The Human Immune System – Part 6

The unique threat posed to us by viruses.

Continuing this essay series on the human immune system, this essay explores the unique threat posed to us by viruses.  As Philipp Dettmer writes in his book Immune: A Journey into the Mysterious System That Keeps You Alive:

Viruses are the simplest of all self-replicating sorts of living things, although, depending on who you ask, they may not even be considered alive. We talked about the lack of consciousness and awareness of your cells. That they are just really complex piles of biochemistry that do what the genetic code and the chemical reactions between their parts compel them to do. Viruses are not even that. The fact that a virus is able to do anything at all is equally depressing and fascinating. A virus is not much more than a hull filled with a few lines of genetic code and a few proteins. They completely rely on proper living things to stick around. And they got extremely good at that. It is not clear yet when or how exactly viruses came into existence, but it is very likely that they are ancient and already existed when the last common ancestor of all living things on earth was alive, billions of years ago … [V]iruses are arguably the most successful entity on the planet. It is estimated that there are 10³¹ viruses on earth. Ten thousand billion, billion, billion individual viruses.

Viruses have become so successful because:

in a sense, they don’t do anything at all. They don’t have a metabolism, they don’t react to stimuli, and they can’t multiply. Viruses are so basic that they have no way to actively do anything. They are literally particles floating around in the environment and have to rely on passively stumbling into victims by pure random chance. The main thing a virus needs to be able to do to thrive is to get inside cells. And for that they abuse a weak point of all cells that living things will never be able to completely protect against: They attack receptors. We already talked a bunch about receptors [see Part 1 of this essay series], they are the protein-recognition parts that cover about half of the surface of cells. But receptors can do much more. They are used for interacting with the environment, to transport things from the inside to the outside and vice versa, and they are absolutely essential. The hulls of viruses are spiked with special proteins that can connect to a receptor type on their victims’ surface. This means that viruses can’t attach to just any cell—only to the ones that have a receptor they can attach to. In a sense every virus has a lot of puzzle-piece proteins that can only connect to a cell if it happens to have the correct puzzle-piece receptor … [I]n general a virus transfers its genetic material into its victim and forces the cell to stop making cell stuff. It is turned into a virus production machine. Some viruses keep their victims alive as sort of permanent living virus factories while others use up the cell as fast as possible. Usually for about 8 to 72 hours, the resources of the cell are turned into virus parts that get assembled into new viruses, until the cell is filled up, top to bottom, with hundreds to tens of thousands of new viruses. Enveloped viruses leave the cell by budding from it, which means that they “pinch off” a bit of the cell’s membrane and use it as an extra protective hull. Other viruses force the infected cell to dissolve and spill out its insides, including the new army of viruses it was brainwashed into building, which then go on to infect more cells. Pathogenic viruses are excellent at circumventing the immune system because they have a superpower: Nothing multiplies as fast as they do. And that also means that nothing mutates or changes as fast as viruses. They are basically impossible to beat on that front because they are sloppy and careless. Viruses are so basic that they lack most of the intricate safeguards your cells have to prevent mutations, so they mutate all the time.

Viruses are especially tricky for your immune system to deal with.  As Dettmer explains:

Your immune system can’t rely on the same weapons to fight a viral infection that it uses to fight bacteria as both the enemy and its tactics are very different. A virus is smaller and somewhat harder to detect than bacteria because it doesn’t have a metabolism that releases garbage chemicals that can be picked up by immune cells. And it hides inside cells for most of its life cycle and tries to manipulate infected cells to trick the immune system to stand down. It can change much more quickly than bacteria and a single virus can turn into ten thousand within a day, turning on exponential growth rapidly. Pathogenic viruses are terrifyingly dangerous enemies. The majority of pathogenic viruses enter your body via your respiratory mucosa. And this makes sense—as we briefly talked about, your Desert Kingdom of the Skin is a really, really bad place to be if you are a virus that wants to invade human cells. Layers and layers of dead cells stacked on top of each other. In contrast, the mucosa of your lung is a very inviting entry point for a virus. This does not mean it is easy to enter here—just like the skin, the body created a powerful defensive kingdom here … Though it’s fun to imagine, your lungs are actually not big balloons, but in a way much like dense sponges with countless nooks and crannies. The parts of your lungs that do the actual breathing have an enormous surface area, in excess of 145 square yards (120 square meters)—more than sixty times the surface of your skin. This vast space constantly interacts with the environment as you inhale a couple thousand gallons of air every day. As a consequence, your lungs are one of the most exposed places of the whole body. Each breath takes in about a pint (500 milliliters) of air, made up not only of the oxygen you need but also a few other gases that your body doesn’t care about, and a plethora of particles … [T]he cells lining your lungs are constantly confronted with an onslaught of toxic chemicals, particles, and microorganisms. While in other areas of the body the immune system would react massively if it were confronted by this explosive mixture, damaging tissue without that much regard, in the lungs this is not a great option. No matter what you do, you can’t stop breathing.

