Inflammation, Innate Immunity, Allergies & Allergens, Immune System Evolution, Fasting & Metabolism | Clare Bryant | #144

About the Guest: Clare Bryant, DVM is a Professor of Innate Immunity at Cambridge University. Her lab studies the innate immune system, pathogen detection, inflammation, and chronic disease.

Episode Summary: Nick and Dr. Bryant discuss: mechanisms of inflammation; inflammasomes & fatty acids; infection & disease; innate vs. adaptive immunity; chronic inflammation; allergies & allergens; the evolution of the immune system; anti-inflammatory effects of fasting; and more.

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* Episode transcript below.

Full AI-generated transcript below. Beware of typos & mistranslations!

Clare Bryant 4:41

sure. So I am Professor of innate immunity at the University of Cambridge in the United Kingdom. So what that really means is that I am really interested in studying the front line mechanisms that fight pathogen infections so predominantly bacterial infection In my case, and in particular, I'm really interested in understanding zoonotic infections. So I after COVID, I don't really have to explain what a zoonotic infection is anymore. I will do, but I used to have to make a big song and dance about this, but basically, infections that are tolerated by animals, but that jump into people, sometimes these infections cause disease in animals, but more often than not, they don't. And I'm really interested in understanding the immune mechanisms that allow these infections to be tolerated by the animals. Yet when they come into people, they cause inflammatory and infectious disease. And actually, from this, I've been, I've been led on to work on a number of sterile infectious diseases that includes Alzheimer's disease, obesity, and a variety of other problems, which is been kind of an interesting migration for somebody because actually, I was trained as a veterinarian, and I find myself working on a host of diseases that affect humans as well as animals.

Nick Jikomes 6:02

Okay, so So you were actually trained as a veterinarian? Yeah, that's, that's

Clare Bryant 6:05

correct.

Nick Jikomes 6:06

What, how to? So you went to vet school, but you're basically doing basic research how to how did that happen? I think that's pretty unusual.

Clare Bryant 6:14

Yeah, it is unusual. So it was, yeah, it was an interesting career track, really, because I wasn't really what I anticipated doing. Although I was very, I did a primary basic training and physiology and biochemistry and did some research then and, and really got excited by the concept of research, I did a summer vacation job, in fact, which really was like a lightbulb moment where I thought, oh, research, this is really interesting. But I went on to do my veterinary degree and complete the training. And what I appreciated very early on was that whilst I found animal disease fascinating, and the patients are really cool, sometimes the owners are a little bit more difficult, which is why I trained to be a wrestler, not a medic. But what was very frustrating for me was that in the clinic, I couldn't really get to a molecular answer. And I realized I really did need to understand a really fundamental basic mechanistic answer, and I was not going to get there in clinical practice. And so that there really decided my career for me, because from that point on, I thought, Alright, I need to understand mechanisms. And that requires me really digging into the research to understand what's going on. And so from that point, on my career track was sort of defined and determined to be really basic biomedical research.

Nick Jikomes 7:42

And so Professor of adaptive immunity, or excuse me innate. Yeah, my

Clare Bryant 7:51

question here is very important. Yes.

Nick Jikomes 7:53

In fact, I think it would be good if you explain for people, what's the difference between innate and adaptive immunity? Yeah,

Clare Bryant 7:59

for sure. So, innate immunity is the first line of defense. So what happens is when a pathogen enters the body, it will encounter initially a set of barriers. So it's things like your mucosal barrier in your lungs or your gut, it will then encounter a set of sort of primary immune cells, for example, neutrophils and macrophages, and the job of those cells is to is to see the pathogen and try and kill it. And, and the specificity there comes from receptors or proteins in the cell membrane that allow you to detect pathogens and discriminate that has been different from the host. And what these cells also do is send out signals to recruit adaptive immune cells. So this is things like T cells and B cells, which provide the memory and repeat response. When a pathogen comes along again, these cells are recruited, they talk to things like the macrophages and a special set of cells called dendritic cells. And this interaction then between naive T or B cells, T cells route between naive T cells and dendritic cells in a whole milieu of pro inflammatory proteins. So inflammation is a very important part of this process, then drives the differentiation of the T cells, which then go on to form B cells, T cells, they drive memory, that all the basis of a response that's long term, whereas the innate response is very immediate and critically important for instructing the adaptive immune response. So it's a kind of two phase response, but the innate responses is your first line of defense against pathogens.

Nick Jikomes 9:44

So as the names of these things imply, the adaptive immune response would be, it's things that are not specifically baked in, they have to be learned through trial and error. That's where we think about things like antibodies for specific infections, and the innate immune response. Is it's baked in? It's it's ready to go, you know from from the beginning? Absolutely,

Clare Bryant 10:05

absolutely. And that's really important. And of course, the critical thing about the adaptive immune responses, the memory. And there's there's some components of genetic modification that ties into innate immunity. But it's nothing really like the profound memory immune responses that we see in T and B cells.

