This Podcast Will Kill You - Ep 121 Tularemia: Hare today, gone tomorrow

Episode Date: July 25, 2023

The CDC’s list of highest priority bioterrorism agents is a short one, with only six pathogens making the cut. Among the more familiar names on the list, such as anthrax, botulism, plague, smallpox, and viral hemorrhagic fevers, is the topic of today’s episode: Francisella tularensis. Unless you’re a hunter or work with small mammals, you may not recognize the name of this pathogen or the disease it causes - tularemia - let alone the characteristics that earned it a place on the CDC’s list. By the end of this episode, though, all that will have changed. Join us as we explore why this pathogen’s brutal biology makes it a force to be reckoned with, how the history of its discovery has surprising origins in the devastating 1906 San Francisco earthquake, and what promises future research may hold for protection against this deadly disease. See omnystudio.com/listener for privacy information.

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Val, bad pun. Outdo it with Intuit QuickBooks. Feature availability varies by product. E.F. Male, age 49, physician, began investigations of tularemia in Delta, Utah, July 23, 1919. His exposure differs from the other cases to be reported, in that in addition to exposure to laboratory animals, he took blood and pus on two occasions from a human case which terminated fatally. On the 30th day of his investigation, August 23, 1919, E.F. became ill in the late afternoon, feeling tired and weak and having a temperature of 102.2 degrees. His fever continued until the 24th day. During the first 12 days of his

illness, he packed up his laboratory equipment and animals in Utah with great difficulty and proceeded with them to Washington, D.C., and after his arrival, made a futile attempt to continue work. The next 14 days he spent in the hospital, lying on the bed, but not confined to the bed. The departure of the patient from the hospital on the 28th day was attended with some forced exercise, which resulted in a secondary rise of temperature,

which lasted four days, after which it remained normal. The second month was spent in a hotel, lying on the bed most of the time. The third month was one of slow convalescence. Throughout the illness, there was an absence of localized pain or tenderness, except that on the 16th day of illness, a sore throat developed on the right side. Practically, the only complaint was that of languor or weakness and a desire to remain quiet on the bed. Well, yeah.

So long. I know. It's such a long. And then if you kept reading this paper, there were like, oh, and then when it, when it recurred or whatever relapsed or I don't know what what the technical term is for it, protuleremia. But yeah. But the thing that I really like about this firsthand account is that the initials EF,

that stands for Edward Francis. As in Francesella, to Francis. Oh, wow. Oh, poor guy. I know. I know. It took him like a long time, apparently, according to one paper I read, to realize that this was tularemia, that what he was experiencing was tularemia. But then in retrospect, he was like, oh, yeah.

And then he tested his blood and the blood of several other laboratory workers and found that indeed it was tularemia. Oh, my gosh. Yeah. So that was from a paper that he and a colleague wrote in 1922. Wow. Yeah. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike.

And this is, this podcast will kill you. And today we're talking about tularemia. Yeah, this is kind of a classic one, I would say. And my guess is that a lot of people have never heard of it. Which is interesting because, like, I knew the name tularemia and then I had this vague association with rabbits in my head. And that was it. But there are so much more to this.

And it's such a big name in terms of. of public health because it is, you know, a potential agent of bioterrorism and all. So, yeah, it's very interesting that I also knew very little about it. And I think there's probably a lot of people who've never even heard of it. Yeah. And by the end of this episode, you'll be going, how did I not know about this? I hope so. That's the goal.

Yeah. Okay. But let's get into the episode, you know, starting with. Quarantini time. Quarantini time. What are we drinking this week? We're drinking a drop will do you? We are.

So named because the infectious dose is like 10 to 50 individual bacteria. Yeah. 10 bacteria. It's scary. But the recipe is not. It is a very, did you like that segue? Yeah, I sure did. It's a very delicious and fairly simple kind of take on a mojito with watermelon and, of course, mint, and lime.

A little bit of simple syrup and some vodka this time instead of rum. Right not. Change it up. We'll post the full recipe for that quarantini as well as our non-alcoholic placebo. On our website, this podcast will kill you.com and our social media. Oh, I liked that. Thanks. And on our website, you can find all kinds of things, including but not limited, certainly, because I don't have the website in front of me, to things like our sources for each and every one of our episodes, our transcripts, our merch links, links to music by Bloodmobile, links to our bookshop.org affiliate account, our goodreads list, Patreon, more stuff. Check it out. wonderfully said, Erin.