Dettmer then describes how evolution has resulted in a variety of defense mechanisms at work in your respiratory system:

The defenses of your respiratory system begin in the nose, with a pretty large filter of actual hair—not useful against anything small but meant to keep big things from entering. Like large enough dust particles or pollen for example. Then, as in any mucosal environment, the mucus is covering the surfaces and in your respiratory system can be rapidly expelled by the explosive sneezing reflex. The mucus is being moved constantly either outside or swallowed. In the deeper parts of your lungs these mechanisms are not useful though because to breathe, your alveoli, tiny sacs full of air, can’t be covered by mucosa or breathing would not be possible. So at your deepest and most vulnerable places in your lungs, there is literally only a single layer of epithelial cells between the inside and the outside and nothing else. Talk about an exposed area. A perfect target for all sorts of pathogens.

One particularly nasty virus is the flu:

“Only three more days until the weekend!” you think, as you enter the break room where one of your colleagues is making coffee. Just as you pass her, she suddenly coughs violently, quickly covering her face with the crook of the arm, but not fast enough—the first cough hit the air unhindered and a fine cloud, made up of hundreds of droplets, shot through the air. On the scale of cells, these droplets are not like bullets but more like intercontinental ballistic missiles, traveling a distance equivalent to continents in seconds. And they are not filled with nuclear warheads, but an equally dangerous load: millions of influenza A viruses that cause a disease we know as the flu. You breathe in, and a few dozen of the virus-filled missiles are sucked into your airways and violently splash onto your mucous membranes, where they release their viral load. You just make your coffee without realizing what a serious sequence of events has just been triggered. A bit later, as you begin to consider getting another cup, the first virus takes over one of your cells. It will be the first of billions … [M]any of the virus particles that you breathed in never reach their goal because they are caught and destroyed in time. But in truly dramatic fashion, a single one of the viruses reaches the cells below the protective mucus. Your epithelial cells, the “skin” of your insides, have receptors on their surfaces that the influenza A viruses can connect to and manipulate to enter the cells. It takes the virus only about an hour to gain control over the cell by conquering its natural processes. Without knowing what it is doing, the cell carefully wraps the virus inside a package and pulls it deep inside towards its nucleus, the brain of the cell. Natural processes, again triggered by the cell itself, signal to the virus when it has reached its destination and when it has to release its genetic code and a bunch of different hostile virus proteins. Within ten minutes the influenza tricks the cell into delivering its genetic material directly into the brain of the cell, the nucleus. Viral proteins begin to dismantle the cell’s internal antivirus defenses, and with that, the cell has been conquered … The influenza virus A, for example, just dumps a number of RNA molecules into the nucleus, where it pretends to be commissioned from your own genes and tricks the cell into building specific viral proteins. But of course the viral proteins are harmful and interrupt the production of healthy cell proteins and instead produce virus proteins, or in other words, virus parts … If we assume this process plays out without resistance (and each virus infects only uninfected cells) then one infected cell becomes 22, which then become 484 infected cells. Then 484 turn into 10,648, which turn into 234,256, which turn into 5,153,632. In just five reproductive cycles, each taking about half a day, a single virus has turned into millions.

