Microorganisms have several major advantages over us, such as their incredibly huge numbers and their ability to adapt very rapidly (bacteria can create offspring every 20 minutes). Imagine a bowl of pudding that is left outside the refrigerator: if it initially contains only 50 bacteria (which is usually considered a minute amount that will not easily make us sick), then after 3 hours at room temperature there may be already 25.000 bacteria teeming in the pudding and another 2 hours later over 1.5 million !
In order to get an impression of the staggering numbers of microorganisms around us, consider that each human carries a huge population around on and within our bodies. This population of microbes is called 'the microbiome', and consists of 10 times more individual organisms than the number of cells we have in our body and a gene pool of 100 times bigger than our human genes. The average human being carries less than a kilogram of microbes around. And to be fair to these organisms: without them we would not be able to survive, since they work closely together with us to process our food, to produce vitamines that we are unable to synthesize ourselves and without which we would die.
The microbiome also makes sure that most of the living space for microorganisms in our bodies is already occupied, so that invading pathogens will meet with a lot of competition from our 'friendly microbes'.
In the chapter of applied immunology we already explained the major lines of defenses within our immune systems. At the start of this page we have seen how fast microbes can multiply and with each multiplication step, some genetic errors may occur, some of which will kill the microbe, yet in rare occasions the genetic change makes the microbe stronger against our defenses. Such offspring will have a better chance of surviving in our body, and pass their new genetic trait to millions of offspring.
One way to evade our defenses is to avoid being detected. Some microbes develop the ability to cover themselves with bits of our own natural antigens, to make our defenses believe that they are not foreign, yet a regular part of our body. Others are able to hide in cells and tissues where our immune surveillance cannot reach them so well. Some even hide in the cells of the immune system themselves (such as HIV). Others do not worry so much of being detected, because they continuously change their coat with new antigens, so that our immune system has to build up new memory (such as influenza virus).
For example, take a look at worms that can live in our bodies for up to decades. They are not really small (several inches in length) and they are clearly foreign to our body. Some of them produce chemicals that render our defenses harmless.
Then we have pathogens that attack our weapons: some destroy our antibodies, some kill our T-cells or B-cells. Some produce decoys, that keep our immune response busy, while the real pathogen can work undisturbed.
Diseases such as influenza, malaria and sleeping sickness all are caused by pathogens that are quite able to change their antigenic fingerprint and fool our defense mechanism. Our immune system has to recognize 'self' from 'non-self', by identifying the antigens on the surface of pathogens. It was already discovered early that the parasite that causes sleeping sickness (Tryponasoma brucei) is able to change the antigens on it's surface, hence evading a targeted immune response. This parasite is able to do that, by switching on and off certain parts of its genome that code for the various antigens and even by further changing their genetic code during the infection to create even more variant antigens. This is also the reason why we have not been able to develop an effective vaccine against sleeping sickness. The same is true for malaria parasites. This poses one of the great challenges in infectiology science.
The influenza virus approaches its identity changes differently. It does not have a collection of different genes for different antigens, yet instead it changes the antigens through gradual mutation from one generation to the next. This causes the influenza antigen to slowly 'drift' out of the reach of our immunological memory. This is also the reason why we need a new influenza vaccine against seasonal flu each year.
Then there is one more trick that Influenza virus has up its sleeve: it has the ability to exchange its entire set of genes that code for one particular class of antigens with another influenza virus. When that happens, the antigenic fingerprint of flu 'shifts' instantly to another. Such a shift could lead to an entirely new type of flu virus that the world has not yet seen: this could trigger a worldwide new epidemic, or pan-demic. Without such drastic shifts of the major antigenic proteins, the flu virus would have huge problems to keep circulating.