On that note, shall we get started? Let's do it, right after this break. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients, so there's no meal planning and no extra grocery trip. There, assemble and bake meals take about five minutes of hands-on prep. Just spread the pre-chopped ingredients on a sheet pan, put it in the oven, and that's it.

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stretch wide-leg jeans, and they are now in constant rotation. They are so comfortable. The fit is amazing, and they come in a bunch of different washes, so I'm about to go order some more. Refresh your wardrobe with Quince. Go to quince.com slash this podcast to get free shipping on your order and 365-day returns, now available in Canada, too. That's Q-U-I-N-C-E-com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. Francisella Tullerensis is a gram-negative, facultatively intracellular, coxobacillus bacterium, and the causative agent, of course, of Tulleremia. It turns out that there are four subspecies of Francisella Tularensis, subspecies Tullerensis,

subspecies Holartica, Media Asiatica, and Novosida. or novicida. That one I saw sometimes put in its own species and sometimes a subspecies. And I was like, there's probably some drama behind this, but. There is some drama. And from what I can tell, it was like in 2006, they made it a subspecies. And then 2010, people were like, no way, it's its own species. But then after that, they're like, nah, nah, it's a subspecies.

So that's how we'll call it. Yeah. In any case, we're not going to talk about that one very much because it. It's only Francisella tularensis subspecies Tullerensis, which is endemic to North America, that is the most virulent and the cause of the most severe disease. And Halectica is found throughout Eurasia and in North America and is the other major subspecies of Francisella Toularenceus that causes disease in humans. So those are the two subspecies that I'm going to be focused on. They're also sometimes called type A and type B in the literature.

sure. But realistically, I'm just going to be talking about Francisella Toularencis, or I might even just say Tulleremia for the rest of this section. Sounds good. Great. So like we said at the top, Aaron, I kind of knew that this was going to be an interesting episode because I at least knew that Tulleremia was a potential agent of bioterrorism or a potential bioweapon. But as I often do with this podcast, I really underestimated just how interesting of a bacteria. this is. We're always underestimating how. You would think that we learned by now. Yeah. Well, let's get into it, shall we? So like I said off the top, this is a facultatively intracellular bacterium. What that means is that it can live both freely in the environment, as well as live in and replicate within other, i.e. host cells. And we'll talk a little bit more about that,

what cells it's replicating in in detail. But as far as hosts go, this is a bacterium that can infect hundreds of animal species, mammals and birds, and many different species of invertebrates, which end up serving as arthropod vectors. It was giving me Shagas disease vibes in that regard. Yeah, totally, totally. But even Shagas disease, it's mostly, it's really just one vector. Right. Exactly. Yeah, multiple species, but one, one vector. Yeah. Meanwhile, tularensis is just like anytime, anywhere, anything, you know, let's make it happen. So I am going to focus on what the disease tularemia looks like in humans and therefore how the life cycle ends up spilling over into human populations, how we get infected. But this is by no means primarily a disease of humans. It's fortunately quite a rare

disease of humans and primarily a zoonotic disease of many different wildlife species. And like we mentioned early on, Franceslla is also highly infectious. So as I talk about how it gets into us and does all of these party tricks, keep in mind that as few as 10 individual bacteria can cause infection in humans. Did you just describe causing disease in humans as party tricks? Yes. Is that not a party trick for a bacteria? I guess technically, yeah. Look what I can do. Yeah. Look at me, mom, you know. So let's get into this nitty-gritty of how this bacterium lives its life, how it infects ourselves, and what it actually looks like when we get sick. To begin the life cycle of Francesella Toularencis is a little bit difficult because we don't fully know the ecological niche of this bacterium at all. all. We don't know the major natural reservoir hosts or the major environments even that are

conducive to the growth of this bacterium. And keep in mind, like I said, there are several different subspecies that can all persist in the environment and live intracellularly inside of host cells. Because it's a pretty difficult bacterium to grow in the lab in culture, there is some thought that perhaps in the environment it's not just persisting on its own. Maybe it's in a host like an amoeba or a protozoa. Who knows? It's unclear. But it can infect and be a pathogen of a whole bunch of different animal species. One paper I read said over 250. Other papers said over 190. So like a lot of animals. A lot. including mammals and birds and arthropods. Which is amazing. I know. Just the different, like how diverse the animal species are that this bacterium can infect.