Nick Jikomes 10:25

And so, the innate immune response, let's say you have a bacteria infection, some some bug has gotten into the body, somehow, the innate immune system is detecting that you mentioned that there are receptors that are recognized or proteins that are recognized on the bacteria. Can you talk a little bit about how that works, what kinds of receptors are recognized? And what does that process actually look like?

Clare Bryant 10:52

So So what actually happens is there are receptors in the cell membrane that will recognize molecules in the pathogen. So if you're talking about a bacteria, the bacteria has a host of specialized coatings on its surface, one of which is called lipid polysaccharides. So that's a lipid. It also has bacterial proteins in its surface, it has big can have flagella which are tails, which cause the bacteria to swim. The either the proteins or the lipids are then recognized by receptors in the innate immune cells. And so one of those, for example, like polysaccharides, is a massively toxic molecule. And there's a receptor called toll like receptor flora, which is part of a family of receptors called pattern recognition receptors. And their job is exactly what it sounds like. They recognize molecular patterns from non self molecules, okay, usually from non self molecules. So they'll recognize, for example, bacterial lipopolysaccharide. And the interaction of the target receptor or the pattern recognition receptor with the bacterial molecule then triggers the signaling cascade, which ultimately results in the production of an inflammatory response. And it's a very powerful inflammatory response. And the whole point of that response is twofold. One is to kill a pathogen and two is to instruct the adaptive immune response to say, hey, this, this pathogen is here, you need to come help me kill it. So that's kind of the Cascade that's involved in a bacterium arrives. And there's a whole family of pattern recognition receptors, we understand a lot about them. Now, they're really interesting. Some of them recognize nucleic acids, some of them recognize lipids, some of them recognize proteins, some of them recognize carbohydrates. But all of these things are actual key features to instructing the innate immune system to tell the body that that a pathogen has arrived.

Nick Jikomes 12:45

Yeah, so it strikes me here that there could be actually an analogy between the innate immune response and basic sensory detection and sensory perception. So I have a neuroscience background. So you know, when you think about vision, or olfaction, or the sensation of things in the physical environment outside the body, right, in the visual system, you've got a retina, there are specialized receptors on the neurons in the retina that detect, in this case, photons of light, they detect certain photons of light, they respond in certain ways, those signals downstream are then combined in ways that lead to visual perception. This seems like an analogous situation, the stimulus is something from the outside world that actually gets into the body. But there are it sounds like specialized receptors that are detecting some feature that is found only or mostly on other types of creatures, but not in ourselves. Can how far can we take that analogy? Yeah,

Clare Bryant 13:42

it's pretty similar, actually. And I would say one of the things was that pattern recognition receptors were discovered, relatively recently, young people would not say it's relatively recently, but it is relatively recently in the late 1990s. And it was something that we knew there had to be a system out there to see these patterns, but we didn't know where it was. And indeed, it is informed by all the other receptors that we know exists for a wide variety of physiological processes. So it was became increasingly obvious there had to be something similar for for pathogens, and it was a really phenomenal of advance for which the Nobel Prize actually was awarded. To actually find what is the receptor that sees a bug, there's got to be one there. And when they were found, you know, everybody, we were all very excited because it gave us a mechanism suddenly go okay, now we can work out what's going on, we can work out how to stimulate this to improve our vaccines, we can work out how to inhibit it to prevent inflammation, and so forth. So the the analogy is very real. I think. The only addition I would add to that, is that these receptors now not only recognize pathogens, but can also recognize a host damage molecules, in other words, things that would normally prevent producing disease, or things that are in the wrong place. So You know, normally bits and pieces of this, of the cell machinery exist in a certain compartment in the nucleus, for example, for nucleic acids or in different vacuoles in the cell, if things get out of the wrong place, or things get out of the cell, which we call damage associated molecular patterns, some of them can be picked up by these pattern recognition receptors. And we think this is part of the way in which a number of chronic inflammatory diseases occur just by detecting these things in the wrong place. And these receptors then then do their job, which is to generate inflammation, but of course, that can be damaging to the body.

Nick Jikomes 15:36

So it sounds like this is a system for detecting biological components that are out of place, not necessarily distinct organisms.

Clare Bryant 15:45

Yeah, I mean, it's predominantly distinct organisms. But imagine, for example, as a neuroscience context, we know that these receptors can recognize amyloid beta, which is associated with Alzheimer walking and recognize Alpha synuclein, associated with Parkinson's, and it's a particular size of these proteins and ligaments, that we know that they're associated with pathogenesis and that we think that the, these these proteins are detected by these receptors, they drive inflammation. And this helps to explain why there's a neuro inflammatory components are these really nasty brain diseases?

