb into a special pouch on their mothers’ belly to continue developing. These pouches contain the mother’s nipples, to feed the young, and offer protection while the baby marsupials continue growing. Some of the best known marsupials are kangaroos, koalas, and the happiest animal on Earth, quokkas. One marsupial that’s predominantly known more for its cartoon depiction is the Tasmanian Devil, which is currently the largest carnivorous marsupial. Unfortunately, their population is at high risk of extinction. Extinction of species is nothing new; it happens all of the time. Extinction can be caused by high predation, changes in food or climate, high rates of disease or infection, or a slew of others reasons. The pathway to extinction of devils is particularly interesting because their population is threatened by a rare type of disease—a transmissible cancer.

That’s right, the devils are transmitting cancer to each other, like humans can spread a cold.

Before the 1400s, Tasmanian Devils populated the entirety of Australia. However, due to heavy predation by dingoes and indigenous people, the devils were isolated to the Australian island of Tasmania. Since then, major population crashes have continued to affect the devil population. From 1830 to 1930, locals made efforts to exterminate the devils because they preyed on their livestock. In 1909 and 1950, there were smaller epidemics of infectious disease that hurt the devil population. In 1941, however, laws were enacted to protect the devil population because half a decade prior, another carnivorous marsupial, the Tasmanian Tiger, went extinct. These laws aided the devil population drastically, until about half a century later.

In 1996, the first case of Devil Facial Tumor Disease (DFTD) was documented in the Tasmanian Devils. This cancer, as the name suggests, causes large facial tumors on the devils. These facial tumors eventually cause the devils to die of thirst and starvation, as they are unable to eat, drink, or see. The fascinating thing about these tumors, as I previously alluded to, is that they are passed from devil to devil through biting. This transmissibility is incredibly rare in cancer. Usually, cancerous cells develop within one individual and cannot be passed from one person to another. Curiously, the same phenomenon helps to explain why cancer cannot be spread in most species and why it is spread through the devil population.

Each of our cells contains markers (these are basically proteins that cover the exterior of the cell such that other cells can “see” them) on its surface to tell other cells that they are part of the same organism. They mark our cells as “self” as opposed to other cells, that either have “nonself” markers or have no “self” markers. One self marker is the Major Histocompatibility Complex (MHC) molecule. These molecules are critical to our immune responses because they will hold motifs (kind of a protein pattern) that allow other immune cells to recognize what is infecting the body. Because they need to bind to so many different kinds of proteins (they have to be able to display features of all the bacteria, viruses, fungi, etc. that invade our bodies), you can imagine that have different forms is a good thing for your immune system, because you can bind various forms of such proteins, instead of a smaller subset, which would allow you to react to a greater variety of things. Mammalian immune systems have this taken into account. MHC genes are some of the most diverse, or polymorphic, genes out there. This means that there are many, many forms of it throughout the population (don’t worry, they still work great!). Because you have two copies of DNA (one from your mother, one from your father), you get two copies of these MHC genes. This means that the more different your mom and dad’s MHC genes are, the greater variety of foreign proteins you can display on your MHC. This positive aspect of MHC genetic variety can be more greatly appreciated when you see a population where this variety doesn’t exist. This loops us back to the Tasmanian Devils.

Due to the massive population downsizing and isolation of a small population of the devils, they have a very limited variety of these MHC molecules. This observation is one of the major reasons why DFTD is so rampant. As I mentioned before, MHC molecules are self markers. The variety that we see in these molecules allows for a greater system of defining what “self” is compared to nonself. For example, if you have a signal of two letters for variety, there’s only 262 (676) options. So out of the 7.1 billion people on earth, your body will see 10.5 MILLION people’s cells are your cells. If you have a signal for ten letters of variety, there’s 2610 (140,000,000,000,000), so your body will only recognize your body’s cells are your cells.