All of our different cell types, different immune systems that it's having to evade. It's really impressive. Yeah. When it comes to spillover from animals into humans, the two biggest groups of animals that are commonly found infected and thought to be kind of like the culprits of spill. are lagomorphs, so rabbits and hares, and rodents. So things like mice and rats, but also prairie dogs, voles, even aquatic rodents like muskrats and beavers and things. And I had to look up to make sure that all of these things were really rodents. What a diverse group rodents are. Really, truly. Yeah. But in many of these species, this bacterium seems to cause an acute infection

and make all of these animals quite sick. So it's perhaps less likely that any of these species that we commonly find Francesella Toularences in are actually the natural reservoir host in the environment. So we don't really know. But then how do we actually get exposed? If these are the animals getting infected, we should at least have an answer for how humans get sick.

And it turns out that that's more complicated too. Of course it is. Like we alluded to already, Francesella Tullerensis has been shown to be transmitted not by one or two or three, but many different arthropod vectors. And by that I mean it can be transmitted by ticks, a whole bunch of different species, horseflies or tabanids, a bunch of different species, and mosquitoes, a whole bunch of different species. Normally, when we talk about vector-borne diseases on this podcast, I have this whole section on the life cycle of the pathogen in the vector, right? We go over a mosquito sucks up contaminated blood. The pathogen travels through the guts, bursts out, goes to the salivary glands. The mosquito bites another host and injects the pathogen, blah, blah, blah.

That's how most vector-borne diseases work with whatever species or few species. species that are able to serve as vectors. But this is not that. Are there different vectorial capabilities among these different vector species? Like are some mosquitoes better than others? I'm sure that there are probably differences between the two subspecies of tularensis of human health importance. Yeah.

Yeah, great question. Who knows? So different geographical regions do have different arthropods that seem to serve as the primary vector. For example, in Russia and Finland and Sweden, it's mostly various species of mosquito. Throughout most of the rest of Europe, it's thought to be primarily tabanids, so horseflies and ticks. And in the U.S., there are a few species of tick and tabanids that seem to be the primary vectors. It's not strictly based on just which subspecies of Francesella Tullerenses we're talking about, since in Europe we really only see subspecies Holarkdica.

And North America, we see both Holarkdica and Tullerensis, as well as a little bit of the other ones that are less important for human infections. But what's really interesting is that when it comes to the life cycle of Franceslla in these arthropods, from one paper that I read, they noted that it has never been. demonstrated that this bacterium is found in the salivary glands of any arthropod. And so it's thought that maybe the spread is just mechanical. You have mouth parts becoming infected when a fly or a mosquito bites, but ticks are found infected throughout their life cycle. So if a tick gets infected as a larvae, They remain infected as they become a nymph and an adult, etc.

And we really have very little data on like what is going on in these ticks, which ticks are really the best vectors and all of that. We just simply don't know. Because here's the thing. Transmission doesn't stop there. Vector-borne transmission is one way that people can become infected. Right. But human infection with tularemia is also associated. with waterborne transmission from contaminated water sources.

And perhaps the scariest and most severe possible route of transmission is aerosolized bacteria that we inhale. And this can come from contaminated soil or grasses or even directly from animal carcasses that were infected themselves. This is the way that makes Francesella Toularencis a potential bioweapon agent. That combined with the very low infectious dose. Right. Do we know how long Francisella Toularencis is, like, how durable is it in the environment? Excellent question. It's been isolated. I love when you ask a question that I actually have the answer for right away. It's like that rarely happens. So love it. It's been isolated from water and mud that has been stored like in laboratory conditions in a fridge, nice and cold for up to 14 weeks. So pretty long time. Yeah.

