So they focus on a mosquito and Jurassic Park, maybe they should have focused on a kissing bug. Yeah. Would have gotten a lot more DNA out of it. [laughs] [music] Science! Hello everyone and welcome back to People, Parasites and Plagues. Podcast aimed at delivering information about the fascinating pathogens among us from the scientists who study them. I am David Peterson. And I'm Kim Klonowski, your host for today's episode. The human microbiome is frequently in the news these days, along with advice about the importance of maintaining a "healthy microbiome." Today's guest studies a very different microbiome, but one that's also critical for the health of its host. Our guest today is Dr. Kevin Vogel, assistant professor in the Department of Entomology, College of Agriculture and Environmental Sciences. Kevin, welcome to the podcast. Thanks for having me. So one thing we'd like to ask our guest is about their path to a career in science. So was science always the plan for you? Yeah, I feel like I was one of those kids who from a very early age knew that I wanted to be a scientist. Didn't know what that looked like and didn't know what it meant. So kind of went down the traditional, "I'm going to go to medical school pathway." But then in early undergraduate, took introductory biology. And that class was very focused on current research. And it just absolutely blew my mind. And you know, within a month or two knew that that's what I wanted to do with rest of my life. So did that involve getting into the lab pretty early on? Did that kind of hone your experience into doing research? So I was really fortunate in that in my sophomore year I was able to get into a lab studying entomology. Initially I was a microbiology major as you can see how these things dovetail. But when I was an undergraduate, I had the opportunity to work in an entomology lab because they hired a lot of undergraduates. And sort of rekindled this love of the natural world that I guess maybe I had lost a little bit in my early days of college in late high school. And just absolutely fell in love with working with insects. And really after that sought out ways to combine those two things. And I had two like absolutely excellent undergraduate mentors who really shaped and like brought me into the process and kind of guided me on this pathway. So how did they get you excited about working with bugs? That's a good question. I think maybe I was inherently excited about it. But I think what really made the difference of working with them was that I was you know quickly treated as like an actual important part of the team instead of just you know the kid who does dishes or the kid who rears inside. And you know it I think it was just a great combination of personalities. And I think they were just really really good mentors and knew what they were doing. So one thing I'd like to do off the bat is offer congratulations on your being awarded the NSF early career award. Thank you very much. So that's that's a huge deal. And you're going to use it with your work on triatoma bugs which are transmitters of shogas disease. But I thought we'd start out with having you given overview of shogas. So shogas disease is a eukaryotic parasite, trapanosoma cruisie. And it's transmitted in a number of ways. But the way that I am interested in is that it's transmitted by kissing bugs, which are a group of blood feeding exclusively blood feeding arthropods. They feed on verbrate blood. And in the process of taking those blood meals, they can acquire the parasite which stays in their digestive tract. Goes through a complex developmental cycle. And then in subsequent feedings of this bug when it's feeding on a host, it can defecate. And the parasite is excreted in the feces and either through the bite wound or through scratching near the bite area or close mucus membranes. That parasite can then invade the vertebrate host can establish a different infection cycle in another host. These bugs are a lot different from mosquitoes which are probably the blood feeding insect most people are familiar with. So for one thing, they're a lot bigger. Much. So a mosquito can take a blood meal of a couple of microleaders, whereas a kissing bug, some of the species that we maintain in the lab can drink up to a milliliter of blood. So almost a thousand times more. You would definitely notice it if you saw it. But they have a tendency to feed when their hosts are sleeping or inactive. So a lot of the times you don't realize you've bitten, bitten, until you've seen the resultant sore near the bite wound. And one of the things also that distinguishes kissing bugs from mosquitoes is that mosquitoes have complete metamorphosis, right? They go through larval stages and pupil stages and become adults. Kissing bugs don't go through complete metamorphosis. And one of the consequences of that for kissing bugs is that they