How do parasites evade our immune system? (featuring Dr. John Hawdon)

27:07All right, and we're back. And now we are talking about the schistosomes. They cause a disease called schistosomiasis, and they're quite nasty parasites. And Daniel's laughing at me. Why are you laughing? I'm laughing because we just went from the ones you get if you eat poop to ones called schisto, which, you know, has some sort of resonance with other words we shouldn't say on the podcast. So tell me, is this another poop-related parasite? John? Indirectly. Indirectly. Its life cycle is a little bit different for a couple of reasons. The adults live in the bloodstream, and the eggs come out in the feces.

27:46But let's just start with the feces, and the eggs come out. They have to get into water. and when they get into the water they hatch and they get a small larval stage that now is on the hunt for a snail and in the case of schistosomes the snail is very particular it has to be a particular species they find it they penetrate into it and then they do several generations of asexual reproduction and what this does is it builds up the number of the next stage which is called a cercaria and this is the stage that's going to infect people. So in order to get schistosome you have to have contact with water that has had both feces and the right species of snail.

28:29And if you do the schistosome will swim and it will penetrate into your skin and then it will undergo a migration that goes pretty much hits all the highlights in the body. It goes to the liver, it goes to the lungs and eventually they come back to the liver and they pair up as a male and a female, and they move up into the vessels. And depending on species, it's either the vessels of the large intestine, small intestine, or the bladder. And here the male and the female live in what's called in copulo forever. The male has a body that's split, hence the name schisto, soma, split body. And the female nestles in there and is mating essentially all the time.

29:14with the male. And then they release their eggs into the bloodstream that then undergo a remarkable journey to get out of the bloodstream. This is ridiculous. I mean, it just seems so implausible, like step after step after step, and then you got a snail and it's got to do this and you got to go swimming. But my specific question is when you're swimming and the thing crawls through your skin, how big is this thing? Is this something you notice or just like you went swimming, you have no idea and now it's inside you. Yeah, I don't think you notice it. It's pretty tiny. And why did they have to be snailosexuals?

29:48Like, why do they have to do this thing inside the snail? Why can't they just do it themselves in the water? Well, they, first of all, will need something to feed on. They basically will feed on the snail and it absorbs nutrients from the snail and makes all these new stages, these circaria. The purpose of this is that this allows them to go from a single myricidium, it's called, that infects the snail into thousands of these cercaria that's going to affect the next host. And what that does is it increases the odds of infection by putting more of these infective stages in the environment. If the myricidium just tried to infect the host directly, even if it developed to the infective stage, the odds of that happening are pretty low.

30:33But the more of these infective stages you can put into the environment, the higher the The odds are that one or more of them is going to get into the next host. And in the case of schistosomes, you need a male and a female circaria to get in. So the snail is like a schisto amplifier or something. It's just like, wow. That's exactly what it is. Crazy. It's kind of ingenious. You know, the snail goes around grazing and collecting more food, and that energy goes towards making more parasites. And so the parasites are getting like a buffet for doing nothing once they establish in the snail. This is a pretty gruesome parasite in the host, though.

31:06It causes a lot of problems. And it's not because of the worm, which is relatively tiny and living in the blood vessels. It's because of the eggs. So this mechanism that gets the eggs out is really elegant, but it's very inefficient. So a vast majority of the eggs don't get out. They end up in the liver. And they form what are called granulomas when the host reacts to them. And that's where the damage comes from are these granulomas in the liver and other organs as well. Well, that was going to be my question. The hookworm we were talking about was mostly in the gut, and there was some sort of negotiation.

31:39You can hang out there because it's difficult for us to attack you anyway. But these guys are all over. I hear them being in the blood. They're in the bladder. They're in the liver. So the immune system does respond to them. It forms these glastelomas. Granulomas? Granulomas, yes. Thank you. Yes. Why doesn't it get rid of them? Well, the worms in the blood are pretty much untouched, and they have a bunch of immunovasive mechanisms as well. Wow. sort of similar to the hookworm, but different mechanisms. The eggs, on the other hand, they alter the immune system to make what's called a TH2 response, which is when you get a whole bunch of cells will come in and they'll surround the egg and form this granuloma, and then it will slowly move it through the tissue, right?

