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  • Merel Sijbranda

The fortress of Mycobacterium tuberculosis

Last November, I was in beautiful, sunny Lisbon, and as my parents and I looked back at the pictures we took there, something caught my eye. One of the iconic yellow trams shuttling between the tourist hotspots in the city had ‘TBC’ written on its front. TBC is, at least in Dutch (and in other languages as well, I noticed), the common abbreviation for tuberculosis. I myself am not an expert in graffiti slang, so I’m not sure if the creator of this graffiti was really referring to the disease tuberculosis (probably not), but my biomedical brain immediately linked it to this illness. For me, this was just a little reminder that tuberculosis is still incorporated into everyday life.

My dad took this photo of one of the yellow trams in Lisbon

Although the death rate of TB has dropped enormously in the last centuries, this yellow tram was only one sign that tuberculosis still is very present nowadays. The ‘Captain of all these men of death’ nickname might perhaps not be the most accurate anymore, but TB is still the second top killer in the category of infectious diseases (behind COVID-19), claiming 1.5 billion lives each year. And even more strikingly, according to the latest data almost 1 in 4 people in the world are infected with Mycobacterium tuberculosis (Mtb). That is a quarter of the world’s population… a quarter. Let that sink in. And who is noticing it? At least, not a lot of us… (including me before starting this project).

The question that arises is, why is tuberculosis so present but still so unseen?

It all comes down to how Mtb interacts with your body, and how your body reacts to Mtb. So, I will take you on a journey through the life of Mtb again. We are continuing the story where we left off the last time (if you didn’t read the first blog, it’s here).

Do you remember the contented Mtb, hiding inside its shelter - the macrophage? Seems perfectly fine for Mtb, don’t you think? But from our human perspective, it is not at all beneficial. In fact, this is not where the Mtb life story ends.

We know by now that Mtb is good at sneaking into the first gatekeepers of our immune system – the macrophages – and disabling those cells to kill them. Interestingly, population data shows us that only 5-10% of people infected with Mtb develop actual TB disease. This means that even if Mtb gets into our immune cells, it might not have any immediate effect. So, there has to be more to the story of Mtb infection than we know at this point.

Let’s see, can we explain this low rate of disease development, even in people who get infected?

Well, to begin, Mtb likes it so much within macrophages - there’s plenty of food - that it starts growing and reproducing itself inside our cells. In most cases, the macrophages become kind of ‘nauseous’ from this feeling of something growing inside them, which they are not able to kill. So, what happens next?

Eventually, most infected macrophages die… However, because the Mtb bacteria just had their feast and are still feeling good when the macrophages die, they come out alive and kicking. Suddenly the immune system can sense the bacteria out and about in your body again. In response, new macrophages are called into the crime scene to do their duty. But unfortunately, a similar fate befalls them. The macrophages take up the bug, thinking they can kill it. But, Mtb counteracts and designates the macrophage as its shelter, where it starts growing and reproducing. Ultimately, most macrophages die and Mtb bacteria again go free. Same story over and over again.

But remember, most people who get infected with Mtb don’t ever develop any noticeable disease. So, there must be something that the body can do to stop the annoying Mtb from growing and spreading, right?

Fortunately, the short answer is: YES, in most humans, there is. I’ll explain. To succeed, the immune system calls in other types of immune cells. Those cells line up and surround the infected macrophages and Mtb bacteria, walling off the harmful Mtb bugs from spreading further. Let me clarify this with a real-life example. You can imagine the lining up of cells as the immune system building a fortress. And more specifically, a dirty medieval fortress with high brick walls, locking away pathetic prisoners. In the body of a TB patient, these prisoners are the infected macrophages and Mycobacterium tuberculosis bacteria. The surrounding walls of the fortress are made of burly immune cells. So that’s it, a fortress built out of strong immune cells with imprisoned mischievous Mtb bacteria within, inside the lungs of TB patients. Scientists call this fortress a “granuloma”.

Because there are hardly any gates to give access to the fortress – the granuloma -, and the walls composed of cells are firm and big, the inside of the fortress becomes desolate. Most left-over macrophages die, turning into a sticky, soft, white substance, which looks a bit like… cheese! Fun fact: the official scientific name for this desolated fortress is a “caseous granuloma”. Caseous literally meaning cheesy. Sounds like a lovely place, am I right? (sarcasm)

And what is left over besides this?