When rejection occurs after an organ transplant, this is due to the acceptor’s body recognizing the MHC on the donor’s organ, thereby seeing it as nonself and attacking it. Although this isn’t good for a transplant, this keeps a lot of problems at bay. Unfortunately, due to their lack of variety of MHC genes, Tasmanian Devils do not have this ability. The cancer cells of the DFTD can be found on teeth and on lesions on infected devils’ faces. When they bite another devil, these cells are transferred into the wounds of the uninfected devil. If there were enough variety in the MHC genes of the devils, the newly infected devil would recognize the cancerous cells as nonself and would eliminate them, preventing the development of a facial tumor. However, because there is so little variety in the devil’s genes, the newly infected organisms do not recognize the cancerous cells as nonself, and instead see them as self. Self cells are not attacked by the system normally, so the cancerous cells stay, and develop into tumors. This perpetuates the cycle, leading to the cancer spreading throughout the population.

There are currently two other known transmissible cancers. One is a venereal tumor that affects dogs that has been spreading around the world for the past 11,000 years. The second was recently confirmed as a transmissible cancer—it is a soft-shell clam leukemia that has spread throughout the east coast of North America.

The extinction of the Tasmanian Devil is being driven by this transmissible cancer that the devils are unable to eliminate. However, without the initial downsizing of their population due to human predation, its highly probable that the population would have enough diversity of their MHC genes that this cancer would not have been able to even come about.

Male Odor Bride

By: Ross Federman

If you have ever been sexually attracted to someone, you likely know how powerful a feeling it can be.  You may have also made the discovery that the person you’re attracted to smells really great.  And while you find that they smell amazing, your friends may not always react the same way.  Why is this? The answer is surely a laundry list of factors that we don't understand fully and plenty that we don't even know exist yet.  However, some of how this process works has been studied, and indeed much of what you’re smelling are pheromones—chemicals secreted in sweat and other bodily fluids that have purportedly evolved to attract mates. Several studies have found a fairly significant link between how attractive a potential partner’s pheromones are and how well their combined genetic codes would render their offspring in fighting disease. Evidence really does seem to suggest that one is more attracted to those that will make their future children together healthier.

Although we are very adept at battling infections in general, one of the most powerful aspects of our immune system is its ability to adapt and focus its power on a very specific virus, bacteria, fungus, or toxin that has invaded the body, and to remember that same target if it ever shows up again.  There are two analogous molecules in mammalian immune systems known as the Major Histocompatability Complexes one and two (MHC I/MHC II) that allow little bits and pieces of these pathogens to be "presented" to other components of your immune system.  Under the right confluence of events these bits and pieces of proteins presented by MHC I and II trigger your adaptive immune response to know what to look for.  For example, if some punk kid in a red t-shirt sneaks into a black tie charity gala to get free food and drinks, the MHCs would basically show the red t-shirt to other cells, training them to look for it amongst the crowd.  I can't underscore enough how incredibly important the activity of MHC I and II is to your immune system.

The MHC proteins are made by various genes in the HLA family, and these HLA genes are the most diverse in the entire human genome.  That is to say, within the human population, there are many more varieties of MHC proteins than any of the other proteins that your genome codes for.  Each MHC has its own unique ability to present various types of peptides (which are chopped up bits of larger proteins) to your immune system.  In this case, these peptides are considered "antigens" by your immune system, small molecular signatures that allow for specific recognition, much like the red t-shirt on the moocher in the example above.  And while each unique MHC can present a wide variety of peptides and antigens, no single MHC can do this for all possible peptide antigens.  To answer this, we have evolved to each have several copies of HLA genes instead of just one.  This gives us the ability to try to cover as wide a range as possible in what our immune system can recognize and mount an attack against.

At the population level, this variety is crucial.  It ensures that the human race will have a spectrum of susceptibility to any given pathogen, so that even the worst mega pandemic virus will find some humans whose MHC molecules will present the viral antigens so efficiently that they will (hopefully) survive.  Essentially, evolution has given us the ability, as a whole species, be more suited to survive these horrible occurrences like the plague, the 1918 flu, and countless other similar events that undoubtedly occurred before recorded history.

But back to you and the awesome kids you'd have with that person that smells delicious and you’re finding yourself attracted to.  You and your partner each have a unique set of HLA genes creating a unique blend in ability to present various different antigens.  When you and your mate have very different MHC molecules, your offspring will ultimately get an even greater variety, and since HLA diversity has been so evolutionarily beneficial to our immune systems, our bodies seemed to have developed the ability to pick up on this as a cue.  Thus, we find a far more attractive scent or odor from a potential mate whose HLA genes differ from our own.  So it appears that our senses have been evolutionarily tuned to help us find sexual partners that will give our offspring a survival advantage when it comes to fending off disease, though it is still mysterious as to how this phenomenon occurs at a molecular level.