32:22And eventually they'll come to the bladder wall or the intestinal wall, and they will just basically dump the egg out, but they often get stuck. So you'll have these eggs stuck in the bladder wall. All this depends on the species, where it is. Is it in the bladder? Is it in the large or small intestine? But in any case, you'll get them stuck in the wall of those organs as well as in the liver. And then they're constantly releasing antigens that are pulling more cells in. And these granulomas can get very big and then start impacting the function of the tissue that they're in. And you get fibrosis in the liver.

33:00And it's Schistosomiasis can be really nasty disease. It's probably the most pathogenic of the worms that infect humans. I thought I heard, and remind me if I'm wrong, I thought there were some areas where the kind of schistosome that they have is near the bladder and the granulomas build up in the bladder. And every once in a while, like the males will get it so much that they will start to bleed along with the, you know, with the females of a certain age. And it's almost like a rite of passage. So many kids get this, that blood in your urine is just something you expect for both sexes. Is that still the case, John?

33:35Yeah, that's called schistosome hematobium. It's found exclusively in Africa. And yeah, it will cause, because these granulomas move into the bladder wall, they cause it to erode, and then you will get blood in the urine. And there's some evidence that I think they're pretty convinced now that schistosome, as well, some of these other trematodes can cause cancer as well, including bladder cancer in that case. Because of over years and years of this erosion occurring and the body responding to it and the eggs releasing these antigens, that it could result in cancer. Well, that sounds like something we should vaccinate against.

34:17Yes. I would be in favor of that, I think. I think schistosomiasis is one that we can do without. It's going to be just as hard, though, to make a vaccine, again, they have some promising candidates, but we're still a long way away from actually using a vaccine. Again, it's a sanitation thing, right? In this case, if you keep your feces away from water, you're not going to have a problem. Snail control is possible, but it's difficult. It's expensive. We see some promise with introducing predators that actually eat the snails in some areas. West Africa, they've done this. And they've seen, you know, you can combine it with chemotherapy and snail control, and you could see a huge decrease in the prevalence in the schistosome infections.

35:07But step one, you said, was keep your feces away from water. But in the previous segment, we were talking about toilets, and that's like the basic operating principles, like turn your poop into sewage, right? Right. How do you do both at once? Well, as long as you don't have snails in your sewage, you're going to be okay. And plus, People generally, I mean, if you're talking about Western sewage systems, you've kept away from the sewage the entire time. The water, you know, goes through sewage treatment plant and gets treated and converted back into usable water. So, you know, you're still breaking the transmission in that case, right?

35:42Remember, you need water and snails. This sounds like a particularly tricky problem because you've got like the adults that hide from the immune system. And then you've got the eggs that as they pass through the body definitely do not seem to be good at hiding from the immune system. And the immune system responds. And that's what causes the problem for people. So it seems to me that if you made a vaccine, you'd need to be careful to not make the problem with the eggs worse because now your immune system is over responding. Yeah, I think you would have to stop it before they got to the egg producing adults.

36:15And you would have to make your vaccine against the stages that are penetrating into the host. Do we understand how the adults are hiding from the immune system? Right. So they do several things. First of all, they will actually take host molecules and bind them to their cuticle so that then the host immune system doesn't see it as foreign. I mean, that's amazing. Yeah. Like, can we just sit on that for a second? That's like taking, like, you know, taking the skin off of a human and putting it on themselves or something. Wow. It's amazing. They hide with our own material. It's a wolf in sheep's clothing.

36:49Yeah. But that's not all. Go on. They also make what's molecular mimicry. They will make molecules that are very similar to molecules in the host, like a hormone, for instance, that will then get processed by the host enzymes and act as a suppressor of the immune response. Do we know how all of this elaborate machinery evolved? Do we have any idea of the history here? Is it like, do you need all these pieces together to survive? Can you do it one step at a time and refine it? How does it work? How does it evolve? Incrementally, and ones that add more and more mechanisms probably are better at survival.