It's been isolated from tap water after three months and then in like dry straw for six months. Oh my. It's a long time. It's unclear how long it might persist under real environmental conditions, like not ideal conditions, especially in the world health organizations' estimates of what would happen in the case of a bioterrorism attack where you're just aerosolizing dried bacteria and spreading it, then you'd probably. have a lot more like UV decay and things wouldn't probably persist quite as long, is the thought. Hmm, hmm, hmm. We don't know, really. So that is definitely an interesting thing in the column of mechanical transmission for non-tick arthropod vectors. Yeah, it's maybe. There's also been suggested that maybe it's water that becomes contaminated and that's a reservoir where flies and especially

mosquitoes during their larval stage could become infected, so not necessarily from biting a host. But we really just don't know. And so there's a lot of these different theories. What root of transmission is the most common? Or like, how does that, how is that pie sliced? That's such a good question. I don't really know. Because surprisingly, the epidemiological data that I found didn't really break out infections by different. type, as we'll see, there's different symptoms that you see depending on the root of transmission. One paper that I read suggested that the form that you see after vectoral transmission or, like, direct contact with a mucus membrane or like a wound, say, which would be a very similar route of transmission from like an infected animal through the skin, through a break in the skin,

that that might account for up to 90% of cases. but I didn't see that number reported in very many papers, so I'm not sure. Interesting. Yep. Honestly, almost the only way that this is not transmitted, and this is a good thing, is directly person to person. So human to human transmission is incredibly rare, if not entirely non-existent, which is very good. Yeah.

Can you imagine? It would be terrifying. Absolutely terrifying. So once we are exposed, again, to even incredibly low bacterial modes, Francisella tularensis exists mostly intracellularly, and it predominantly infects our macrophages, which are white blood cells. But it is capable of infecting a really wide range of cell types, both in animals as well as in humans, which kind of makes sense when we think about just how many animals it's infecting overall.

It's just really versatile. Yeah, but like how? Like how is it so good at doing this when the most other bacteria are not? Yeah. Great question. Do you want to guess my answer? We don't know. We know some things.

Part of what they do is they disrupt what's called the phagosome. And so this is when something like a macrophage especially engulfs a, bacterium in order to try and, you know, our immune response, get rid of these bacteria or other substances that are potentially pathogenic or just non-self. They form this structure called the phagosome. It's just like phage means eat, right? So what Francesella Toulerensis is able to do is kind of like stabilize this phagosome initially, prevent it from doing its normal thing of killing those bacteria and then escape and replicate in the cytoplasm. While we don't fully understand all the mechanisms by which they do this, it's not entirely

uncommon compared to other intracellular bacteria. A lot of other intracellular bacteria are able to do kind of similar things. One thing that's interesting and cool about Francesella Tullerensis is that after they've, you know, burst out of the phagosome, replicated a whole bunch in the cytoplasm, they then induce apoptosis, aka cell death, in the cells that they've infected, which allows for them to be released, go throughout the body, and infect for their cells. Virus style. Exactly.

And the exact mechanism by which they induce this cell death, we don't know, but it does seem to be unique to Franceslla Tullerensis, meaning it's a different method than other intracellular pathogens like coxiella, legionella, salmonella, etc. So, yeah, we don't fully understand. And that actually continues in terms of we don't fully understand our immune response to this pathogen either, which then has implications for our development of things like vaccines. Question? Answer maybe. If you become infected with one of these subspecies, do you then have immunity to the second

subspecies or to reinfection with the first? It's a good question. I don't know the direct answer to that. What I can tell you is that the initial vaccines that were developed were based on the subspecies whole arctic. Yeah. And they provided at least some protection against the Tularensis. subspecies, which is, of course, the more virulent subspecies and the one that people really

wanted to be able to develop a vaccine against. Yeah. So, yes, at least some. How long does that immunity persist? Unclear. And that's been one of the big issues, is trying to develop a vaccine that really does a good job of protecting against tularensis, subspecies tularensis, rather than just whole arctic. And in the past, the vaccines that have been developed have been mostly based on.

halerctica because it's safer to work with because it's less pathogenic. Right. Okay. Gotcha. So, yeah, that's what it's doing. Let's get to what does this illness actually look like. What is tularemia? Right?

Mm-hmm. Mm-hmm. In general, after exposure, the incubation period initially is about three to five days. Symptoms often start with a fever. Oh. And then some non-specific symptoms like chills, malaise, headache. But there are multiple different forms of this disease that vary based on the root of transmission. So in addition to just non-specific symptoms, let's look at all of the different kind of types of tularemia.

The first, and what, like I mentioned, is in some papers at least reported as the most common, like up to 90% of cases, is called the ulcero-glangular form, or less commonly there can be a glandular form without the ulcer at the beginning. What does this mean? This happens with vector-borne transmission, so from a tick or a mosquito or a fly that bit you on your skin somewhere, or from direct contact with an infected animal with like a break in the skin. What you see with this form of tularemia is at the site of the bite or the infection and ulcer. So it usually starts as a papule, like a little bump that then progresses to a puschule, like a blister with pus in it that looks inflamed, maybe warm, maybe tender, and can often kind of open to form this open ulcer. It might just look like a bug bite.

