Your body is a battlefield. On the open plains of your skin, respiratory tract, gastrointestinal system, and genitourinary system, scouts from opposing armies are constantly probing for weak points. Bacteria, viruses, and other “pathogenic”, or “disease-causing” organisms poke and prod at these so-called barrier tissues, attempting to squeeze their way into the warm, nutrient-rich kingdom that is you.
Because of their important barrier function, we immunologists typically consider these tissues - your skin and 'mucous membranes' (the type of tissue that composes your respiratory, gastrointestinal, and genitourinary tracts) - to already be a part of your immune system. The cells that make up those tissues are your barrier between inside and out, your Great Wall of China or your border control.
But every so often, a scout finds a weak spot. And the pathogenic army infiltrates. And if you’ve ever had a viral infection, you might be able to guess what happens next. The invading virus or bacterium will start replicating -making more of itself – and then the rest of your immune system will spring into action.
Traditionally, immunologists describe the defences of our bodies to be a 'two-armed' system, including the so-called "innate immunity" and "adaptive immunity". I like to think of innate immunity as our own personal "Distant Early Warning Lines". During the cold war, a system of radar stations in Canada's frigid far north, which would give advance warning of any Soviet attacks. If incoming bombers were detected, this arctic line of radar would provide sufficient notice to the more populated southern centers to identify the exact threat, prepare their defences, and possibly mount a counter-attack. Our innate immune system acts as a warning system that permits preparation for a subsequent, more nuanced defense to pathogenic invaders. But our innate immune system is also more than that: in and of itsself, it also constitutes a line of early, non-specific defense.
Non-specific defense? What does that mean? Well, when the innate immune system is activated by the infiltration of an enemy scout, it gets moving right away – no matter what the identify of that scout is. Some innate immune cells, like macrophages, dendritic cells, and Langerhans cells, will jump into action by scurrying about your body and eating up any of the pathogenic soldiers that they can find - literally gobbling them up and gorging themselves on viruses or bacteria. As they eat, these immune cells also have two other tasks. First, they send out signals to additional immune cells that call them to the site of the problem. These other cells will help mount an attack against the enemy, and eventually promote healing of any wounds at the location of this battle. Secondly, they digest their prey. And upon digesting the soldiers that have entered, they pull a rather medieval trick.
Much in the way ancient harbours would publicly gibbet, or hang in chains, the bodies of pirates and other criminals in an attempt to deter future misdeeds, innate immune cells like macrophages and dendritic cells display the digested remains of the pathogenic army. Bits and pieces of the unlucky bacteria, virus, or other pathogen will be studded across innate immune cell surfaces as a warning to 'all ye who dare to enter here'.
But for these clever cells, it's more than just a simple warning. It's also a call to action for the second arm of the immune system: adaptive immunity.
These satiated and scout-studded innate immune cells travel to central hubs in the immune system called lymph nodes. If you've ever felt your tonsils (which are simply lymph nodes in your neck) swell up as you start to notice the onset of a sore throat, it's because your immune cells are rushing in. In my mind, inside every lymph node, scenes from the Star Wars Cantina on Mos Eisley are playing out. These immune organs are where everybody goes to trade information, and to to hire mercenaries. Although they are highly effective in their own way, the scout-studded dendritic cells or macrophages –you can imagine them as a sort of Jawa, to keep with the Star Wars metaphor - are only intended to be the first line of defense. It is at the lymph nodes that they hire a more targeted team of assassins: the adaptive immune cells. T cells, which act as tanks and directly blow up the enemy, will be sent out. Alongside the T cell, B cells, which produce antibodies and thereby lay traps that can entangle the enemy, will both help with the current campaign against the enemy microbe – and retain a memory of the battle. The memory of the adaptive immune cells means that, the next time the same enemy microbe tries to enter the kingdom of your body, the defense will already be lying in wait. The defensive forces now know exactly what that particular enemy looks like, which means that they can more quickly mount their defense.
This system is incredibly elegant. By eating up the invaders as quickly as possible, innate immune cells not only take out some of the enemy army, but they also gather information on what they look like. They pass this information on to the adaptive immune by way of their gibbet-like, cell-surface display of digested pathogens. The information is slowly spread, and assassin adaptive immune cells are grown and trained, and then these adaptive immune cells set out just like Luke Skywalker to destroy the Death Star... ahem... pathogens. This also explains why it takes around a week for you to start feeling better when you encounter a new type of virus or bacteria. It simply takes a few days for the adaptive immune cell assassins to be hired, trained, completely clear out the infiltrators. But luckily for us, as I mentioned before, the adaptive immune system also has a memory - which means that these assassins have a memory. If they see signs of a second Death Star in the body, they already know exactly what to do, and will be able to act on shorter notice from the Distant Early Warning Lines.
You might have noticed that the innate immune cells’ gruesome armour composed of the digested remains of enemy microbes, plays a key role in linking the innate and adaptive arms of the immune system. It also brings us to a third arm of the immune system that is often forgotten: cell-intrinsic immunity.