Pneumonia is another terrible virus:

[T]he bacterium Klebsiella pneumoniae [is] a pathogen that causes, among other horrible things, pneumonia. It avoids the whole complement affair by hiding itself from complement proteins behind a sticky and gooey structure called a capsule. Which is quite literally a slimy sugary coat the bacteria produce to cover the molecules the immune system would recognize. Simple and effective, like a deodorant for bacteria.

As is the measles:

Measles is one of these controversial diseases whose fate is tightly bound to the movement against vaccinations. While measles was on its way to becoming the second human pathogen to be completely eradicated since smallpox, it has made somewhat of a comeback in the last few years as more and more people decided to not vaccinate their kids against the virus. Ironically these movements are primarily based in the developed world where people have forgotten how much of a serious disease measles still is. Globally, measles killed more than 200,000 people in 2019, most of them children, a 50% increase since 2016. Despite this sad and unnecessary rise in deaths, if you get measles in a developed country with access to good healthcare, chances are still very good that you will recover. But there is a vicious part of measles that is not discussed as much as the disease itself: Kids who overcome a measles infection have a higher chance of getting other diseases afterwards because the measles virus kills Memory Cells. If you think that sounds a bit scary, that is the correct reaction—the virus basically deletes your acquired immunity … The measles virus is extraordinarily infectious— considerably more infectious than the novel coronavirus for example. Similar to many other viruses, measles spreads through coughs and sneezes and floats through the air in tiny droplets that stay airborne for up to two hours. If you have measles, you’re so contagious that 90% of all susceptible people that come close to you will be infected just by being in your vicinity. So if you have it and other, non- vaccinated people share a subway train or a classroom with you, it is highly likely that you will infect others. So in the end, being infected with measles erases the capacity of the immune system to protect you from the diseases that you overcame in the past. Even worse, a measles infection can wipe away the protection that you might have gained from other vaccines, since most vaccines create memory cells. Therefore, in the case of measles, what does not kill you makes you weaker, not stronger. Measles causes irreversible, long-term harm and it maims and kills children.

Not surprisingly, with a body full of chemicals, humans’ first line of defense against viruses involves chemical warfare:

If one of your cells realizes that it is infected by a virus, it immediately releases a number of different emergency cytokines to the cells surrounding it and to the immune system. There are a lot of different cytokines that are released in this situation and they do a lot of different things but here we want to highlight a very special class: Interferons. Interferons got their name from “interfere.” They are cytokines that are interfering with viruses … [W]hen cells pick up interferon molecules, it triggers different pathways that make them change their behavior drastically. One important thing to understand here is that at this point it is impossible for your body to deduct how many viruses are present, how many cells they have invaded, or how many cells are already producing new viruses in secret. So one of the first changes is for the cells to temporarily shut down protein production. Every moment of your life your cells are recycling and reconstructing their internal building blocks and materials to make sure every protein is in good shape and works as intended. So some interferons tell cells to chill out a bit and to slow down the production of new proteins. If a cell doesn’t build a lot of proteins, it can’t build a lot of virus proteins if it happens to be infected already. So basically just by ordering cells to slow down, interferon slows down the production of viruses considerably. Your soldier cells realize that they are dealing with a virus infection and that they need help on a larger scale, so they release another set of cytokines: Pyrogens. Pyrogen loosely translated means “the creator of heat,” an extremely fitting name in this case.

Pyrogens are what activate “fevers” within us:

Simply put, pyrogens are chemicals that cause fever. Fever is a systemic, body wide response that creates an environment that is unpleasant for pathogens and enables your immune cells to fight harder. It also is a strong motivator to lie down and rest, to save energy, and to give your own body and immune system the time they need to heal or to fight the infection. Pyrogens work in quite a cool way, in the sense that they directly affect your brain and make it do things. You probably have heard about the blood-brain barrier, an ingenious contraption that stops most cells and substances (and pathogens of course) from entering the very delicate tissues of your brain, to keep it safe from damage and disturbance. But there are regions of your brain where this barrier is partially penetrable by pyrogens. If they enter and interact with your brain they trigger a complex chain of events that basically cranks up the temperature by changing the internal thermostat of your body. Your brain cranks up the heat in two main ways: For one, it may generate more heat by inducing shivering, which is just your muscles contracting really quickly, which generates heat as a byproduct. And by making it harder for this heat to escape by contracting the blood vessels close to the surface of your body, which reduces the heat that can escape through your skin. This is also the reason why you can feel so cold when you have a fever—your skin is actually colder because your body is trying to really heat up your core and create unpleasant temperatures at the battlefield to make pathogens really unhappy. Most of the pathogens that like humans operate really well at our regular body temperature and the higher temperatures during fever make their lives much harder. Just imagine the difference between going for a run on a fresh spring morning in contrast to going for a run in the summer heat at noon without any shade. It is just that much more draining to do anything if you are too hot. So the increased body heat actually directly slows down the reproduction of viruses and bacteria and makes them more susceptible to your immune defenses. While not all mechanisms and effects on the immune system are known, generally the Innate and Adaptive Immune System work better through higher temperatures from fever in a variety of ways. Neutrophils are recruited faster, Macrophages and Dendritic Cells get a bit better at devouring enemies, Killer Cells kill better, antigen-presenting cells get better at presenting, T Cells have an easier time navigating the blood and lymph system. Just overall fever seems to activate the immune system to improve the ability to fight pathogens. How exactly does the actual temperature increase stress out pathogens and make our cells better at fighting them? Well, it all has to do with the proteins inside cells and how they work. To put it in a simplified way: Certain chemical reactions between proteins have a sort of optimal zone, a temperature range in which they are most efficient. By increasing the temperature in the body during fever, pathogens are forced to operate outside this optimal zone. Why does this not affect your cells but even helps them? Well, as we alluded to earlier, your animal cells are larger and more complex than for example bacteria cells. Your cells have more sophisticated mechanisms that protect them from higher temperatures, such as heat shock proteins. Also, your cells have more redundancies, if one of their internal mechanisms is impaired, they probably have alternative mechanisms that can take over. This is also the reason fever is helpful to your immune cells, since they can handle the heat, they can make use of the effect that higher temperatures tend to speed up certain reactions between proteins. So the complexity of your cells, in contrast to many microorganisms, makes them not suffer from fever but instead work more efficiently. Of course there is also a limit on how hot we can get and for how long before our systems break down too.

Dettmer then describes the delicate process by which our immune systems have evolved to kill our own cells when necessary to destroy viruses, but in a way that doesn’t cause unnecessary damage to the rest of us:

The best way to kill a lot of viruses is to destroy infected cells, and the viruses inside them. Let us pause for a moment to appreciate the magnitude of what we are talking about here. Your immune system needs to be able to kill your own cells. So, how does your immune system do this without causing horrible damage? … [T]o detect the danger of these corrupted cells, your immune system has developed an ingenious way that makes it possible for your cells to look inside other cells. In a nutshell: They do this by bringing the insides of cells to the outside. Wait, what? How does this work? … [Y]our immune cells can’t look through the solid membrane of your cell to check what kinds of proteins are being manufactured and if everything is all right. Nature solved this differently: It brings the story the proteins tell from the inside to the outside by using a very special molecule that works like a display window. As we said before, cells are constantly breaking down their proteins so their parts can be recycled and reused. The crucial thing here is that while this recycling happens, your cells pick a random selection of protein pieces and transport them to their membranes to display them on their surfaces. The MHC class I molecule [that is, the major histocompatibility complex of genes consisting of a linked set of genetic loci encoding many of the proteins involved in antigen presentation to T Cells] showcases these proteins to the outside world, just like a fancy display window would showcase a selection of the items the inside of a store has to offer. This way, the protein story of what is going on inside the cell can be told to the outside … [Y]our cells constantly showcase what is going on inside them, to assure the immune system that they are fine … If it recognizes things in the windows that should not be inside the cell, the infected cell will be killed. Another thing that is special about your cell display windows is that they are a badge of your individuality. If you don’t have an identical twin, it is very likely that your MHC class I molecules are unique to you specifically. They work the same in all healthy humans, but the proteins that make up the molecules have hundreds of slightly different shapes and they are a tiny bit different from person to person.