It might not be that gnarly looking of an ulcer. And it usually heals within a week or so. But if it doesn't, then what that means is that this infection has spread to the lymph nodes nearest the bite, which will then start to get enlarged. That's the glandular part of the name. These lymph nodes will get swollen and tender. And if this infection becomes severe, you can have such severe swelling of these lymph nodes. lymph nodes that they actually begin to drain pus from the lymph nodes to the skin, which is very, very serious.

That sounds so painful. I know. And on top of that, you're having these systemic symptoms, right? Like just fever and chills and feeling very sick in general. That's the ulcerol glandular. Or in rarer cases, you can have just the lymph nodes without that ulcer to begin with. then there's the respiratory form. Respiratory, meaning that most commonly you have inhaled an aerosolized bacteria, which is often happening from farming activities where hay or grasses

or something are mowed or dealt with, or from hunting activities where you're dealing with carcasses and maybe aerosolizing something from a carcass. Now, if you have a respiratory infection from Francisella Tullerances subspecies Holarkdica. Usually it's a pretty mild flu-like non-specific respiratory illness. But with subspecies Tularenses, what we see are those fevers, chills,

add on a cough, very severe chest pain. It can progress then to hemoptosis, so that's coughing up of blood. You might also see even more systemic symptoms like nausea and vomiting diarrhea, so this like GI tract becoming involved. Commonly one thing that we see is what's called pulse temperature dissociation, which is something we talked about. Way, way, way, way back. I was like, this sounds familiar.

What episode? I can't remember, and I was going to try and look through, but it would have taken a long time because we covered dengue, legionella, leptosephabre. sprosis, luschmeniasis, typhoid, yellow fever. All of those can do this. Maybe it was typhoid, because that's pretty classic, or maybe dengue. Okay, but what does that mean? Yeah. So a typical physiologic response to fever when anyone has a fever is that our pulse will increase. So as our body temperature increases, our pulse increases. That is a typical physiologic response. So what a pulse temperature dissociation means is that you see a relative bradycardia, meaning your heart rate in comparison to your temperature is low. Our pulse does not increase in compared to our temperature.

So it appears slow. It's not that the pulse actually decreases. That is fascinating. I want to know so much more about this. Yeah. I know nothing more. Unclear with the cause is. Okay, so we don't understand how this works, but what are the implications of this? Great question. Part of the implication is just that it gives clinicians a sign to think there's only a few pathogens that tend to cause this. So it can help narrow down a diagnosis. In terms of what is this doing in our bodies, it's kind of a little bit unconsory. clear, but probably not a good sign because what it means is that this infection has significantly altered the way that our physiology responds to infection and has disrupted that process.

So like what does that mean? It means that our body is not working the way that it is supposed to. So we can see this in up to 42% of cases with respiratory tularemia. and the case fatality rate of respiratory tularemia, if left untreated, can be upwards of 30%. And so it kind of tracks that this is a sign of a pretty severe infection. It is fascinating how differently this infection can manifest based on how you get exposed. Yeah. And there are a few other forms as well, because like we mentioned, there's a few other possible roots of exposure. When people are infected from contaminated water sources, it can cause

like an oropharyngeal infection, so more of like a mouth and throat infection and a GI infection, nausea, vomiting as the primary symptoms. And it can also cause an oculoglandular infection if the eye is the first root of entry, right, a mucus membrane, which then leads to a conjunctumptial dwindivitis, so infection of the eye and drainage from the eye and then the lymph nodes where your eye drains. All of these different forms, while they are very different, especially initially, can then lead to a systemic bloodborne infection, which can then lead to sepsis and septic shock and death. So the difference in severity between the two subspecies, Tullerensis and whole arctic, is that due to which type of infection they are most likely to cause? Or is it just like the damage that's done or the likelihood of that turning into a blood infection? Like, where does that difference come into play?