Nick Jikomes 16:20

And so with innate immunity, how, how specific can the recognition capabilities of this phase of immune response get? Is it simply able to detect that a bacteria has entered the body? Or is there a specificity? Is it more specificity in that kind of detect and distinguish between certain species of bacteria, bacteria versus fungi, et cetera? And then relay that for the adaptive immune response? Or is it just sort of like something for it is in here?

Clare Bryant 16:51

Now, there's really quite a lot of sophistication in there. And this is an ongoing area of research, actually, because it, you know, the link between innate and adaptive immunity and how do you tell it a specific bug there, I think is is remains a part what I would call a partially resolved question. But for example, toll like receptor four, which is my favorite, one of my favorite pattern recognition receptors, recognize this bacterial polysaccharide, which is a lipid, in the outer coating of a bacterium. This lipid, each bacteria makes its own like polysaccharide. And depending upon the structure of that lipid, it can be seen very differently by Toll like receptor for so some lipids are massively proactive, and they cause a lot of inflammation. But sometimes the bugs are clever. And sometimes a bug can, for example, decrease the number of what we call a cell change, which is a fatty chains in the bacterial lipopolysaccharide. Such as it's, it's no longer seen, or it's seen as what we call an antagonist or an inhibitor by the TLR. Four. And a real key example of that is your senior pastors, you know, the playbook, everybody loves the playbook. It has the capability to switch this lipid polysaccharides. So it can switch between an inflammatory and an anti inflammatory species when it's in the body, and that's part of the way why how it manages to evade detection by the body. So we have this kind of arms race, whether the pathogen tries to evade the innate immune system in order to have to do what it wants to do. Meanwhile, the body is trying to adapt to this. But obviously, the pathogen can evolve much faster than the immune system and dealing with these kinds of issues.

Nick Jikomes 18:27

Well, so it really is like a form of camouflage, or, you know, I'm almost imagining someone in the Special Forces blending into the culture, they're actually infiltrating.

Clare Bryant 18:39

Yeah, exactly that it's very interesting. The biology we learned from, both from what we understand by the immune system, but also, what bacteria or viruses or fungi data high from the immune system becomes very important, particularly thinking about therapeutics, because these are potential mechanisms that we can we can leverage to modify the immune system and its responses. So

Nick Jikomes 19:02

these lipid polysaccharides, these are components of bacteria, they vary from species to species, so they can be used as a kind of fingerprint to get more specificity there. But are they also just a general purpose discrimination tool? Are these things that are never found on our own cells? Or do we have similar structures in our own cells? So

Clare Bryant 19:21

we that's an interesting question, and I'll tell you why. Because it's it for a long time we we were trying to understand whether or not these were specifically just for a bacterium, or did they have other functions and there is some nice evidence to suggest that certain lipids in the body can also be seen by some of these receptors. And that's an emerging field and we've certainly thought about this in the context of some of the intracellular intracellular as well as cell membrane receptors. And we thought about this in the context of intracellular receptors and certainly some work has been done on toll like receptor for and things like ceramide and cholesterol species can A trigger to a degree some activation of tolerance receptor for this is very much an emerging, it's an emerging field because sometimes these these molecules are quite difficult to, to manage and use and, and work with in our experimental systems. From a bacterial point of view, though, it's been very clear, and it is very, not very well worked out. But we understand more and more all the time. And we know a lot about bacterial endotoxins. Because they've been so important in infection biology for a long time. But the the host, on the research is, is sort of emerging more and more now, I think, as we become more sophisticated understanding metabolism and the metabolic products that are produced in the body, we become more able to explore this biology.

Nick Jikomes 20:48

And so all animals, as far as I'm aware, have an immune system of some kind. I imagine there's both a lot of conservation at one level and a lot of diversity at another level, when it comes to the innate immune response. And things like the initial detection of pathogens through these pattern recognition receptors. How, how old in evolutionary terms, is this system? Is this something conserved across the animal kingdom? Or how can we think about how how and when this part of the immune system evolved,