This uniqueness in our MHC proteins has the unfortunate side-effect of making organ transplants difficult:

This is incredibly important and unfortunate for one thing though: Organ transplantation. Because the MHC molecules are the place where your immune system can recognize that a cell on an organ that a generous person donated to you is not actually you. It is not self, it is other. And once other is recognized, your immune system will attack and kill the organ. Something that makes this scenario even more likely is the nature of organ transplantation … This is the unfortunate reason that after you receive a donated organ, you need to be on strong medication that suppresses your immune system for the rest of your life. To minimize the chance that your immune cells find the foreign MHC class I molecules and kill the cells carrying them. But of course this will leave you much, much more vulnerable to infections.

Let’s take a moment now and explore some of the other specialized types of cells in our immune system, which Dettmer describes:

[T]he Killer T Cell punctures the infected cell and inserts a special death signal, that is conveying a very specific order: Apoptosis, the controlled cell death we mentioned before already. This way the virus particles are neatly trapped in tiny packets of cell carcass and unable to do further damage until a hungry Macrophage passes by and consumes the remnants of the dead cell. This process is extremely efficient and the virus count drops harshly as thousands of Killer T Cells move through the battlefield, checking every cell they meet for infection, in a process that is called “serial killing.” Yes, this really is what it is called, praise where praise is due, immunologists nailed this term. Millions of viruses are destroyed before they get the chance to infect more victims. But also hundreds of thousands of infected civilian cells are ordered to kill themselves this way.

Natural Killer Cells do not look inside cells. No, instead they do something different: They check if a cell has MHC class I molecules. Nothing more, nothing less. This is solely to protect against one of the best anti–immune system tactics virus and cancer cells have. Generally cells that are either infected or unhealthy do not show MHC class I receptors in order to hide what is going on inside them. Many viruses force infected cells to stop showing them as part of their invasion strategy, and many cancer cells just stop putting up display windows, thus making them invisible to the antiviral immune response that we have shown thus far. The Adaptive Immune System is now suddenly harmless to these cells. In a very real way, without their display windows, the infected cells go dark and become impossible to detect. This is quite an effective tactic if you think about it—all a virus or cancer cell needs to do is to stop making a single molecule and boom, the extremely powerful response of the body is helpless. So the Natural Killer Cell just checks for one thing: Does a cell display a window? It does? “Great, please carry on, sir!” It doesn’t? “Please kill yourself immediately!” That’s right. The Natural Killer Cell is specifically looking for cells that do not share information about their insides, that don’t tell stories. The Natural Killer Cell removes the fatal flaw that otherwise could so easily become deadly. This is such a simple principle but has such a powerful effect.

Memory Cells. Approximately 100 billion living beings, 100 billion parts of YOU, sitting all over your body, doing nothing but remembering what you went through. Isn’t this a tiny bit poetic, the fact that being immune means that there is a part of you remembering your struggles and making you stronger by its presence? Memory cells are one of the main reasons why young children often die of diseases that their parents shake off easily: There are just not enough living memories in their tiny bodies yet, and so even smaller infections can spread and become a mortal danger. Their parents, with an Adaptive Immune System that is remembering thousands of invasions, can just rely on their living memory. And likewise, as we reach old age, more and more Memory Cells stop working as well as when they were younger or just call it quits, leaving us exposed in the last phase of our lives. If the enemy shows up ever again, it will immediately get attacked by these antibodies and probably has no chance to become a real danger again. This is an extremely efficient tactic and in fact a single drop of your blood contains about 13,000,000,000,000 Antibodies. Thirteen million, million. A protein memory of all the challenges you overcame in your life.

[T]here are also Memory B Cells … [The] reason why you are immune forever against so many diseases and pathogens you encountered in your life [is that] your Memory B Cells basically can activate directly, without going through all the complicated dances and confirmations that we showed throughout the book so far. They are shortcuts that can activate your Adaptive Immune System in a heartbeat.

In the next and final essay in this series, we’ll explore evidence for the reasonable exposure of ourselves and our kids to pathogens, in order to boost their immune systems, the so-called Hygiene Hypothesis.