Monday, February 13, 2012

The War of the Immune Worlds

The previous post in this series can be found here.

Another blog post, another month when the immune war wages on inside all of us; the pathogenic siege perpetually held at bay by your tireless immune soldiers and tacticians. In my previous posts I’ve talked about the organisation of the immune system and how it makes decisions about which weapons to employ in its endless fight. We may feel blessed to have such a powerful army at our backs but we have, in fact, earned it! Not on a personal level but as a species, and as the species that preceded Homo sapiens, and those that came before them stretching back long into the depths of evolutionary history. In ‘The War of the Worlds’, H.G. Wells writes of how the Martian invaders are felled by simple infection rather than by any of Man’s weapons:

“ ...the Martians--dead!--slain by the putrefactive and disease bacteria against which their systems were unprepared; slain as the red weed was being slain; slain, after all man's devices had failed, by the humblest things that God, in his wisdom, has put upon this earth.

Tripods, perhaps, but you won't get far without T cells!
For so it had come about, as indeed I and many men might have foreseen had not terror and disaster blinded our minds. These germs of disease have taken toll of humanity since the beginning of things--taken toll of our prehuman ancestors since life began here. But by virtue of this natural selection of our kind we have developed resisting power; to no germs do we succumb without a struggle, and to many--those that cause putrefaction in dead matter, for instance--our living frames are altogether immune. ... By the toll of a billion deaths Man has bought his birthright of the Earth, and it is his against all comers; it would still be his were the Martians ten times as mighty as they are. For neither do men live nor die in vain.”

We have an immune system because we need one, in the same way we have lungs because we need them. I have mentioned briefly before how individuals unfortunate enough to suffer from any of various immune deficiencies often die early in life or are severely debilitated throughout. If, as a species, we lacked this defence, we would be as the Martians in Wells’s novel and would most likely not survive a single generation. Natural selection has rewarded those individuals with more resilient defences and punished those without. From this we have evolved the elite varied military that I have previously described. The price we have paid for this is heavy : “the toll of a billion deaths” wrote Wells. However, we cannot be complacent in our immune invulnerability – to turn to H.G. Well again:

“Yet across the gulf of space, minds that are to our minds as ours are to those of the beasts that perish, intellects vast and cool and unsympathetic, regarded this Earth with envious eyes, and slowly and surely drew their plans against us.”

Sure enough, we are being surveyed and assessed, our defences tested and our weaknesses discovered. The pathogens that launch their never-ending onslaught regard the material of our bodies with envious eyes, and while they do not have the intellects of fictional Martians, they have one substantial advantage: numbers. We may have lost billions in our efforts to repel the invaders, but they have lost trillions of trillions, and in the process have developed sophisticated strategies to counteract or evade our grandest defences. The ensuing immune arms race between host and pathogen has churned out countless ingenious mechanisms for both invasion and repulsion of invasion. I’ve talked previously about how we repel pathogens, so in this post I will run through a small sample of the lengths pathogens to go to survive our immune army. 

Armour – from chainmail to bullet-proof vests

Among the most basic defences that pathogens such as bacteria have is a cell wall. This is simply armour to protect against the weapons of the body – it acts as a shield to chemical attacks and hides the vulnerable parts of the pathogen from exposure to potentially devastating antibodies or complement components. The cell wall was one of the earliest defences to evolve in pathogens for the simple reason that it is not complex and is easy to evolve!  However, the degree of sophistication varies from one pathogen to the next. Many bacteria have only minimal shielding made from the most basic chemical components, which provide them some protection but are not relied upon heavily in the course of battle. Others are entrenched within the molecular equivalents of tanks, equipped with sophisticated anti-weaponry equipment. Staphylococcus aureus is a common human pathogen that is usually fairly innocuous but can cause severe infection if it manages to (the famous MRSA is a strain of S. aureus). We’re going to come across S. aureus a lot over the course of this post because it’s a pretty smart bug that has lots of interesting tactics. In the case of its armour, it’s pretty beefed! Its thick peptidoglycan cell wall has been chemically modified to be more resistant to lysozymes, the enzymatic weapons that macrophages use to destroy engulfed pathogens. Moreover, S. aureus also chemically modifies the lipid components of its cell membrane to make them less negatively charged. This makes them less attractive to a group of molecules called defensins that are secreted by immune cells to damage the membranes of invaders and, almost literally, spill their guts onto the battlefield.