So take a second to forget about all of the crazy things going on in your head and your body when flirting, dating, or just meeting someone for the first time.  If you find yourself drawn to their scent, it could very well be nature's way of saying, "Hey if you two have kids, they'll have well equipped immune systems to fend off disease."  And with the lower and lower numbers of parents vaccinating their children recently, it might not be such a bad idea to keep this mind.

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. 

Monsters of med school: monocyte

Monocytes are an integral part of the innate immune system. In tissues, they can differentiate into macrophages, the gluttons of the immune system. While macrophages perform a variety of functions, one of their most important roles is to eat up, or phagocytose, material around them. They eat dead cells, debris, and, importantly, infectious organisms, a process that is critical for host defense. Macrophages are also the primary infectious target of   M. tuberculosis.

Monocytes are an integral part of the innate immune system. In tissues, they can differentiate into macrophages, the gluttons of the immune system. While macrophages perform a variety of functions, one of their most important roles is to eat up, or phagocytose, material around them. They eat dead cells, debris, and, importantly, infectious organisms, a process that is critical for host defense. Macrophages are also the primary infectious target of M. tuberculosis.

Did someone really prove that eating red meat causes cancer?

By: Ross Federman

One frustration facing many scientists today is the manner in which primary research articles are interpreted by other writers and subsequently reported to the general public.  Often, important subtleties and details regarding the experimental design are disregarded, and while researchers are careful to qualify their conclusions based on this, other writers may not be. The past few weeks has provided a clear example of this.  This research article provides some implications, and promises to guide future research to gain more insight into the question at hand. However, many articles covering the research, such as this one from The Telegraph, are stating these implications as a concept that the article “proved,” in this case, that eating red meat will cause cancer.

First off, it should be noted that there is long standing epidemiological data to show that those who consume meat in their diets, on average, have a higher risk of developing cancer than those who abstain from meat consumption.  It’s also a widely held opinion that this is likely due to increased chronic inflammation that is present in meat eaters.  To date, there was very little mechanistic evidence or insight into why meat eaters suffer from more inflammation and thus higher risk of cancer.  An article published at the end of last year in The Proceedings of the National Academy of Sciences, a very reputable and highly respected journal, provided some a possible mechanism to account for this.  They showed that there is a specific sialic acid molecule (N-Glycolylneuraminic acid or Neu5Gc for short) present in almost all meat consumed by humans, and that this molecule becomes incorporated into the human body after consumption.  The molecule is of course also present in any animal that the meat came from.  To these animals, Neu5Gc is considered “self.” That is, their immune systems are trained to ignore it.  Humans however, do not produce this molecule on their own, so their immune systems likely see it as foreign.  This in theory could lead to an antibody response whereby antibodies specific for the molecule are created, and induce inflammatory conditions wherever it is present. In a meat consumer, this would be all over the place.  The resultant chronic inflammation would thus increase an individual’s risk of cancer.

So what did these researchers actually do?  They used a mouse model in which they deleted the gene in mice that produces Neu5Gc. This deletion essentially made the mice more like humans in the sense that they would now see Neu5Gc as foreign.  They artificially introduced antibodies directed at the molecule, found that these antibodies did indeed promote chronic inflammation, and that mice treated with the antibodies had significantly higher incidence of cancer.  This provides a mechanism whereby a mammal that does not produce Neu5Gc inherently may be able to produce antibodies against it that promote inflammation.

What did they not show?  First off, none of this work was done in humans, and while mice provide a great experimental model, they are different animals, and not all conclusions drawn from mouse work can simply be transferred to our understanding of humans.  But more importantly, the antibodies that mediate this mechanism were artificially introduced into the mice, and without them, there was no response to the foreign meat residue whatsoever, or at least not enough to significantly impact tumor development.  The authors justify this by stating that antibody responses to this molecule have been shown in the past, but that they are quite complex and not easily controlled in an experimental system.  That’s not a major problem in terms of the research itself.  This still provides a model mechanism to explain the increased inflammation caused by meat consumption.  However, this does become problematic in others’ interpretations of the work because it is a subtle distinction that any immunologist would look and therefore take some of these implications with a grain of salt.  Those covering this research for broader scope publications however may have either not picked up on this, or simply chosen to ignore it. 