feed on blood at every stage of their life. And then they post them asketos were only the adult females blood feed, the larvae feed on to tritus and water, the males feed on nectar. And so this is the only food source that these insects consume. And that means that they have multiple opportunities throughout their life to pick up these parasites and transmit them because they need to take a blood meal every time they go through a developmental stage. They need to take blood meals every time they reproduce. And also the interesting consequence of that is that blood is not a great meal to subsist on. And there are other groups of insects that have evolved this feeding habit and all of them require bacteria to be able to successfully develop. Okay, great Kevin. So that gets us to your research. And you're looking at the microbiome that's present in these insects. And you talk about what encompasses the microbiome of these insects. Is it like humans where you have a high diversity or organisms? Just tell us a little bit about the basics and start there. Yeah, so what's interesting is this is one of the first systems that people really intensely looked at the microbiome and it started back in the 20s. And initially it was that, oh there's this one bacteria and it's super important. And that's the symbiot. But then as people started looking at more and more different species of kissing bug and I should say that kissing bugs are about 130 species. As they looked at these other species, every time they looked at like well, it's a slightly different microbe that's living in that gut or maybe it's a couple of microbes that it's not consistent between populations. And then with the advent of modern molecular sequencing, we can survey at great depth these microbial communities and it turns out if you go out in the wild and you survey these communities. A lot of times there, you know, dozens to hundreds of species of microbes living in their guts. And what we're really interested in is which of those microbes are actually important and which might just be commensals that are hanging out. So again, you alluded to this earlier that the blood meal is not sufficient for the bug to get all the nutrients. So is the microbiome participating in again this mutualism with the bug itself by helping it with some nutrients sources? Yeah, so the role of these microbes has long thought to have been producing B vitamins. And B vitamins are just popperate, biologically unavailable in vertebrate blood. And all other insects that exclusively feed on vertebrate blood have bacteria and those bacteria seem to be able to synthesize those essential B vitamins. And so if we take those bacteria away from the insect, they can't develop because they lack that essential nutrients. So these are important for the successful development of the insect. So another part of your work is the interaction between these insect gut bacteria, the microbiome, and the host insect immune response. And these are also hot topics in human disease, human immune response, human gut microbiome. But before we get any deeper here, why don't you tell us a bit about the insect immune system? Because I think it differs quite a bit from animals. Definitely. So insects lack the adaptive immune system that we are familiar with in humans where you have the cell population can produce antibodies and they have this cellular immunity that allows them to respond more effectively upon subsequent exposure. And insects have an innate immune response that is pretty powerful and is good at fighting off infections but doesn't have that branch of it. Vertebrates also have an innate immune response and in some ways these are homologous between the lineages, but it does change the way that we think about things in that it's like what are the responsive elements of that insect immune system? And how do they, quote unquote, learn what's friend and what's foe? That's something that we're very interested in. And just maybe remind people who are immunologists who are thinking about innate immunity, the toldic receptors were originally discovered in insects. So we know a decent amount about the innate immune response in insects. Maybe, maybe not. I haven't really followed that so I don't know how far we've gotten if it's just the identification that receptor. We know quite a bit and what's been fascinating as genome sequencing has advanced is how much variation there is among insects in what the components of these pathways are, how they interact with each other. Obviously, you know, we know a lot about Dr. Soffil and the Lanagaster and we know a lot about the mosquitoes that transmit diseases because those obviously are hot topics of research. For a long time, it was thought that kissing bugs lacked one whole path of the innate immune response that insects have. And only once we sequence this genome where we're using it.