Clare Bryant 21:22

so it's been around a long time. So for example, the sea urchin so that's way back in the day, way early in the evolutionary tree has, if I remember right here, it's something like 271 toll like receptors, which are pattern recognition receptors. So what we see as animals as animals developed an adaptive immune system, the need to have so many toll like receptors reduce or so many pattern recognition receptors was reduced, because you're gaining a sophistication and, and a way of, of fighting infections that doesn't wholly rely on the innate immune system. And I think that's why you see the kind of shrinkage from the the animal the very early stages of animal immunity. So thing as I see it, and so early in the evolutionary tree, what becomes then very interesting is when you start to look at different animals, is the really awesome, very interesting differences in the innate immune receptors across our species. So So if we think about birds, which are really just flying dinosaurs, obviously. And there's, they're super interesting, okay, they have a quite a condensed immune system. As you go down the tree, if you look at humans, they've got quite an expanded humans and mice, for example, haven't expanded innate immune tree. So that means they have a quite a lot of pattern recognition receptors, nothing like the sea urchin can do nothing like the sea urchin boat, you know, we're talking 1012. And then what then is interesting is looking at other animals. And this is research that's being done coming through as we speak, really, because as the sophistication of genomics in species other than humans and mice, becomes more and more and more worked on, we now have a, you know, fantastic resource, but it's improving all the time people are sequencing genomes all the time, you begin to be able to study the innate immune tree. And that's the only bit I've looked at, of course, because I'm, I love the innate immune system. And I'm, particularly pattern recognition receptor. So I'm very focused on what I look at, for example, the carnivora, so we're talking dogs, cats, the species have actually started to lose some of these receptors, which is very interesting. And they've lost some of the receptors, and they've lost what I call the effect or protein. So you have the receptor that detects the pathogen, and then you have an effect or system which initiates the inflammatory response. So, so dogs and cats, for example, have lost, you can see that some of the pattern recognition receptors have become pseudo genes. And that's the first step in these receptors being lost. And presumably, that that's because their immune system is evolving. They're carnivores, they have a high protein diet, they have lots of antimicrobial peptides. And we think that perhaps this this diet and and so forth, actually means that some of the innate immune systems that are present for example, in the gut may not be necessary because the the mucosal barrier is very well populated and learns to deal with these things and you need to do that if you're a dog because dogs are these dogs eat terrible things. Cats are very sophisticated and very picky but dogs are not right. Yeah.

Nick Jikomes 24:38

I think what you're saying is right though the lifestyle of the animal in terms of its diet and other things, but but in the context of pathogens, it's you know, the the pattern with which it encounters pathogens in the world is going to dictate the type of immune system it needs. Some might need something like sea urchin need to, you know, hard code the identity of a bunch pathogens early on. Others have this adaptive response. So they can, they can learn through experience to fine tune their immune response. And you don't need to encode all that information in the genome upfront. But you said something that was kind of interesting to me, which is, you said that there was this reduction in sort of the innate immune system repertoire, as you go from earlier animals to later animals. Presumably, that reflects a greater need over time to respond to a greater diversity of pathogens. And there's a sort of information encoding problem where you simply can't hard code all of them in the genome. But at the same time, you said in different lineages like the human and the mouse lineage, there was this sort of expansion of some kind. Yeah. Does that have to do with things like diet where you know, if a mouse or a human is the type of creature that is a opportunistic omnivore that is going to be scavenging lots of questionable food items they might need to have, they might need to amp up certain arms of the immune system compared to other animals.

Clare Bryant 26:03

I mean, that's my best guess. Okay, I would love to be able to prove this, because it's, it's extraordinarily interesting. So yes, I think that's, that is part of the deal. And, you know, I think perhaps the elephant in the room we haven't discussed as the bat, of course, and the bat has, has lost also lost a number of genes. But you know, the, the argument is, bats fly, and they have a high metabolic rate. And that that may mean that they lose some of these immune genes, because they can't afford to still have them there. I don't know whether that's true or not, but it's certainly an interesting hypothesis. And I think lifestyle, the way in which animals live, what they eat, and how they thrive is, is central to the reasons why there's such diversity in the innate immune system, which which is kind of interesting, because this means them the you that these animals have the capability to tolerate some pathogens and just not be seen. It's really underpins the zoonotic problem, right. You know, people come into contact with animals in the wrong place, with the human, for example, as an immune system, which will see the pathogen whereas the battle, the bird, for example, will house the pathogen and doesn't really care, it's there. And, and it's a series of events, the pathogen involving the human being and the human being in the wrong place that all these kind of ecological, immune, and pathogen factors create the perfect storm, which is what happened with COVID COVID. We think came from bats, we think, and it's still controversial,

Nick Jikomes 27:32

about SARS one or sour SARS, to SARS, T,

Clare Bryant 27:35

SOS T. And we know for example, that SARS, SARS, cov, two during the pandemic actually went into minke came back out again and mutated on Route. And we've just got through talking about differences in the innate immune system in link. Again, this is a possible way in which these kinds of events and mutations events occur. It's it's it's a series of really interesting questions that, you know, I think, from the immune point of view are super important for us to understand moving forward to be prepared to deal with emerging pathogens and pandemics in the future.