Thus, while this research is well executed and appropriately interpreted by the authors, the interpretation by some of the writers that have covered this article are really not supported by the work.  The interpretation that this work has “proven that meat eating causes cancer” is far too great of an over-simplification, and not a correct conclusion to draw from this particular study.  Again, the mice and human differences cannot be overlooked.  Hopefully, because of this study, researchers may begin to look at human antibody responses to this particular molecule, but until that is examined, the relevance to human health is merely an implication, certainly not a conclusion.  The other elephant in the room here is that the gene deletion was not enough to induce this mechanism without the artificial addition of antibodies specific for the residue.  This implies that the true mechanism at work in a physiological context is likely far too complex to be easily explained by this particular study.  So while this is great science, and certainly contributes to the story of “cancer from carnivore,” it is not sufficient to prove much other than the fact that this particular mechanism is possible given all the right conditions that may or may not be present in human meat eaters, but they could be, potentially, and that is really the heart of the paper. 

In all reality, very few individual research papers “prove” major concepts such as these.  Rather, each paper contributes in a way that creates a larger and larger foundation for future studies, fills in knowledge gaps in the field, or both.  This paper does both.  It sheds light on the knowledge gap between meat consumption, and cancer promoting chronic inflammation, while guiding efforts to begin to examine the human antibody response to the molecule in question.

At the end of the day, this shouldn’t really change what the average person thinks about meat consumption.  It was already known that this diet habit is linked to higher rates of cancer.  There are many similar associations of this nature.  Pilots and other flight crewmembers have significantly higher risk of developing acute myeloid leukemia likely due to the increased UV radiation exposure that occurs at flying altitudes over accumulated flight hours for example. This has not stopped us from taking full advantage of flight as a convenience of the modern age, and for many to pursue careers as pilots. Most people would be amazed to see the list of materials or conditions that cause cancer. It’s astounding. And based on how long mankind has been consuming meat, it is likely that the impact meat consumption has on cancer development is fairly minimal. The long history of meat consumption (as far as our records can tell) would imply that if meat consumption significantly impacted human cancer development to such a great extent that it impacted our fitness, we likely would have evolved to be strictly herbivores.  The bigger concern should always be for those highly potent carcinogens, materials like asbestos, benzenes, or even gamma radiation, all of which are not nearly as enjoyable as eating a nice delicious steak. If you’re not going to eat meat, do it because you don’t like it, or you care too much about animals, not because you think this particular research article proved that doing so causes cancer.

Viral infections and the microbiota

By: Helen Beilinson

Take home points:

1)    The microbiota can influence viral infections—exacerbating disease or preventing disease—so we need to be mindful of how we take antibiotics during viral infection

2)    Antibiotic treatment during flu infection can exacerbate disease

3)    Antibiotic treatment during other viral infections could prevent viruses from taking advantage of immunosuppressive properties of microbiota

 The microbiota—two words that have been splattered across scientific papers, the evening news, and “yogurt for women” packages. The multitude of bacterium that live within and on us constitutes, essentially, another organ that plays a role in many aspects of development and maintenance of the larger organism. It has been long appreciated that the microbiota plays a beneficial role in a host’s metabolism. However, only recently it has been shown that the microbiota is a significant player in the host’s immune system. In fact, it has a huge influence on how we interact with external pathogens and on the pathogenesis (the development of disease) of these pathogens. The predominantly bacterial microbiota live mostly at mucosal surfaces of the host (such as the gastrointestinal tract, genital mucosa, and upper airways), as well as on the skin. Interestingly, viruses are predominantly spread through routes where they would interact with the aforementioned microbiota. Thus, it is highly probable that the microbiota and viral pathogens interact and influence each other in some way. In fact, it has been documented that the microbiota can either obstruct or advance infections of various viral pathogens (or have no effect).