That is one big question that especially vaccine researchers and things are trying to answer. We don't fully know what these virulence factors are and what the big determining factors are on why subspecies Tullerenses is so much. much more virulent than subspecies holarktica. We don't really know. Both of them can cause all of these different types of infection. And I don't have enough data to be able to say, like, holarktica is much more likely to cause X than Y, except that overall horalectica causes much less severe disease. Right.

Compared to tularensis. So that's a lot. When it comes to animals, by the way, because I mentioned a lot of the species that we associate with tularemia actually get quite sick from this pathogen. And in a lot of cases, tularemia has a pretty high mortality rate in animals like rabbits and rodents and things. But the symptoms of this are going to vary so much by different animal species

that I'm not going to go into detail on all of them. But in general, it's not super dissimilar to humans in that there's a lot of fevers, there's a lot of lethargy, it can be kind of a long infection. And again, there's a potentially pretty high mortality rate. What about our domestic animals? We've talked a lot about wildlife, but our cats, dogs, horses, cows, gerbils, yes, but when would a gerbil encounter a wild animal to get tularemia? I really can't think of any other domestic animals. Tortoises?

I never saw reptiles listed, so I don't know about that. Cats and dogs, yes, cats far more likely to become infected and get sick compared to dogs. Dogs get a lot less sick from tularemia. And then among livestock, I think it was sheep that tend to get the most sick of all of our livestock species. Okay. Yeah. Huh. Yeah.

Yeah. But all of them potentially can get infected. It's just a matter of how sick they get. The good news is that so far at least, antibiotics still work. That's good. That's good. That's good. But it can sometimes take prolonged courses of treatment.

I didn't get into detail on this, but like was kind of mentioned in the firsthand account, this is something that even if it's not fatal can cause a very prolonged illness. that can also result in relapses where people become sick kind of again, like get better and then get sick again. I didn't look into detail in this. It didn't come up a lot in the papers that I read. It mostly was a side note, which is why it's a side note for me here. But I'm sure that there's some very interesting research in terms of the immune response and why this is possible, right? Is it because it's hanging out in our immune cells?

It's infecting a lot of our white blood cells. Does it hide in our spleen or our liver? What's going on? I don't know. But it's interesting. It is. And terrifying. Yeah.

I feel like there are so many questions I have about like, how does it do this? Yeah. And I think the intracellular part of it is always something that's just like so fascinating. Yeah. it's obviously it's a huge part of the story of tularemia right especially in that it's doing this living inside of cells in so many different species right across the entire animal kingdom it's phenomenal yeah but that is the biology of tularemia so tell me aaron how did we get here where did it come from what's the deal uh yeah let's go through whatever I have right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat.

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From a paper by Walter Simpson published in 1928, quote, the history of tularemia makes fascinating study. It is, in every respect, the first American disease. The physicians of this country should be thrilled by the thought that not only was this disease discovered by American investigators, but also because its specific etiologic agent, the determination of its modes of transmission from animal to animal and from animal to man, the descriptions of its clinical manifestations and its pathology and bacteriology were made known by American workers. And leading all as the guiding spirit, which has made this accomplishment possible, is Edward Francis of the United States Public Health Service.

It's a very long quote to kind of kick this off. But I feel like that kind of sums it up. But yeah. This designation of tularemia as an American disease, first of all, I just find really interesting because I don't think that we've come across that before. It's like extreme patriotism about a particular disease. Usually it's like more like racism about disease or something. Right to like claim it. Like this one's ours.

That's weird. Right. We stake our claim, yeah. Yeah. Yeah. But this designation as an American disease would stick with tularemia for a really long time. Like long after the bacterium, or at least subspecies of this bacterium, had been found to be globally distributed. But did Francesella Tullerensis originate in North America?

Honestly, I have no idea. That's my line. Perhaps. Yeah. We don't fully understand. But yeah, there's like quite a bit of really interesting and thorough research on the evolutionary relationships among Francisella to Lorenzo subspecies and with other Francisella species and like the virulence genes potentially. when it acquired them and when it lost them and all of that cool stuff. But there doesn't seem to be a whole lot of consensus on which subspecies came first and from where, especially. And it's no wonder

because the ecologies of these bacteria are so different and their distribution is so wide-ranging. Honestly, it's amazing that anyone has been able to make any sense out of it at all. Yeah. So this is what we think we do know about the two main subspecies that cause disease in humans. Like you said, Aaron, Francisella tularensis subspecies tularensis is the big baddie can cause very deadly disease with the vast, vast majority of samples found in North America. With one exception, in 1998, a paper reported that two isolates of this deadly Toularence's subspecies were found in Slovakia near Bratislava. Isn't that interesting?