Of course, the stubborn Mycobacterium tuberculosis… But there is some good news: the bug becomes less harmful than we’ve seen before. Because the macrophages die, there is less food available for the bug population inside its fortress. And also, since the fortress is so secluded, there is very little exchange possible with outside of the fortress. As a result, the bacteria go into a sort of ‘sleepy’ state. Call it the energy-saving mode. Being in this sleepy state, the Mtb does not try its hardest to get out of the fortress. It chooses its battles. And once again, it reverts back to its best trick: HIDING. But this time, instead of hiding within living macrophages, it hides inside its filthy, cheesy, pesky medieval fortress.

However, this fortress does do its job: Mtb stays within the big walls. Like real bricks-and-mortar fortresses, not all of these immune fortresses are exactly the same, but from our immune system’s point of view, they all have the same purpose: keeping Mtb trapped within. In most TB patients, these fortresses containing Mtb will stay in their lungs for their entire lifetime. And actually, this is not that bad of a situation for either the human or the Mtb. The human and the bugs have reached some sort of agreement: Mtb bacteria can stay in the body, as long as they remain sleepy inside their fortress, and the body is not bothered by the bugs. Problem solved, right?

At least, in most cases, the problem is solved. Around 90% of the people getting infected with Mtb do not get sick at all – they’ll never develop active TB disease. However, in some cases (5-10%) the Mtb bacteria can wake up from their “sleepy” state and try their ultimate best to break through the walls of the fortress. And this is a problem.

Can you think of any reasons why the walls of the fortress would not serve as well as they used to? I will give you one example. With real fortresses, as time passes by, the walls erode because of the antiquity of the bricks. This is exactly what happens in the body. When the body ages, the immune cells - being the fundament of the walls - decay in quality. The walls become wobbly, and less force is needed to break through them. And you may think, but those Mtb were sleepy, right? How can sleepy bacteria have enough force to break through those walls? Okay, I agree, but sleepy Mtb are not dead Mtb. And sleepy Mtb are still alert. You know, they still are the same sneaky bugs we talked about in the first blog post in this series. Remember all those shifty actions it could perform with its cell wall? Well, Mtb always has more tricks up its sleeve…

When those fortress walls become unstable, Mtb starts to fire up from inside the fortress. It is not totally understood how Mtb is capable of reviving from its sleepy state. But what we do know is the result. The once perfectly closed wall is disrupted, enabling the bacteria to escape. Once on the loose, the bugs can patrol around, spreading through other parts of the lungs and even other parts of the body. It is when the bug starts affecting the essential organs in the body the real trouble starts… And this is when people start becoming really sick.

Fortunately, in societies where people have great healthcare, good hygiene, and healthy immune systems, this happens less often. In the majority of cases, Mtb stays peacefully in its well-guarded fortress. We actually now know that because of their fortress-based agreement, the bacteria and the human body can co-exist together for a long time. However, in most of those cases, the body is not able to totally get rid of the bacteria. This creates an ever-existing vulnerability for the human body when it’s infected with Mtb. The immune system has to be well armed to sustain its protection – to keep its prisoners chained within the fortress. When environments make it easy for Mtb to jump from person to person, and it’s difficult to access the medication that can give the immune system that extra boost to finally execute its Mtb prisoners, it’s more likely that Mtb will eventually win this long war. And unfortunately, this is also one of the reasons why tuberculosis has long been, and remains, such a big problem in less developed countries.

To wrap up this time, Mtb is the bacterium that goes unseen - both by the body and by society. It hides in human macrophages as well as in the human-built immune cell fortresses. Thanks to those fortresses, in the majority of people, Mtb infection never leads to actual TB disease. Therefore, the major part of Mtb infections are not visible for society, and it seems that this 90% of the infected people is perfectly fine - which indeed is the case for as long as they have a healthy immune system. But when the immune system is down, for instance, due to another infection or simply older age, Mtb makes its move. It attacks the body without holding back. So, by now, maybe you can imagine why they called TB ‘Captain of all these men of death’ in the past? First, it acts as a well-behaved prisoner, but in the end, stabs us in the back. Or rather, in the lungs.

Be sure to come back next week for the third and last instalment of this three-part series on Mycobacterium tuberculosis. Then we’ll see how all of what I’ve told you about Mtb also hampers its treatment.

Hope to see you there and thank you for reading!

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