able to actually find those genes, they're very divergent. The immune system is highly paired down relative to certain other insects. Say we're on the cusp of really starting to understand what's going on in kissing bugs, much more than we used to be able to. Is there anything that's unique in kissing bugs? Not unique necessarily. What's surprising is what they've lost. Gost. Right. Right. Right. So. In terms of at least I know for humans is that the immune system also is important for the establishment of the microbiome. So there's kind of this crosstalk between them, but that's mostly on the adoptive immune side. IGA is very important for setting up the commensals that eventually colonize your gut. But does it play an important role of kind of selecting what organisms can stay as a part of the microbiome? Does the immune system play a role in that? So that's this active area that we're really excited about right now. I don't have a firm answer for you yet. Okay. But that is a main thrust of a research program in our lab is, you know, how does the immune system shape that microbiome? So we know in the bugs that we study that there's this one bacteria, rotococcus rodneyi, that is very, very important. If they don't have that bacteria, the bugs can't develop. That doesn't mean that there aren't other bacteria that are involved in it, but that's the one that we've been able to focus on and we've kind of reduced it to this very simple system. And what we'd like to know is how does the host immune system recognize that as not a pathogen. And to be honest, we don't know yet. So we're actively looking at that. And we think that there are certain genes that are involved right now. We're just not in a place that we know it for sure. But we think we've identified some genes that are really important for both maybe either recognizing or allowing that bacteria to adhere to the gut and stay there. But we do know that that symbion doesn't elicit the same immune response as a pathogen does. So you have this one species, rotococcus rodneyi, which is in rodneyus prolyxus. That's a mouthful. That single bacterial species alone will allow the bugs to mature and survive. But if you add an additional species of bacteria, the bugs grow better or do you just need that one and that's it? So from our results in our lab with our colony, it seems like that one bacteria is both necessary and sufficient. And in fact, when we have more complex communities, the fitness of the bugs decreases slightly, significantly but slightly. They lay fewer eggs. It takes them a little bit longer to reach adulthood. You know, they're still healthy and that's how we normally rear the bugs in the lab. But when we are really careful and we make sure that they only have this one bacteria in them, that's when they seem to have like peak fitness. But again, that's a lab thing and probably in the wild is not likely to exist. Okay. And I think you've also shown that this one symbion, the rotococcus rodneyi actually grows better in the gut than other related bacteria. Yeah. So again, this might be related to the immune system and we don't really know. But when we inoculate the bugs with the same amount of various different bacteria, rotococcus rodneyi reaches much higher concentrations, titers than other bacteria. Eating bacteria quickly purged from the gut and whether that they just can't hang on and they get washed out through digestion or whether the immune system is attacking them, we're still investigating that. We think it might be a little combination of both. So if you, so this bacteria is so important, if you target this bacteria, do you basically eliminate the vector? Is that kind of the idea behind that? So it's interesting because in reality, what we want to do is support the bacteria and there's been a lot of work done by some folks at the CDC back in the late 90s, early 2000s where they took that bacteria and they genetically altered it to produce an anti-tropanosomal molecule and then they infected the bugs with that bacteria and then they were resistant to being infected with T.C. Resisting. Sounds like a great answer. It does. And the best part about it was that they then took this and how do you then apply this in a field setting and what they came up with was basically artificial kissing bug poop. And they would spray this in these mesocasms and in these test houses and then see if the bugs could pick up the bacteria and then whether those bugs maintain that ability to fight off T.C. And they did. They called it cruise guard. And unfortunately for a number of reasons that never got commercialized or never got deployed, I don't even think it was meant to be commercialized but it was never deployed in the field at scale. I think people were a little bit afraid of the idea of releasing a genetically modified bacteria into the environment and you know, once it's out of the bag, it's out of the bag. Right. And we think about people who get their panties in a knot about things like genetically modified crops, right, to produce a better tomato or corn or whatever we're talking about. And now we're talking about releasing an organism. I can only imagine some of the