Nick Jikomes 28:14

So the other another little thing that you said there? That was interesting, I think is you mentioned that certain certain carnivores have lost certain components of immune system, and you said, I think that they produce you, basically, so they produce anti microbial molecules in your gut. So the question I have related to that is, so we've got this innate immune system, it's capable of detecting with some amount of specificity, different types of bacteria and other pathogens. So it's this sort of almost sensory detection system, it's got some level of specificity, are there also just sort of very general purpose anti microbe mechanisms at play, just molecules that get released that just sort of do not discriminate? And what are some of those? Yeah,

Clare Bryant 29:02

so I mean, this is not my area of expertise. But anti microbial peptides are a really nice example of this. So in your gut you produce if it is a whole layer of nonspecific mechanisms in the gut, you produce mucus, for example, which helps to provide a barrier to sort of prevent bacteria crossing the track, if you produce your gut moves, right. And the movement also stops the bugs getting a handle on it, will produce antimicrobial peptides, which helped to coat the bacterium and, and help to destroy it, basically. So there are a bunch of sort of nonspecific mechanisms, which are really all your frontline of defense, before you actually get to things like the macrophages with the sort of level of specificity, the innate immune cells rather with a level of specificity. So there's, there's a whole bunch of really important factors that help to prevent you getting infected. Otherwise, to be frank, if you think about it, we have a microbiome. In other words, the microbial population Son, in the lungs and in our guts, and if we didn't have these kinds of barriers, we just be all time.

Nick Jikomes 30:08

Okay, so let's, you know, this will maybe be a little bit of a big question, I'll let you sort of drive the level of specificity. But on a high level, let's, let's assume we're talking about a human being. And we're talking about a bacterial infection of some kind, maybe we'll just think of some common bacterial infection. The bacteria gets in, it somehow gets in, and, and the innate immune response happens. And then everything downstream of that happens. What are some of the key steps from detection of the pathogen initially to resolution of infection? What are some of the key steps that are happening there? Along the way? Yeah,

Clare Bryant 30:45

so So you have the pathogen, it's seen by receptor itself. Step number one, okay. The innate immune cell will do things like trying to engulf that pathogen doesn't always succeed, but it will try but say it does, okay, well then try and kill that pathogen. So if it, one of the things it's able to do then is take bits of that pathogen, and that that's, they call this antigen, okay. And it's able to then take that out and put it on the cell surface. And while it's responding to the pathogen, it's also product produced a bunch of signals, which are recruiting naive T cell cells, or T cells that are don't have any fixed role, right. So the T cells are recruited, and they have T cells have receptors that recognize antigen. And so the antigen on the innate immune cell, particularly dendritic cells, will be presented to a T cell. And there's, there's the T cell is always has has, receptors has phenomenally complex series of receptors. And it's so sophisticated, it's beyond my, my mental capacity to really understand how this works, because it's so sophisticated, but somehow it has the capacity to be able to recognize any antigen effectively. So you've got your bug antigen, you've got your T cell, which is has found it's a little bit of peptide, which recognizes this thing causes multiplication of the T cells that then go off. And this all happens in the lymph node, they then go off, and they make B cells, which produce antibodies, they make other T cells. So killer T cells, for example, that can come along and take out the pathogen cytotoxic T cells, so that there are a whole bunch then of responses downstream. So these then come in, and further promote, amongst other things, the innate immune cells to then keep on killing the pathogen.

Nick Jikomes 32:42

So so so if I'm following, it's basically like the pathogen gets in the, the macrophage has these toll like receptors that can can recognize certain components of the bacteria. If we liken that to a security guard, and the security guard identifies the invader, captures the invader, takes off a little identifying piece of the invader, and then shows other security guards what the invader looks like, and what to look out for. And then at the same time, is also just sort of like blowing a whistle or something. There's a nonspecific signal that just says, Hey, I need help over here. And through both of those pathways, you get a bunch of other security guards that come in. Some of them are very specific and identifying specific things. And some of them are probably just general purpose muscle to get rid of

Clare Bryant 33:33

them. Yeah, that's second. That's not what I said in a nutshell. And this, this is the whole basis of the links then between innate and adaptive immunity. And then what happens is, of course, your adaptive immune system cells go off, they send in further security guards for the further on the analogy, which helps to combat the rest of the infection, but also it seeds a memory cell. Okay, so so so security guard goes off and sits in his nice, warm, warm, warm cell, waiting for further the call next time and next time He comes. That's Kochi as brings a whole whole army so that it shuts down an infection very quickly.

Nick Jikomes 34:10

After this happens, once, you know you've you've got a photograph of the perpetrator if you fingerprinted him, and so you're then on guard looking for that particular pathogen in the future. So the responses is just quicker and more effective.

Clare Bryant 34:25

And that's exactly right. And that's the whole point behind vaccination. It's

Nick Jikomes 34:29

a it's a really deep down on that memory component.