Resisting interrogation and torture

Armour can get you only so far, though. What if you are captured by the defending forces and interrogated for all you know about your comrades in arms? This is what cells such as dendritic cells do when they present antigen to helper and killer T cells, as I discussed in an earlier post. Any pathogen that can resist interrogation will not only survive to fight another day, but will withhold vital tactical information from the enemy. Natural selection has thrown up a number of ways for pathogens to resist this fate. A common tactic is to attempt to avoid capture in the first place; many bacteria secrete molecules that actively disrupt a protein called actin in the cells of the host. Actin is responsible for the shape of cells as it acts as the cellular cytoskeleton. When an immune cell engulfs a pathogen, its actin rearranges itself to for a shape that surrounds and then encloses the pathogen. Pathogens that can disturb this process can flee the scene while their would-be captors are left helpless. They sometime achieve this by rewiring the attacking cell’s regulatory network that controls actin shape; for example, some species of Yersinia bacteria inject immune cells with a protein called YopH that changes the chemical signals attached to important cytoskeletal proteins and so prevents actin reorganisation. This is the immune equivalent of shooting out the tyres of the pursuing vehicle in an attempt to get away!

Other pathogens don’t evade capture, but instead lie in wait to make their escape before they can be destroyed. Shigella bacteria secrete enzymes called lysins that burst the cellular compartments in which they are being held – like blowing out the wall of a prison! The bacteria are then free to invade the rest of the cell and hijack it for their own use.

A Shigella prison break inside a human cell (bacteria are the rod-like pink objects, the human cells are everywhere)

Those hardy pathogens that have no fear of death meet the immune interrogation head-on! These brave souls do not evade capture or escape, but instead try to undermine the techniques used to destroy them within the immune cell. One such technique is the use of reactive oxygen species  (or ROS) by immune cells to damage pathogens on a chemical level. ROS are molecules that contain a highly-reactive oxygen atom, such as peroxides or oxygen ions. They react irreversibly with almost all organic molecules and basically just mess them up so they don’t work anymore. The next time you see a food being advertised as ‘rich in antioxidants’, it is against these ROS that you will apparently be protected! Immune cells such as macrophages have enzymes that are designed to generate ROS in the compartments where captured pathogens are being held and so help to destroy them. S. aureus is one pathogen that doesn’t take this lying down. It has two enzymes, superoxide dismutase and methionine sulphoxide, that reverse some of the damage done by ROS on its chemical structure. It also has carotenoid pigments that mop up some of the ROS, and also give it its lovely yellow colour. Some viruses directly subvert the manufacture of ROS within the cells by interfering with the signalling networks that control the activity of the enzyme nitric oxide synthase that is vital for their production.

Undercover operatives – hiding behind enemy lines

An alternative to resisting responses is to try to evade them altogether. Such a deception is not easy and comes with its costs. Generally speaking, pathogens that evade detection cannot multiply to the same extent as those that meet it head on, as to do so would blow their cover. Instead they tend to bide their time and propagate slowly and cautiously. Many viruses, including herpes simplex virus or Epstein-Barr virus, have a complex life cycle in which they are completely latent for perhaps years at a time. During this period the virus does not exist in a physical sense at all and so can’t be detected or destroyed! Instead, it has inserted the genes for its manufacture into the host cells and left behind molecular sensors that detect when the time is right for the virus to rise from the ashes to infect more cells – usually when the carrier cell is undergoing stress and so may well die, taking the virus with it. If you have ever had a coldsore then I’m afraid you still have the virus that caused it, it has just become part of you now! In fact, the human genome is littered with seemingly independent stretches of DNA known as ‘transposons’, some of which are thought to be the remnants of viruses that got cosy in their latent phase and so never left; shedding their protein-encoding genes and existing as self-protecting strings of DNA. We are all in part virus – something to remember the next time you bemoan your cold!