Unlike innate and adaptive immunity, which need to be 'turned on' by signs of the enemy, the components of cell-intrinsic immunity are constitutively expressed - or in other words, constantly 'on'. And unlike the cells of the innate and adaptive immune systems, the actors of cell-intrinsic immunity are proteins - perhaps more like machines than soldiers. These proteinaceous machines are within cells. To keep with the Star Wars analogy, these proteinaceous machines resemble defense droids. They are "designed to defend their organic masters from hostiles", and are constantly on the lookout. As soon as a virus enters a cell, the proteinaceous defense droids will jump to action.
As in the Star Wars universe, there are many different types of proteinaceous defense droids, with many different strengths and abilities. However, they all have a single goal in common: to defend the cell.
My research focuses on one specific branch of cell intrinsic immunity, which is the one linked to digestion of incoming enemy microbes: Autophagy.
In the Star Wars world, autophagy would be the garbage compactor on the first Death Star, where Luke, Han, Chewy, and Leia were temporarily stranded. But autophagy is also so much more than just a waste disposal system.
Just like your apartment before you did your spring cleaning, cells can also accumulate too much stuff. For cells, however, this is really a life-or-death scenario. The excess stuff in cells can be potentially dangerous, such as misfolded proteins. Remember, proteins are the machines within cells – they do almost all of the work needed to keep a cell alive. If proteins are misfolded, i.e. incorrectly made, they might still do work, but do it the wrong way. You can think of this like a droid that is supposed to put away all of your clean dishes, but instead it smashes them on the floor. On top of dealing with misfolded proteins, cells continually have to make new proteins and organelles, or cellular organs, to replace the old ones and stay healthy – and those old ones have to go somewhere, right? To deal with all of this turnover of material within the cell, an elegant process of cellular recycling evolved: autophagy.
So autophagy, which translates to "self-eating" from Greek, is just that. Cells begin by wrapping up material that is no longer needed in a double-membrane structure made of fat, which kind of looks like two garbage bags layered inside one another. This structure is called an autophagosome. The autophagosomes, carrying material that needs to be recycled, go on to fuse with another membrane-bound structure inside the cell that carries acid and enzymes that break up stuff, kind of like a stomach. Once this fusion happens, the recycling inside the autophagosome is broken down, and the smaller pieces of it can be re-made into new proteins or organelles, in the same manner as what we humans do with our old plastic bags and cardboard boxes!
So, why am I telling you all of this information about cellular spring cleaning in a lecture about immunology? Well, because sometimes, cells are able to use autophagy to recycle invading microbes! In the same way that they can recycle old proteins and organelles, some cells are able to recycle bacteria like Mycobacterium tuberculosis (causes tuberculosis), Salmonella enterica (Salmonella food poisoning), and Listeria monocytogenes (listeriosis). So if each of the cells in our body are Death Stars, well, they indeed send unwelcome invaders like Luke and friends to their on-board garbage compactor!
As well as bacteria, some viruses, too, can be recycled this way. In fact, my doctoral supervisor, Dr. Carla Ribeiro, was the first person to discover that one specific type of human immune cell – the “Langerhans cells”, which you might remember are part of the innate immune system – can actually degrade HIV this way! Of course, not all human cells can recycle HIV using autophagy – otherwise this virus wouldn't be so much of a problem for us. But, the fact that cells can accomplish this feat suggests that medication that targets autophagy could help with treating or preventing HIV infections.
And this is exactly what I aim to do with my research. I want to dig into the details of how autophagy can either help or hinder viruses in their quest to infect us. Today, I’d like to tell you a story about how I set out to train human cells to “declutter” HIV-1 using autophagy.
Why HIV you might ask? Well, Although we often think of HIV as a pandemic of the past, it's still a major issue today. Every day, 5000 people are infected. Plus, we lack a cure for it - it's a life-time-sentence, and existing treatments aren't always available or effective for all. So, adding extra weapons to our anti-HIV armoury is surely socially and scientifically important.
Now, because autophagy is key throughout the immune system, many drugs that tweak it do already exist, for example to treat non-infectious disease like transplants, cancer, epilepsy. So, we asked, can we repurpose these autophagy drugs to treat infectious disease? And, more specifically, can we help other types of immune cells – like the dendritic cells of the innate immune system and the T cells of the adaptive immune system – gain this function of the Langerhans cells, to send HIV-1 to the garbage compactor?
To test this, I developed new models using human tissues that are left over after surgeries – like skin that is left over after tummy tucks, for example – which allowed me to screen autophagy drugs for their antiviral abilities, and to identify exactly which human cells were impacted by the drug treatment. To make a long story short, I showed that, YES, autophagy-enhancing drugs could both prevent HIV-1 entry into different types human cells, and put the brakes on ongoing HIV-1 infections. This means, there's potential to proactively cast off not only incoming virus, to stop infection, but also for decluttering HIV after it's already inside your cells, which is a key goal for treatment of people living with HIV.
Excitingly, the user-friendly, human-relevant, animal-free experimental models that I helped develop for this HIV-1 project are now also allowing me and my colleagues at the Autophagy-directed Immunity Research group in Amsterdam to quickly find potential new antiviral therapies to other emerging and relevant viruses. Right now, we are investigating how tweaking autophagy can help protect us from the likes of SARS-CoV-2 and Dengue virus. So, stay tuned for more upcoming research from us on how to send your viruses to the garbage compactor.