pushback. Yeah. And our bacteria doesn't fall into this umbrella but it is related to bacteria that can cause disease in humans. So the ability of bacteria to shuttle genes between themselves is a real concern. And you're introducing a gene that perhaps makes it more pathogenic, probably unlikely given what it was targeting but my understanding was that that was the major reason why it never really took off. Yeah. And that makes sense now with that information, sure. So I think one of the findings of your work was that the host immune genes which we've alluded to already are actually upregulated in kissing bugs that are colonized by this rotocopy rotocus radnii compared with bugs that don't have any bacteria. That it almost seems counterintuitive if you want to keep the bacteria around why upregulate these immune genes or am I overthinking this? No. You got that right. And we're really fascinated by this because it seems that when the insects are infected with their symbiont, they're almost supercharged in their ability to fight off other pathogens. Whereas if you take that symbion away, they're incredibly susceptible. When we challenge them with a pathogen, if they don't have their symbiont, it's almost 100% lethal, 100% at a time. Whereas if they have that symbiont, even against pretty virulent pathogens towards these bugs, we still get 75, 85% survival. And some of that seems to be due to increased expression of immune genes and some of it right now seems to be related to increased presence of immune cells. So insects have cellular immune responses where you have these specialized blood cells that go around and have various ways of killing parasites and pathogens in their bodies. So when they have the symbiont, that immune system seems to be supercharged. So are these analogous to like a macrophage? That would be the kind of closest thing that we would know and not knowing very much about vertebrate immune system. Well, so we're talking, this is a good conversation, right? Because I'm coming from the vertebrate immune system and you're coming from the invertebrate and trying to, you can see we're dancing around. Oh my, I don't want to say, and it makes me sound too stupid. Yeah, so they have cells that are capable of agystetizing bacteria and viruses. They have cells that can attack larger bodies that will encapsulate the pathogen and kill it that way. They also will melanize things so they produce something called melanin and melanin is pretty toxic to bacteria. So right now what we know is that the hemolin of those bugs by itself with no cellular components in it is lethal to certain bacteria. We've tested that in vitro. And then in other circumstances in vivo, we see increased production of these immune cells in the bugs that have their symbionts relative to the ones that don't. And then the other thing that we've done is we've used bacteria that are not symbiotic but are not pathogenic. So E. coli kind of hangs out, doesn't really do anything. Some of the bugs will survive to adulthood and reproduce, but not nearly as many as when they have Robococcus runny. And E. coli doesn't seem to be capable of doing this. So it's there, probably serving some nutritional function can produce some of the B vitamins they need. But from the immune standpoint, that doesn't seem to do the trick. So there is an amazingly close interaction between the host and the bacteria here. The bacteria is necessary. It has a very specialized place. So the, I'm using bug int for too many things here, both the host and the gut bacteria. So the host bug basically gives the bacteria a special dispensation to survive. And the bug provides necessary nutrients. the host says, "Okay, even if I upregulate my immune system."
I'm leaving you alone. Yeah, and we're not, one of the questions we have is this, this is just a function of, this bacteria is immune to those responses, right? Using them, using immune in a bad way here. But is the bacteria resistant to host immune responses? That's something that we're actively looking at right now. I don't have an answer for you yet, but it seems that it's possible that there's something about this bacteria that masks it from the host immune system, but then how does it trigger this differential immune response? And there's no other member of the bio and that's related to it that you can look at the differential to kind of see if it's specific to that particular organism. So we do have this really cool situation where we have what we think is the closest known relative of this bacteria. And it's called rotococcus tritome. It was isolated from a different kissing bug. And so you have this other bacteria that was isolated from another kissing bug. And the first thing we said is, well, what if we put that in Rodinian's prolixes? Does it work as a symbion? And it doesn't. Like it's lost very quickly from the gut community. And we haven't yet tested whether or not it functions in this immune way, but we're guessing that it probably doesn't. And they share 85, 90% of their genes. So that narrows it down quite a bit in terms of what might be different between these. We have some ideas, but right now they're all just speculative