Viruses are particularly good at evading the immune system, primarily because they don’t have many other options. They don’t have the manufacturing capacity of bacteria and their genomes have to be kept compact for efficient replication. Another tactic used by some viruses, to spread directly from one infected cell to the next, without ever being exposed to the antibodies that might be circulating around in the blood. By far the most effective viral strategy, however, is variability. All of our adaptive immune defence relies on the principle that there must be something common to all of the invading pathogens that can be targeted. Viruses like influenza or the rhinoviruses that cause the common cold are hyper-mutatable and so mutate significantly as they spread throughout the population, meaning that your immunity to it is only good until it changes, and that governments have to stock up on fresh batches of ‘flu vaccines each winter. The mutations that occur are limited to the exposed regions of the virus, those areas that are most likely to be targeted by antibodies or T cell receptors.

The undeniable master of such disguises has to be HIV. HIV has a double-shield system: firstly, when it buds off from infected cells it takes with it a bubble of membrane that comes from the host cell. This membrane surrounds the whole virus and appears to immune system to be nothing out of the ordinary – just a normal bit of cell membrane. In this state the virus is relatively invulnerable to the innate immune system’s attacks as these usually target pathogenic membranes or cell walls. The second level of HIV’s protection is its so-called dynamic glycan-shield. It needs this because in order to be able to infect its target cells, HIV must present some of its own proteins at its surface. These might make it vulnerable to attack by antibodies, and so it has constructed these proteins out of hypervariable regions that are constantly changing from one virus particle to the next. The host immune system finds it impossible to keep up and so is unable to launch antibodies against all of the possible combinations of HIV protein. Moreover, the virus protects those parts of the protein that must remain constant for it to retain its function. This is where the ‘glycan’ part of the shield comes in, because the variable regions are covered with sites that bind to complex sugar structures that are common on the proteins of higher organisms such as humans. These sugars physically block the binding of antibodies and are different for each HIV particle. Moreover, they are indistinguishable from normal host glycans and so don’t evoke any attention from the body’s defences. It is, in many ways, a perfect disguise, and is the reason why HIV vaccines have been poor at best and usually useless.

An HIV virion - each as unique as a snowflake.

Guerrilla fighters – undermining local defences

Those pathogens that do not hide from the immune system sometimes launch sting operations against the immune patrols within the area of the body that they have invaded. S. aureus is one such guerrilla soldier with numerous ways to outwit nearby immune cells. For example, neutrophils are vitally important footsoldiers in clearing bacterial infection. When an area becomes infected, pathogen antigens trigger the presentation of a molecule called ICAM-1 at the surface of the endothelial cells that line the vessels in that area. ICAM-1 binds to LFA-1 on neutrophils and so allows them to anchor themselves in the affected area and mop up the bacteria. S. aureus has other ideas and so secretes a protein called Eap that binds to ICAM-1 and so blocks its binding to LFA-1. The helpless neutrophils are then unable to stop at their desired location and instead zip helplessly on while the bacteria get on with their business. Even if they do manage to disembark correctly, the neutrophils may not be able to activate fully because S. aureus also secretes a protein called CHIPS which binds to and inactivates two key receptors on the surface of neutrophils that are required for full activation.

Missile defence systems – taking out the artillery  

Antibodies are the laser-guided missiles of the immune system; cruising around the body and latching onto pathogens to either target them for destruction or directly neutralise them. The pathogenic response to these has been to develop secretable enzymes that specifically degrade the various classes of antibody that might be encountered. This is particularly common in bacteria and helminths that infect the gastrointestinal tract, where the missile of choice is IgA class antibodies. IgA proteases are so abundant in the gut that IgA has to be produced on a massive scale to counteract it: roughly 5 grams are produced by your body’s munitions factories every day, which equates to about 20,000,000,000,000,000,000 rounds of IgA artillery!