Clare Bryant 34:33

Yeah, absolutely. So, you know, this is why the COVID vaccination policies were so important because once you have vaccinated a COVID arrives and income security guards to can as quickly as possible,

Nick Jikomes 34:45

and you know, so on on that theme, on the one hand, you know, human beings have figured out how these mechanisms work, and so we can invent things like vaccines that induce this adaptive immune response, before or in place of good During a full blown genuine infection, on the other hand, sometimes people get vaccinated, and then they get infected with a virus anyway. And this gets back to this idea of this arms race that happens, I suppose so. So I guess things like viruses and bacteria, they themselves are constantly evolving new abilities to get around this adaptive immune response. Yeah,

Clare Bryant 35:21

that's exactly right. And, you know, COVID is a great example of this, actually. So, you know, what, what happened with COVID was we made vaccines against against the spike protein gave, which was a very specific part of COVID. And this then, particularly drove drove to things that drove antibody production. But what happens is the antibodies then recognize that spike protein from that particular strain of the virus, okay? It also drives the production of, of killer T cells. So they are a little, they they recognize COVID, as well, but they seem to be a bit more broad spectrum, the antibody is very, very specific with what it recognizes. And then what happened is, as you know, COVID was extremely efficient at mutating, it was a spike protein in particular, that mutated. And if you get, because an antibody is so specific, and model recognizes it recognizes amino acids in the spike protein. And what COVID did was it mutated lots of those amino acids in the spike protein. And at a certain point, so many changes in those amino acids and Spike protein occurred, that the antibody could no longer very efficiently bind on to that spiked protein, and so the vaccines became less effective. And so hence, the reason to update the vaccines all the time, because you then can fine tune it towards the spike protein and of the mutating virus at some is probably the best example. Certainly the moment of you know, the how the virus evolves, and how we need to be responding to prevent that. And we're very lucky because with the new RNA vaccines, you can do exactly that. It's fairly quick to change the RNA sequence and an RNA vaccine, which is exactly for the spike protein. So you can just change some of the sequences in the RNA vaccine, which then means you make a very, very specific new vaccine against the new strain. And it's constantly evolving, evolving system.

Nick Jikomes 37:17

Oh, see, this actually brings me to another question I had, which is, so when COVID was first happening, I got the initial two doses of one of the mRNA vaccines. And I became very symptomatic in response to the vaccine. I then subsequently, after getting vaccinated, got infected with COVID. And there was a somewhat similar but distinct set of symptoms that I got. And so symptoms coming from the immune response on its own without infection symptoms coming from either the infection per se, or my immune response to an actual infection. When we get sick, when we have a bacterial viral infection, we have a runny nose, or were vomiting or whatever it is, do those symptoms come primarily from the immune systems response to the bug? Or do they come from, say, toxins being released by the pathogen? Or is it is it a mix of the two

Clare Bryant 38:12

is mix of the two? Okay, so ultimately, the immune system has a very specific set of responses. So and so one of the things the body does is produces not only messenger proteins, but inflammatory proteins, okay. And these inflammatory proteins, inflammatory mediators do a whole host of things, for example, they make you they drive a fever response. So you'll know if you have a viral infection, you get a fever, that that that's a host response, the host inflammatory response, driving an increase in body temperature. And the reason for that is because if you've got a high body temperature, you you're providing a hostile environment for the pathogens to proliferate. And so it helps to slow slow the proliferation of the pathogens. And so there's a whole bunch of responses that occur like that to try war off killed, controlled pathogen, but the consequences of that is yeah, you you've you can feel sick due to the immune response to the pathogen, but some pathogens can produce toxins in their own right. So the cholera for example, a part of the pathogenesis is due to a toxin, which then triggers diarrhea and which is due to causing problems in in your gut epithelial your gut barrier. And that's toxin driven. But it's, I guess, you you're almost at the point of saying it's a toxin that then changes the host cell and the host cell then responds in this way. So it's, it's a moot point as to its is it's an immune response or is it pathogen toxin pathogen Toxins will trigger a change in the body which will then trigger a response. So it's how your body responds to the pathogen. That's, that's absolutely key and that can be toxin driven, or that can be driven by pathogen or both. So

Nick Jikomes 39:53

yeah, so ultimately, it's the response of the immune system to the body that's generating the symptoms, in some cases. for the detection of the pathogen, you're detecting an otherwise benign component of the pathogen that isn't actually directly harming you like a weapon. In other cases, they do produce toxins that are part of their pathogenesis. But ultimately, it's how we're responding is generating most of the symptoms. It sounds like Yeah,

Clare Bryant 40:17

yeah, indeed, yeah.

