When strolling through the streets of Utrecht, the town in the Netherlands that I live in, you sometimes hear people using ‘Tering’ as a swear word. What actually most people using this word don’t know, is that it dates back to an ancient disease, which has been found in 4000-year-old skeletons. Such an old disease should have also been eradicated a long time ago already, right?
Actually no, it is not at all. ‘Tering’ refers to tuberculosis, or in short TB, and there are still 10 million new cases of active tuberculosis each year worldwide. This means that every 6 seconds, someone develops TB somewhere in the world, and every 21 seconds someone dies from this disease.
Tuberculosis was already present in the Roman and Greek civilizations, and great thinkers of that time described it as phthisis or consumption. The term ‘consumption’ came from the idea that the disease consumed people, leaving them weak and emaciated. Often TB was also referred to as ‘Captain of all these men of death’, illustrating the major wave of deaths it caused. There grew a great stigma and fear around TB, because not only did this disease cause death to so many, but people also did not understand how they would develop it.
It was only during the first half of the 19th century, that people really started to understand TB. On 24 March 1882, German doctor Robert Koch discovered the bacteria that cause the disease: Mycobacterium tuberculosis (Mtb in short). Mtb is spread from one person to another through tiny droplets in the air (the good old aerosols, which we’ve heard a lot about during COVID times) while talking, coughing, or singing. Initially, Mtb mainly affects the lungs, but from there it can spread through the whole body. In the years since its discovery in 1882, this bacterium has been extensively researched, making it one of history's most studied bugs. Nevertheless, Mycobacterium tuberculosis still poses many mysteries and unanswered questions that have not yet been revealed.
With 140 years of research behind us, what do we know about this bacterium? And what makes it so successful - at least from a bacterial point of view - that it lasts throughout centuries, despite our best efforts to eliminate the bug?
Actually, by looking at illustrations of Mycobacterium tuberculosis (see figure), you can already ‘see’ that this one seems a bit different than the majority of other bacteria (or if you don’t notice, no worries, you will see it after having read the rest of this blog). Contradictory, for our bodies, this bacterium is not at all easy to ‘see’ - you will notice after reading further…
Let’s start at the beginning. You can imagine that when you want to keep things inside, you need something that keeps things inside. And not unimportantly, also keeps the outside outside. Looking at your own body, your skin is a great example for this. Skin is the perfect barrier that keeps all your organs inside, while keeping dirt and potential invaders outside. In fact, bacteria have something similar. But for bacteria, their ‘skin’ is called a cell wall.
Because the cell wall of bacteria is on their outside – their ‘skin’ – that is the part of the bacteria that our bodies can recognize. This makes sense, as this is the part of the bacteria that is in full contact with the human body – it’s the only part of the bacteria that our immune systems can ‘see’. So, what exactly happens when invading bacteria enter your body? Well, the immune system immediately senses that those little bugs are not part of your own body, mostly due to their cell wall ‘looking’ different from the parts of your body. A subsequent attack by the immune system follows, causing the bacteria to die, and the peace returns. And this is all the result of the initial response to the observed cell wall!
For Mycobacterium tuberculosis, however, it is a bit of a different story…
Mycobacteria – including Mtb - have a unique, very thick, waxy cell wall. Let me explain. Imagine pouring candle wax onto a very defined object. When solidified, the structures that were first very clear and easy to distinguish, are now covered in candle wax and turned into a big undefined block. You cannot feel or see any structures that were there before. This is actually how you can imagine the cell wall of Mycobacteria: a thick wax layer like candle wax, which covers the defined recognizable structures of the bacteria. Because of this, the human body has a hard time recognizing Mycobacterium tuberculosis as being an actual bacterium, a foreign invader. And as a result, it is difficult to kill…
Okay M. tuberculosis, I got you, very smart to build such a big waxy wall around you so that you’re particularly hard to see, and the body cannot see what you are hiding. But imagine if you coated yourself in wax - your eyes, nose, and mouth would be clogged! How would you eat?
Turns out, Mtb might have thought of that…
So, there has to be some entry to the inside of those bacteria, right? If you think back to the analogy of the candle wax layer, you can imagine it is really hard to take the wax off of the object. And that doesn’t even get into the issue that this would uncover the whole defined structure of the object, something that Mycobacterium tuberculosis definitely does not want. You might have guessed it… Mtb has found a way to avoid taking big parts of his waxy coat off, and still be able to take up food from its environment. Recently, it has been found that the wax-like layer of the cell wall possesses little tiny gateways, through which the bacteria can selectively take up small nutrients from the environment. In this way, it can still hide its features under a cell wall as dense as a block of candle wax. Apparently, Mtb has created a perfect balance between staying nearly invisible and isolating itself, while still staying in contact with the environment for its own benefit.
But actually, I’ve only told you one part of the story… There are, in fact, particular structures that do stick out of the waxy layer of the cell wall. Those structures of Mtb are recognized by the first guards of the immune system: macrophages. Those macrophages engulf the Mtb bacteria and will eventually try to kill it…
Wait, what? I hear your question: why would Mtb put so much effort into creating a thick waxy wall, so it escapes the recognition by the immune system, but at the same time, stick things out that partially undo this masking effect? And as a result, still fall into the trap of the immune system? Weird, right?
Of course, Mtb would not do it without a reason. Those structures that stick out will actually lead the bacteria to the place it really wants to be: inside those macrophages! When being engulfed by macrophages, the macrophages are totally ready to destroy the invader… but Mtb has another card up its sleeve! Mycobacterium tuberculosis uses other small channels to secrete proteins that block macrophages from doing their job: killing the bug! So, next to those ‘in’ channels for food take-up, Mtb also has ‘out’ channels to influence the behaviour and actions of macrophages. Within the macrophage, Mtb has abundant access to everything its heart desires: a shelter with lots of food (see the part that is zoomed-in in the figure). As a result, it can live, hidden inside the macrophages, happily ever after! Mission ‘becoming invisible’ accomplished again!
To sum up, Mycobacterium tuberculosis still leaves us with many questions unanswered, as it did in Koch’s time. Nevertheless, we have also gained a lot of knowledge since his discovery. Today, we’ve seen at least some reasons why Mtb manages to stay with(in) us for such a long time already. It is just super smart. And in this post, I only pointed out a few of the many manipulatory mechanisms of this bacterium (many to come in the upcoming blogs). Because it has co-evolved with us for centuries, it knows our weak spots and acts on them. We have seen that, although Mycobacterium tuberculosis might ‘look’ different because of its cell wall, this feature in particular makes it nearly invisible to the body. On top of that, Mtb adds an extra layer of invisibility, by hiding inside the gatekeepers of our immune system: macrophages. So, this time’s takeaway: although Mtb ‘looks’ different from other bacteria under a microscope to our eyes, it’s all a trick to become invisible to our immune systems – and what we don’t see, we can’t catch.
Hope to see you in the next post of the mini-series about Mycobacterium tuberculosis! Next week, we dive deeper into what happens after Mtb bacteria hijack the macrophages. The Mtb story is not finished yet.