Over the 18 months or so of the COVID-19 pandemic, even if your first-aid certification isn't up to date, you've probably heard mention of PPE: personal protective equipment. For us humans, that means things like masks and gloves - tools that keep us safe in a hostile environment.
Well, it turns out we aren't the only ones who use PPE. Mycobacteria, like the causative agent of tuberculosis (Mycobacterium tuberculosis) have PPE too.
More specifically, Mycobacteria have both PPE and PE - and to be fair, I've taken some artistic license here. These proteins are not thusly named due to the "personal protection" they afford bacteria, but rather on account of their structure. PE proteins always have a specific sequence that can be denoted "PE" (a proline amino acid followed by a glutamic acid, for you real biology nerds out there) or "PPE" (likewise, proline-proline-glutamic acid). Because these structural features were so consistent, biologists simply named the whole group of proteins after them. Nonetheless, I'm quite pleased with my personal protective equipment analogy, because Mycobacteria do often "wear" their PPE (and PE) kind of like we wear ours. These proteins are often displayed on the surface of the bacterial cells, which is the post from which they do their varied jobs.
Since the late 1990s, biologists have been pretty sure that these proteins are important, partially because there are simply so many of them. PE and PPE proteins can make up about a tenth of the whole Mycobacterium tuberculosis genome - and if they take up that much room, there must be a reason, right?
Indeed, there is. Among other things, one of the roles that PE and PPE proteins have, is to assist Mycobacteria in THE GREAT QUEST FOR IRON.
As Dr. Miguel Soares, an expert in immunometabolism (which is, as it sounds, a complex field that merges immunology and metabolism), put it at a talk I recently attended, "Iron, which came from an asteroid, has been co-opted by evolution to be the electron transfer molecule. That means, there is always a war for iron access [during infection]." In other words, as soon as you get a bug - pretty much any bug - your body will start fighting to keep its iron, and the bug will start fighting to steal your body's iron. This seemingly random element, which came from space, has found itself at the very center of an age-old power struggle. I love this way of thinking about infection and immunity. It's like a cross between the battles over coaxium from Solo: A Star Wars Story and the old hippie idea that ミ☆we're all stardust☆彡
But anyways, over the years, research has indeed indicated that PE and PPE proteins, which often act together, can help Mycobacteria steal iron from their hosts. This probably both helps the Mycobacterium stay alive, and causes some of the clinical outcomes of tuberculosis.
However, because there are so many PE and PPE proteins, and because even though they do share those PE or PPE parts they can be quite different from each other, these proteins definitely are not the easiest field of study. At the moment, because PE and PPE proteins seem to be so important for (at least some) Mycobacteria, researchers are questioning if they should be included in new tuberculosis vaccines. However, newer research shows that sometimes, the lack PE or PPE proteins can actually make Mycobacterium tuberculosis even more of a force to reckon with. So, at its best, including PE and/or PPE proteins in a vaccine could help us keep our iron for ourselves, and make the invading bugs more vulnerable to attack by our immune system. But at its worst, including the wrong PE or PPE proteins could give us protection against only the 'lite' versions of the bugs, and provide insufficient protection against - or even encourage evolution of - types of Mycobacteria that don't have the potentially vaccine-included PE/PPE proteins and may actually be even more dangerous. How to tackle this is a tricky question, and one that can only be solved by more research. My colleague Louis Ates argues that, to start, we need a clear system of classifying different types of PE and PPE proteins into different subgroups, so that there is a clear framework for investigating their functions, and eventually their potential suitability for inclusion in a tuberculosis vaccine. Because, what's in a name? A whole lotta information, and the potential to simplify! Or, as Lynn J. Rothschild so brilliantly put it,
"A rose may still smell like a rose, but Juliet missed the point. The utility of taxonomic nomenclature lies in the wealth of biological information that it conveys."
Until next time - eat your spinach, get your iron, and be like a Mycobacterium and wear your PPE!
~ Alex
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This piece was inspired by the research of my colleague Louis Ates, and by his idea that researchers should "blurb" each others' work more often! It's a long blurb, and a long overdue blurb, but this blog post constitutes my blurb of his work. I hope you've enjoyed it!
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