Nick Jikomes 40:21

So under. So So inflammation is important. Well, first, let's actually just talk about what inflammation is to make sure we've got background from our next question. So I think everyone has at least an intuitive sense for what inflammation is, you know, our tissues often get literally inflamed, they get bigger when we get a bruise, or when you have an infection or something that presumably involves the recruitment of all of these cells, all of these immune cells coming into a region where they're needed. But how would you define inflammation? What are the key characteristics that define it? And are there are anything is there anything here worth mentioning that maybe people don't normally think about,

Clare Bryant 41:02

say, so the inflammation has been known about for a long time, it was defined by the Greeks, if I remember correctly, and there are a bunch of very clear responses that happens so that you get redness. So what happens is, if you get damaged to, under your hands, their skin, you'll see an ink redness, and that's an increased blood flow. So the blood flowing into the site of a damage or site or an infection intrinsically, actually to try and get rid of the infection directed away. So you get redness, you get an increase in body temperature, as I've said, so that increase in body temperature is to provide a hostile environment, you get swelling, and that's often due to an influx of tissue fluid. That then again, dilutes out the environment, whether the tissue is is one other thing and it's gonna elude me now now on the spot, redness,

Nick Jikomes 41:54

swelling, temperature, chain, pain, pain, pain, pain, sensitization,

Clare Bryant 42:00

sensitization, and that the point of the pain is, is to make sure you don't make further damage. area that's there, right? So you have all these signs happening at the same time. I see.

Nick Jikomes 42:12

So so when you get a bruise or a broken bone. It's the pain that you feel is not simply a side effect of something that's broken, it's actually a feature of the body's response to prevent you from messing with the tissue further, yeah, absolutely.

Clare Bryant 42:28

You don't want to be walking on a broken bone, right? If you imagine the prime auditor and sponsor, you're trying to protect that area of your body and not make it any worse. So these are the kinds of signs associated with inflammation, and it is great as a protective mechanism. But when it gets out of control, okay, then it starts to be a problem. And that that's the challenge with a whole bunch of other diseases in infection, it is job is to try and control the, to control the pathogen and get rid of it.

Nick Jikomes 42:53

Yes, I definitely want to go there in a few moments, the control of inflammation in space and time. Before we get there, I want to understand a couple other things. So you mentioned there's this temperature change, there's an increase in temperature. And it sounds like that's also a feature to mess with the ability of pathogens to replicate, rather than being the passive consequence of more metabolic activity. Is that accurate? Yeah,

Clare Bryant 43:20

that's definitely the case. I mean, you know, part of inflammation is a metabolic change. Metabolic change contributes to the increase in body temperature. But actually, the factor that drives the body temperature increases is twofold. So it's a protein, which is a prime foundry cytokine called interleukin one beta. That triggers the production of some lipids, prostaglandins, in fact, prostaglandin e two, which has a very specific prostaglandin. Okay, and that can go into the, into the

Nick Jikomes 43:48

brain. And so those are the things that NSAIDs inhibit prostaglandins. Yes,

Clare Bryant 43:52

that's exactly right. Yes, that's exactly right. So now is because prostaglandins trigger thermo receptors, and that triggers an increase in temperature. So yeah, so if you take and certain non steroidal anti inflammatory drugs, for example, aspirin, that's one of the things that does is it it by blocking the prostaglandins, it will help decrease your body temperature.

Nick Jikomes 44:15

Interesting, so you've got this increase in temperature, which is a feature, you've got redness, which comes from vasodilation, that makes perfect sense you need you need more stuff going there. So the blood flow is gonna carry a lot of the fuel for that. I want to talk a little bit about metabolism here and how expensive this whole process is. I imagine it's pretty energetically energetically expensive. You have to recruit all these different cells, you have to induce cell differentiation. They're doing sophisticated things like engulfing bacteria and sending off different signals. I mean, I'll let you dictate how we talked about this. I don't know what the best way to do it for general audiences, like how how expensive is measured and at PSA is the immune response.

Clare Bryant 45:01

high sec, that's a question I'm really not best placed to answer to be honest, you're dead, right? It is very expensive, it is energetically hugely expensive. And you can see, for example, this is definitely not an area I'm an expert in. But for example, the macrophage has an innate immune cell, you know, you can see real shifts in the use of various metabolites and cell energy metabolites. So when a cell becomes inflamed, the whole of its metabolize, there's an, it's shifted. And that shift is to drive an inflammatory response. And, you know, at a very simple stage, you can you can look at a cell in a dish, petri dish, and you can see the medium changes color, because the inflamed macrophages produces acid base acid type products. And so the medium then then goes from pink to yellow. So the, and the whole field, there's a massive field of immuno metabolism, which is thinking exactly about this, the adaptive immune system, does it the innate immune system does it this huge fuel to try and fight infection? It's a phenomenally energetically important process new, you know, if you're, if you've got a fever, you tend not to eat, which is kind of an interesting because you don't feel like it. Right. Right.