In mouse studies, it has been shown that eliminating the microbiota, either through antibiotics treatment (treatments against bacteria) or by raising mice germ-free (meaning that they have never been colonized with any bacteria), is very detrimental during influenza infection. Mice have more viral particles, higher mortality rates, and more degeneration and death of their lung tissue without their proper bacterial population. The mechanism of microbiota-dependent protection currently is unknown. This trend is incredibly important to study for its implications in human health. Flu infection changes the landscape of our lungs, making it easier for bacteria to infect the lungs. One such bacterium is Streptococcus pneumoniae, a causative agent of pneumonia. The most fatal cases of influenza are due to such secondary bacterial infections. Increases in mortality due to co-infection have been confirmed in mouse models. When patients enter the hospital with bacterial pneumonia, they are placed on antibiotics. This could potentially exacerbate flu disease by eliminating the beneficial bacteria of the patient’s microbiota, leading to death. Unfortunately, there have not yet been studies to show that antibiotic treatment causes patients to fare worse in co-infection situations.

In theory, our immune systems are activated once they sense an invader via certain molecular patterns that are unique to the invaders. For all intents and purposes, however, the molecular patterns decorating pathogenic bacteria are the same as those decorating the bacteria composing our microbiota. Although one of the current mysteries of the microbiota is why our immune system doesn’t eliminate it, it is known that these commensal organisms possess immunosuppressive properties. For example, a molecule that decorates the surface of particular bacteria is called lipopolysaccharide (LPS). There are various forms of LPS, some forms are immunostimulatory, while others, such as those expressed by the microbiota, are immunosuppressive. It has been shown that there are viruses that take advantage of the immunosuppressive properties of commensal LPS to dampen the responses of the host, allowing for active viral replication. Thus, although depletion of a host’s microbiota may be detrimental in flu infection, in cases where the microbiota aids viral replication and disease progression, antibiotics may be a source of treatment.

Studies in mice utilizing two different retroviruses (the family of viruses to which HIV belongs) have shown that these viruses require the presence of the microbiota to be present to flourish. By binding to LPS of the gut bacteria, the viral particles stimulate immunosuppressive pathways, allowing the virus to replicate without the host attempting to eliminate it. These studies were done in mice with murine viruses, so the question remains: Do human viruses interact similarly with LPS? Potentially.

It has been shown that HIV virions can directly bind to LPS molecules. It has also been shown that the presence of LPS during HIV infection (in a series of experiments in cells, not full organisms) decreases the “activated” state of antiviral immune cells, called plasmacytoid dendritic cells, preventing them from potently attacking infected cells. LPS is recognized by Toll-like receptor 4 (TLR4) in our immune system. In an unknown fashion, different LPS variants stimulate TLR4 to produce either a pro- or anti-inflammatory state, which is defined by immune signaling molecules called cytokines. An HIV protein, Tat, has been shown to stimulate the same immunosuppressive pathway as the mouse viruses by interacting with TLR4. This study did not show whether or not LPS was present in the experiments shown (LPS is a pesky molecule that is incredibly difficult to eliminate in a lab setting). Either way, it points to interesting evidence that HIV, as the mouse retroviruses, has possibly evolved the ability to take advantage of the immunosuppressive properties of the microbiota to allow for its replication. Thus, antibiotic treatment could be a potential treatment for HIV replication by decreasing the amount of commensal-expressed LPS that the virus may take advantage of to evade the immune system.

Living predominantly in areas that are directly exposed to the elements and invading pathogens, our microbiota may hold essential information regarding how our body battles infection and either wins or loses. The modulation of our live-in bugs will certainly be a future step in medicine in aiding the treatment of various infections, including those of viral pathogens. So next time you have a viral infection, be sure to ask your doctor whether it is safe for you to take antibiotics—or whether it could possibly help your immune system eliminate the infection.

It is important to note that neither the flu nor the HIV findings have been confirmed in humans, particularly the HIV studies. The intricacies of the microbiota, and particularly the details of how it interacts with intruding viruses, are still very enigmatic. Presented here are very brief summaries of very few papers on this topic, these should not be taken as medical advice.