37:24So you might have one of these things initially, and that lets more of them survive, and then you will get the mutations for the other things that occur, and they just pile up to have a whole suite of things that is really efficient at inhibiting the immune system. So each of these tricks is helpful. None of them are absolutely necessary. And so as you evolve, you develop more and more tricks to sort of optimize survival in the host. Wow. Impressive. I know this episode isn't about the history of Kelly, but when I read about this in Carl Zimmer's book, Parasite Rex, this was like literally a turning point in my life.

38:00I had gone from being like, parasites, oh, they're just kind of gross, to being like, holy cow, it's like amazing the way they've managed to hide inside of our bodies. And like it totally changed the way I looked at parasites and like literally altered the course of my life. So anyway. It infected your mind. It infected my mind. And now we got to share it with everybody. And so I'm very excited. Wait, no, this is the like intellectual version of the snail amplification. It goes into Kelly's brain, gestates for a while. She gets a podcast and then she spreads it to the whole community. Through John.

38:32John is my snail and I am the parasite. And this has gone too far. Okay, so let's, oh, can I play on the word shisto? Like take a break. Can we split for a second? Nope, not clever enough. All right, Daniel, do you have something? In case anybody needs to take a break and have a shist, go ahead and we'll be back in a minute to talk about another parasite. Ah, poop-related jokes, love it.

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42:20And we're back. And we are going to start with John's snail-related joke that he queued up during the break for us. Oh, wait. Did you just say that this might not be appropriate for the show? No, this one's fine. Okay. This one's fine. So I tell this in my class. So this guy goes to a Halloween party, a costume party, and he's got this girl draped over his shoulders. and he goes in and the host says, hey, how you doing? Great and everything. He says, are you a costume? He goes, yeah, this is my costume. I said, well, what's with the girl? And I said, well, that's Michelle. Oh, Michelle, he's a snail?

43:00I think I left out the snail part. Okay. We got there, though, as a team. As a team, we got to the end. Yeah, sorry, I blew the joke. So malaria has some tricky ways of evading the immune system, but we're going to start with the malaria life cycle and get to the immune system stuff in a second. And I've always found the malaria life cycle to be super confusing. It has a bunch of stages. All the stages have similar and kind of hard to remember names. So I'm going to give a super simplified version of the life cycle that I think will be sufficient for the discussion we're about to have. All right, so when a mosquito bites a person who's already infected by malaria, the parasite goes to the mosquito's gut and it starts to replicate.

43:49So after that, it moves to the mosquito's salivary glands. And that's right, mosquitoes have salivary glands. I don't know why that's surprising to me. But anyway, when a mosquito bites a person, the parasites are injected by the mosquito into the human body. The stage of the parasite that gets released into a person is called a sporozoite. This is the only stage we're going to name. So just remember, the sporozoite is the early stage in humans. From there, the parasite moves on to the liver and does some replicating. After that, it moves on to our red blood cells. When a parasite gets into the red blood cell, it's able to sneak proteins through the surface of the red blood cell.

44:31and those proteins stick onto the surface of the red blood cell. This helps the parasite hide from the immune system and I'm sure John's going to tell us more about this later. All right, so the parasite is living in the red blood cell and it's eating the hemoglobin in the cell. And as you might remember from our past conversation about synthetic blood, hemoglobin is the protein in your red blood cell that helps your cells carry oxygen to different parts of the body. So the parasite is hiding in the red blood cell and chowing down on the hemoglobin. It's replicating while it's in the red blood cell.

45:05And every like 24 to 48 hours, the red blood cell will burst open and these newly released stages will go off to search for new red blood cells to infect. So that like red blood cell cycle will start again. Over time, a lot of the red blood cells get infected this way. So you're regularly losing your red blood cells, which can result in anemia and your body gets poisoned when these red blood cells burst open and all of the stuff that used to be in the red blood cells is now like in circulation and that's not good. Plus, when the red blood cells burst, there's suddenly loads of new parasites in the circulation and the immune system goes nuts.

