It is hard not to think of our immune defenses, in military terms. The host defense system has three elements. First, recognition systems that detect the invasion of something foreign. Second, the control and command systems, which take that information and deploy and coordinate the weapons systems. And finally, there are the weapons themselves. The effector cells in the molecules, that actually attack the invader. Human immune systems are incredibly effective. Without them, we would die quickly from overwhelming infections. Yet we still get infected. Why isn't immunity better? One reason, is that pathogens have evolved a staggering array of methods to get round our immunity. That's unsurprising, their very existence is depends on their ability to break in. Pathogens do this, by sabotaging all three elements of our immune defenses. There are pathogens that try to avoid being detected. Some do this by camouflaging themselves with bits of host. Others hide in cells or tissues, where immune surveillance is poor. Some even hide in the cells of the immune system, themselves. Other don't worry about being detected, instead they change identity continually. A slippery moving target. I'll say more about this strategy in a moment, because it's a very important reason why many diseases can't be controlled. And then there are pathogens, that actively interfere with the command and control systems of immunity. What they do is produce molecules, or even induce their hosts to produce molecules, which interfere with the complex processes involved in regulating an immune response. Take worms for instance. They can live in your body for decades or longer, even though they are often many inches in length, and clearly very non-self. Some of them survive, because they secrete substances which manipulate the immune response from weapons systems that are good at killing worms, towards weapons systems that do almost nothing to harm worms. Other worms secrete substances that turn down the whole immune response. And then there are pathogens, that attack the weapons systems themselves. Some eat or disable antibodies, others produce toxins which kill immune cells, sometimes by making the immune cells commit suicide. Other toxins interfere with host cell movement. Others produce decoy molecules, which distract from the real target, much like using flares to distract heat seeking missiles. In fact, all of this attack and defense, really is like an arms race. Pathogens evolve new ways to evade immunity. Hosts evolve new defenses to that attack, or new methods of fighting back. And this molecular and cellular warfare, is ceaseless and ongoing. It is almost certainly the reason mammalian immune systems, are so complex. Pathogens are always looking for weak points. Hosts are always looking to try to shore up the in the latest breach. Okay, so this is the high altitude view of immune invasion. Now I want to talk to you a little more in depth, about those pathogens that invade immunity by changing their identity. These include some very important diseases like Malaria, Sleeping Sickness, and Flu. Host defense systems, have to distinguish self from non-self. They do this by recognizing the molecules on the surface of pathogens, or on the surface of the cell a pathogen is in. Which is different from molecules which we produce ourselves. The molecules that are recognized by T cells and antibodies, are called epitopes. And together the recognized modules constitute the antigenic surface. Over a 100 years ago, Paul Ehrlich, one of the founders of Immunology, reported during his Nobel Prize lecture his work on African Trypanasomes. These are single-cell parasites which cause Sleeping Sickness. He discovered that what he called antibody receptors, would disappear even though the parasites were still there. We now know this as Antigenic variation. The parasites have one type of surface coat, just as antibodies against that coat are building up, the parasites change into a different coat so it slips away. And then just as the immune system is retooling to deal with that new coat, the parasite changes coat again and so on. This immune evasion strategy of constant coat change, enables the parasites to persist for many months in a person. We now know an awful lot about how the parasites are able to change coats. They have a large number of genes coding for these coats, and they can turn them on and off at will. The parasites can even create new gene sequences during the course of an infection, so that code types can be continually generated even after the original repertoire is exhausted. This ability of the parasite to stay one step ahead of effective antibody control, is why we do not have a vaccine against Sleeping Sickness. It is not a problem to produce antibodies against one coat, but to create antibodies against thousands of possible coats, has so far proved impossible. This is also true for Malaria parasites. Each parasite has 60 genes it can use to code for different coats, but it is not the same 60 for all Malaria parasites. The repertoire in any population might be thousands. To my mind, the antigen repertoire of the parasites that cause Malaria and Sleeping Sickness. How the repertoires evolved, and how they are so carefully orchestrated, is one of the most fascinating basic science challenges in Microbiology. Flu does things different. It changes things too, it changes continuously. You know that. It is the reason you need to keep vaccines against seasonal flu. A vaccine that is good one year, doesn't work the next, because the flu virus has moved on. It has acquired different antigens. But in contrast to Malaria and Sleeping sickness, it does not have a genetically encode repertoire of genes to draw on. Instead it changes surface molecules by mutation. The genes encoded at surface molecules mutate at random, like all genes. And sometimes the mutant antigen is sufficiently different, that it is not properly recognized by antibodies directed against the product of the unmutated gene. When that happens, the mutant can escape immunity and so spread in the population. This is called antigenic drift, and it generates an evolutionary tree which looks like this. Continual gradual change, as a result of ongoing co-evolution between the virus and our immune system. Flu can also do bigger more radical changes, called antigenic shift. Which happen when different genetic segments of the virus re-assort, generating new combinations of the NH antigens that you hear about in the news. H5N1, H7N5, and so on. This happened in March 2013 in China, where a new Flu virus appeared. This infects poultry, and has so far cost over $6 billion, and it is not yet under control. In the first three months, the virus killed 36 people. It was able to get into people because it was a new strain, and so able to get around the antibodies that humanity has to strains long past. Without that random genetic shuffle, the virus would die out. But with it comes the ability of, to evade our immunity. And that is why the 1918 Spanish Flu, was able to kill more people then died in the first World War.