about what's going on. But that's definitely, I have way too many projects and not enough money or people, even with these grants, I'm like, anymore. But yeah, that's one of the areas that I'm really interested in. We actually have a new postdoc just joined my lab. And one of the things she's going to be looking at is what happens when you put symbionts from different kissing bug species into a new species and see does it still function? And so that's the, I think that's the first project she's about to tackle is because we also have the species we think that that bacteria, that other sister bacteria was isolated from in our lab in colony. So. Okay. So we can do the reciprocal. So. So how long have these bugs been around and been transmitting disease? I should know this off the top of my head, but I believe that they're thought to have evolved somewhere between 15, 60 million years ago. So in the bug world, that's not super old. They evolved out of a lineage of predatory bugs that are assassin bugs. And, uh, regi-v-ids and probably some of you listening have seen a regi-v-id in your yard and your garden, they're great predators. And we think that they evolved as insect predators in the nests of vertebrates. And then one day they just realized there's this big, you know, defenseless thing sitting right here that's a lot easier to eat than another insect that's running around. They're endemic to the new world. The vast, vast majority of species are only found in Central and South America and Mexico. So yeah, they're somewhat newcomers. They're not near like the tetsiflyes, which have been feeding on vertebrates for a much longer period of time we think. So, so knowing that are there, uh, has this organism, has this microbial organism that's in the bug of the bug, if you will, it has it evolved with the insect, do you know, from like aged bug experiments, zombie mummy bugs, if you will? I don't think that they're, I don't know if anyone's found that my training is in looking at more ancient associations and more obligate associations between insects and their symbionts. And we don't necessarily see the hallmarks in the genome of the bacteria that we would expect of like a vertically transmitted obligate intracellular symbiont, like the symbions of aphids, or the symbions of tetsiflyes. So tetsiflyes also feed exclusively on vertebrate blood and also have bacterial symbionts that are necessary for their development. Those bacteria are transmitted from other offspring with super high fidelity and primarily live intracellularly in the host, whereas ours live free living in the gut. And so the symbionts of tetsiflyes have these hallmarks of an obligate bacterial symbiont where as our bacteria does not. So we don't have fossil evidence that I know of, but again, I'm not a paleoentomologist. I think that's probably a field. It must be. But genome-wise, it doesn't look like it's one of these super old associations. That's not to say that we don't think that there is co-evolution between the host and this bacteria. There was a paper not from my group, but from another group recently that found members of the genus Rodococcus are universally present in members of the kissing bug genus Rodinus. So there are a bunch of species in Rodinus. They surveyed their microbiomes. Every single one of them had Rodococcus in it, which suggests that there's some sort of specific association. And our lab results sort of support like a functional reason for that. That these bacteria are able to persist in the gut better than others. So these kissing bugs, given how long ago they evolved, they could have fed on wily mammoth, giant sloth, saber tooth tigers, maybe dinosaurs. Again, I'm skeptical, not skeptical. I'm hesitant to say what to put a specific date on it. But yeah, it seems my, again, my understanding is that they are ancestry mostly associated with birds. So again, I'm not confident about that. Dinosaur could be in the mix then. Could be. Exactly. Exactly. I think it's, you know, we're talking non-avian dinosaurs, but. So they focus on a mosquito and Jurassic Park. Maybe they should have focused on a kissing bug. Yeah. Would have gone a lot more DNA out of it. So our guest today is Dr. Kevin Vogel from the Department of Entomology. Kevin, thanks for being with us. Thanks so much for having me. This was a lot of fun. Thanks to additional information about Dr. Vogel's research can be found on our Instagram account, which is @PPPodcastUGA. Thank you for tuning in today. Please rate the podcast and if you have any questions or suggestions for future episodes, reach out to us via email at
[email protected]. This podcast is brought to you by the Faculty of Infectious Diseases and the Grady College of Journalism at the University of Georgia. It is supported by the University of Georgia through the Office of Research, the UGA Graduate School, and the College of Veterinary Medicine. Thanks to the new media Institute of Grady for use of their Studio Not Found Podcast facilities and a special thanks to our production assistant Sid Wiggand for research, editing, scheduling, and keeping us on track. [Music]
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