Active attack – the best defence is a good offence

The attack-based strategies of pathogens that we’ve looked at so far can be considered as small-scale localised attacks on the immediate defences. However some pathogens think far bigger, realising that in an army organisation in everything, and that if you can disrupt that then you can turn the tide of wars. One way to do this is to sever the communications linking the different divisions of the immune system. Many pathogens secrete proteins that bind to and inactive the chemical signals that immune cells use to communicate, whereas others cut off the communication between the innate and adaptive immune systems by secreting molecules that inhibit the complement system of targeting pathogens for destruction.

Another tactic is to fight back with highly sophisticated weaponry that kills the cells that act as soldiers in the body’s defences. Our old friend S. aureus, for example, releases a protein known as protein A that binds to the antigen receptor found on B cells. This fools the B cell into thinking that it is receiving  instructions from the chain of command that instruct it to commit suicide and, as any good soldier would, it obeys orders. Depleting B cell troop numbers gives the bacteria better odds of surviving any subsequent artillery fire that might be coming their way. S. aureus also secretes a number of molecules known as leukotoxins that bind to host cells and cause them to lyse open and die. This is primarily targeted at immune cells and so further weakens host defences. A more direct way to destroy immune cells is just to infect and destroy them! HIV is so devastating because it infects helper T cells, which, as we’ve seen before, are the tactical cornerstone of the immune response. HIV does this by binding specifically to a protein called CD4 that is only expressed on those cells. Along with its glycoprotein shield, this gives HIV a nearly perfect strategy of immune evasion, which is why it is still so shattering to those infected.

An even more ingenious strategy is to subvert the trust within the enemy – the classic ‘divide and conquer’ approach. This is achieved by a number of pathogens through the release of a class of proteins known as ‘superantigens’. These bind indiscriminately to the MHC class molecules on antigen-presenting cells, and link then tightly to the T cell receptor on T cells. This causes a massive immune response as pretty much every T cell affected suddenly thinks that it has been called to arms! The resulting cytokine ‘storm’, as it is known, is complete immune chaos, where chemical signals shoot all over the place and no one division seems to know who’s in charge! This can actually be fatal, as is the case in toxic shock syndrome, but that is not generally the pathogen’s aim. Instead, they want to stir up mistrust within the immune system, such that when the initial confusion has died down the immune Gestapo are suspicious of everyone as an insurgent. As a result, perfectly innocent T cells are ordered to stand down and await death in a process known as ‘anergy’ that is usually used to prevent T cells from attacking the body. By tricking the immune police into using their emergency powers, the pathogen can rest easy as otherwise deadly T cells lie hopelessly impotent.

Next time

Well done for making it to the end of this one - it's been a bit of a marathon but you made it! My next post will be somewhat shorter and will look at some of the cutting edge research that is going on at the very basics of immunology, and how that work is being translated into clinical applications.

The next post in this series can be found here.


  1. It would seem that this story has more twists and turns, espionage and counter-espionage, that "Spooks". It's fascinating reading; I'm looking forward to the next episode, which hopefully will make me sleep easier at night, without worrying about all those battles being fought inside me!

  2. Thanks, John, I'm glad you find it interesting! I wish I could write about all of the tricks that bugs use (this is the very, very small tip of the iceberg) - the ingenuity and sophistication is incredible!

  3. James, I have questions:

    - Those enzymes that reverse the damage of oxidisation in the pathogen, can we use them to reverse the oxidisation in, for example, the Shaun Hotchkiss. I want to stop aging, that's all.
    - Do our immune systems, or anything else, ever take part in any sort of deliberate, tactical evolution? What I mean is, instead of stuff mutating by accident and then just getting passed on to the offspring, is there any evolved mechanism that deliberately tries stuff and keeps the good changes? For example, if a pathogen had a particularly good new defence, is there something in the immune system that might "think" about how to adapt, or even steal the idea from the pathogen? Or is it all down to chance?

    It seems like HIV attacking our immune system is both clever and dangerous for the virus. If our immune system is weaker, it helps HIV spread, but it also helps everything else spread. HIV won't kill us, so it thinks it is being clever, but some other bugger will, and it's no good to HIV if we're dead. Then again, HIV seems to be doing a pretty good job of not suffering from this problem, so it probably deserves a little bit of credit for this idea.