Nick Jikomes 46:14

Right. Right. I was actually just thinking this Yeah. Like, you often lose your appetite. But, you know, given what we're talking about, you might think the opposite would be the case. Like you want to fuel this process, which is very expensive. So yeah, how do we even start to think about that? Yeah,

Clare Bryant 46:30

it's an interesting, it's an interesting question. It partly depends upon I think, the pathogen so and that there's kind of an old fashioned saying, which I vaguely remember from when I was Charlie, when I was a child, starve a fever and feed a cold or the other way around, and I can't remember which one it is. And I think there's, there's elements to that, you might imagine that if you've got a chronic, and this is true, if you've got a chronic inflammation, gay or chronic infection, you tend to lose weight in your because your things like your muscle breaks down, and it's being used at feed this inflammatory process. So you can imagine that if you can, you can take on food to combat that is going to help but it's it is fiendishly complex, inflammation is very energetically hungry.

Nick Jikomes 47:16

You're just, I mean, just speaking off the cuff a little bit, you know, we talked, we talked about evolution earlier, different animals have different lifestyles, and their immune systems are going to evolve in concert with their lifestyle, including their diet. When you think about when I think about, you know, what I know about evolutionary anthropology and humans, humans show a lot of features in terms of our digestive and metabolic physiology. And, you know, based on what we know, from fossils, and other things as well, that, you know, we're obviously highly omnivorous. And we've probably done a lot of scavenging of dead food killed by other things in our past. And I wonder if there's something to that, that ties in here. So for example, if at least certain types of infections often come from ingesting a pathogen, you might want to make the animal stop eating, so it doesn't eat more of the cause? Yeah,

Clare Bryant 48:08

I mean, I think that's interesting, right? I think humans have. So humans and dogs are a really good comparator. Right? I said, dogs see horrible things they do. They seem to be industry, indiscriminate, and what they eat, and, and their innate immune system is different to humans, which is, you know, more sophisticated. I wonder how much things like smell and various aversion tactics come into play here. But also, things like carnivores are patterns are patterns. We're not carnivores are a predator animals. And the difference between a predator prey and an omnivore I think the whole that whole balance, and the ecology that's associated with that is super interesting, and infection susceptibility. But one thing I did read relatively recently as they found it, so there's been a lot of sequencing of ancient DNA in the fan of Neanderthal DNA. And there seems to be some conservation with or some of the Antheil DNA in some of our pattern recognition receptors. And the suggestion being that over evolution as immune as as infection has placed a pressure on our immune system, we've kind of selected to certainly acquire from our Neanderthal relatives, some of the genetic sequences and some of the pattern recognition receptors, presumably to make us more efficient at fighting infection. There's a whole interesting, interesting evolutionary investigation there. Interesting.

Nick Jikomes 49:37

So I do so I want to ask one more question related to the inflammatory process itself. There's this term that I'm familiar with, but I really know very little about this. And I know that it's something that you've studied in particular, there's something called the inflammasome What are inflammasome ohms and what role do they play in inflammation?

Clare Bryant 50:01

Okay, so inflammasome are a huge protein complex in itself. And they are, they're formed in response to activation of another pattern recognition receptor, this family of pattern recognition receptors lives in cytosol itself. And they're kind of interesting because they, they respond, obviously to pathogens that get into the cytosol, or bits of pathogens that get into the cytosol. And they trigger a response, which is quite different to the toll like receptors or tolerate receptors, driver transcriptional response. And that causes an increase in gene transcription of a whole bunch of pro inflammatory proteins, the inflammasome, in contrast, it, it has a much more limited function. So it does two things that it chops, the ends off some inactive cytokines, which are pro inflammatory proteins. So that's pro one beta and pro 18. And these then become very important inflammatory proteins that drive inflammation, but also drive adaptive immune responses. But they do a second thing, which is, is slightly cataclysmic for the cell because they kill it. Okay, so the inflammasome cleaves a protein called Gaston, and that puts paws into cells, this then triggers a second port for making protein called a ninja one, and cell lysis. And that's a super important part of the inflammatory process because it releases a whole bunch of intracellular contents to the wrong place. Okay, so that helps to drive further inflammation. It also think helps to drive an adaptive immune response, because it's spattering out cell contents all over the place, and they shouldn't be there. So there's, that is a second arm then to an inflammatory response, how important they are as primary pattern recognition receptors. So the inflammasome forming pattern recognition receptors, are they primary infection receptor, are they primarily a sensor of disrupted homeostasis, I think is a is an interesting concept. And it's something that a lot of us are interested in at the moment. But they're certainly t