45:44You get chills, you get fevers, et cetera. And the parasite is bad for a lot of other reasons, some of which I'm sure John is gonna tell us about in a few moments here. And all of this, I'll note, is particularly dangerous for children or for adults who have never been exposed to malaria before, like travelers, for example. And does it use the mosquito just as a way to get from one body to another? Or is it something that happens inside the mosquito, like snail amplification? Oh, yeah. Very important part of the life cycle happens in the snail. So there is an amplification in number, plus there is also sex or recombination occurring in the mosquito.

46:19So we can definitely blame the mosquito for part of this. Absolutely. Absolutely. Good. And, you know, you blame the female mosquitoes because they're the only ones that take a blood meal. I don't like where this is going.

46:33I'm broadly anti-mosquito. Female, male, I don't care. I'm not sexist about it. You know, it doesn't work without the male, so they're partially involved, but they're not the ones that are biting you. Yeah, exactly. Blame them all. I'm broadly anti-dipteran. So dipterans are flies and mosquitoes. I'm not a big fan of any of them. But anyway, so inside the body of us, We get these cycles where they live in our red blood cells, they replicate and then they burst out of our red blood cells and then they go back into red blood cells. So it seems like when they're in red blood cells, I can imagine it would be harder for our immune system to find them because they're like hiding in our cells.

47:09They have evolved ways to transport things across their membrane, across the vacuole membrane, to be displayed on the red cell membrane. and one of the things that they display is a molecule called in the case of plasmonium falciparum which is the most dangerous one erythrocytic membrane protein one or as we i call it pfemp one and pfemp one then is expressed on the surface of this of the cell so there is an immune reaction that develops against this pfemp one molecule and the pfemp is interesting because it is able to bind to receptors in the blood vessels, the veins of the host. And it basically takes those out of circulation, right?

48:00So they're bound to the inner vessels, right, of your larger veins and everything. And they just sit there, so they're not being circulated through the spleen, which would recognize the red cells as being deformed and would take them out of circulation. So that's one way they avoid the physical destruction associated with the spleen. And they'll sit there and they'll do their replication bound to these vessels. And that's also a major cause of the pathology because when they bind to the small vessels, like in the brain or in the placenta, in the kidney, this is where you get this micro occlusion of the capillaries and you get decreased oxygenation And then you get the metabolic acidosis.

48:43And these are the kind of things that cause the big problems with malaria. I'm not 100 % sure I understand. Let me see if I can explain it back and if I'm right. So I think what you're saying is that the red blood cells, they end up with the stuff that sticks out of the cell. It connects them to like the veins or arteries so that they don't go to the spleen, whose job is to remove infected or disfigured cells and get rid of them. So they essentially keep themselves from going to the police station by hanging on in one spot. And if that happens like in your brain or in a placenta, it causes clogs that are bad.

49:20Right. And it seems to be particularly bad. Like that's one of the major causes of the cerebral malaria, which is the big killer. So then what are the possibilities here for a vaccine since this sounds pretty bad and we all hate mosquitoes and nobody wants this stuff in your brain? Yeah, that's a good question. So I think most of the success for the vaccines has been against the sporezoite. If you have an immune response to sporezoite when it gets into the skin, that can stop the infection right there. And there are some promising vaccines, some that have actually been used or in use that maybe give you 60 % protection or so.

50:01I'll take it. Yeah. It's kind of what a flu vaccine does too. Yeah, so there are some promising ones, and there may be more in the future because it put a lot of effort into this vaccine development for malaria. And definitely would be a good thing. You just need to prevent people from dying because as they live there, they're going to build up this natural immunity that occurs over time, and it won't be an issue anymore. But it'd be important for kids and also for travelers. Like if you're going into Africa and you've never had malaria, then that would be very useful to have a vaccine or for the military or something like that.

50:42So there's definitely a need for vaccine here. We're getting closer, I think. There are, like I said, several have been deployed. So it's promising, I think. More so, I think, than with the worms at this point. Oh, yeah. We never said what kind of an organism malaria is. So the first example we talked about was a nematode. The second one was a trematode. And malaria is a protozoan. Protist. Protist, yeah. Why is it so much harder to make vaccines for parasites than for bacteria and viruses? And so my first question is, is that actually true? I feel like the answer is yes. And then is there a big picture reason for why?

51:19Well, okay. It's generally it's true, but think about HIV. I haven't had a vaccine against that yet, right? Yeah. So it's not always easy to do. But I think it's because the immune system seems to be much better able to handle small things, right? You can make an antibody response. It'll bind to the bacterium or to the viral particle. And then you can get your complement system involved to destroy it. But, you know, the pathogens have ways to get around the immune system as well, right? So your bacteria and your viruses could subvert the immune system too. Wait, I didn't understand that first thing you said, and it reminds me of a big puzzle in physics.

52:02You said essentially the immune system is better at attacking small things, but big things are all made out of small things. So why can't it just attack all the small things that a big thing is made out of? It's like the puzzle of like every classical object is made of quantum particles. Why can't we understand it? I'm not suggesting there's quantum mechanical magic happening here, But what keeps the immune system from attacking each individual cell inside one of these bigger objects? In case of the worms, they all have a cuticle that protects the inner cells from damage, right? In the case of like the hookworms, the immune system is able to go after the small part of the worm, which is the gut, right, that is exposed.

52:42It also takes a lot of cells to kill, you know, a bigger worm. It's just harder to do, I think. And like I said, a lot of the mechanisms where worms involve things like, well, we're just going to flush them out, right? We're not going to try to kill them. We're just going to try to flush them out. Whereas we have cells that will actually ingest viruses and opsonize viruses, at least, and bacteria, right? They recognize the antibody and they bind to it and then ingest it and destroy it, right? So it's a lot easier to do that than it is to try to kill a big worm that's got this protective armor around it and is living in the gut, for instance.

53:23Yeah. So as a biologist, one of the things I think is super interesting about this conversation is not just how do the parasites evade the immune system, but it's also just that they have such complicated life cycles. There's so many different places where you could choose to try to protect against parasites. So, you know, for mosquitoes, you can pay for bed nets because the mosquitoes are most active at night. And maybe you just keep the mosquitoes from biting. And maybe that's even, you know, better than some of the medicines. Just, you know, if you don't encounter them in the first place, that's helpful.

53:49But, you know, all of these systems are evolving. So if you, for example, go after the mosquitoes with pesticides, they evolve resistance. And anyway, it's a very complicated problem. And all of those complications is sort of what got me interested in parasitology in the first place. Anyway, back to Kelly's origin story. But this has been a fascinating, fascinating chat. Thanks so much, John, for coming on the show to tell us all about the parasites you study. You're welcome. And the parasites you don't study that I put you on the spot to talk about anyway. Well, you know, all these years of teaching, I've learned something.

54:22That's excellent. You've learned how to nail a snail joke or snail it, I guess. Yeah. Well, John, let's save those for another episode. We don't want to overwhelm the audience. Thank you. It was fun.

54:39Daniel and Kelly's Extraordinary Universe is produced by iHeartRadio. We would love to hear from you. We really would. We want to know what questions you have about this extraordinary universe. We want to know your thoughts on recent shows, suggestions for future shows. If you contact us, we will get back to you. We really mean it. We answer every message. Email us at questions at danielandkelly.org. Or you can find us on social media. We have accounts on X, Instagram, Blue Sky, and on all of those platforms, you can find us at D &K Universe. Don't be shy. Write to us. This July 4th, come celebrate at America's Block Party, hosted by America 250.

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56:06Grab the fam, head to a Simon Center, and make it a day for the books. It's a celebration thing. Sign up today at SimonPlus.com. Rewards program terms apply. See SimonPlus.com for details. Ready to finally clean out your closet? With Trashy, you can donate your clothes, reduce waste, and earn cash rewards. All in one simple step. Just fill a take-back bag, send it in, and get rewards cash back for every bag. And now with Trashy Unlimited, you get unlimited bags for just$48 your first year. Clean out, donate, earn rewards. Visit Trashy.io to get started. With my mom and dad living in Orange County, when we bring my five and seven year old to visit, we are sometimes in for a two hour drive that could feel like 10.

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