Yeah. And as far as I could tell, that's been the only instance of this subspecies found outside of North America and how it got there and what it means is still a mystery. Where was it? Like, what kind of sample? That's a good question. I don't remember. Hmm, interesting.

Yeah. But the paper will be on our website. Okay. So if you want to check it out. Mm-hmm. But the other subspecies of human health important, again, like you mentioned, Aaron, subspecies whole arctic, that's been found throughout the northern hemisphere. And so I feel like if you had to guess which came first, you might be more

inclined to guess the one that is globally distributed. But in fact, most papers think that the Toularences subspecies, the one only found in North America, asterisk, is actually older, and that the whole arctic species evolved from it. And, really, really, Researchers think this because of the genetic diversity of the two subspecies. Toularencis is much more diverse than the whole arctic they've tested. And in fact, whole arctica is so unexpectedly not diverse that they think there was some sort of bottleneck event. That was just like, okay, everyone is now the same. The same, yeah, that is interesting.

But the bottom line and what nearly every one of these papers ends with, and rightly so, is that there's a whole lot more Francisella-tour. Toularence's diversity out there just waiting to be explored. And so this story will probably change, or at least more details, will emerge as that research is done. So we don't know where in the world Francisella Toularence's first emerged, nor do we know when in history or prehistory this pathogen, these pathogens, first made their appearance. Or at least I didn't find it in the papers that I read. But as I was hunting for papers on Google Scholar, I came across at least three papers proposing that Francesella Toularencis was the causative organism for several different ancient plagues. Each paper went into a particular plague. All of the papers were by the same individual author and all were published in the same journal medical hypotheses.

And these were like wide-ranging plagues. I'll make that point. Okay, so that right away kind of stuck out as a little suspicious, but interesting enough to look into. And so I started to skim these papers, and the biology proposed in them didn't really make much sense, at least as far as what we know about Toularencis. So then I was like, okay, what's going on with this journal? So I googled it. Turns out that it uses quote unquote unconventional peer review, which I looked into it more. isn't very rigorous, which is intended to be that way because they're publishing the papers

that no one else will publish. And it has been known to publish articles denying AIDS, as well as articles on other horribly offensive and completely non-factual topics. So I dug a little bit deeper to see if I could find any other mention of tularemia and the Hittite plague, which is the subject of one of these papers, and I found an amazing book chapter called Beyond the Differential Diagnosis, New Approaches to the Bio-Archaeology of the Hittite Plague by Smith-Gusman, Rose, and Cuckins. I'll put it on our sources on our website. But anyway, I came across this chapter because it mentioned that the Tullaremia hypothesis had been disregarded because of a lack of biological plausibility, and then I kept reading

because it provided this amazing 11 steps. like step by step discussion of how you could incorporate so many different and varied methods to arrive at a likely causative agent for ancient epidemics, which often have very limited physical evidence. By the way, they concluded that malaria was a likely culprit for the Hittite plague. So this was kind of a long detour with like not very much meat to it. But I really wanted to include it because I feel like it illustrates how hard it can be sometimes to tell whether something is a legitimate source or not. You can find these papers on PubMed and on the National Library of Medicine Journal archive. It's on Google Scholar, right? So just because it's on Google Scholar, it doesn't mean

it's necessarily legitimate or, you know, just like, ah, it just shows how crucial it is to keep doing that little bit of extra digging to help you decide if something is a good source. So keep going down that rabbit hole because at the end of it, you'll get better at spotting these crappy sources and you get to appreciate the good ones. And hopefully not get to Leremia. But I'm just getting it. Radical. Sorry. Wow. I'm so sorry. I'm so sorry. Moving on. But I agree 100%. Yeah, it was kind of like a nice refresher of, oh yeah, okay, stuff like this is, you know, anyway, so that's all I've got for tularemia in ancient times, which isn't really anything at all, turns out. So instead, let's move on to the discovery phase of this disease. Let's. The story begins with the 1906 San Francisco earthquake, or rather the fallout from it.

Not what you were expecting. Not at all. Yeah. To call this earthquake devastating would be an incredible understatement. An estimated 80% of the city was destroyed and 250,000 people were left without a place to live. As listeners of this podcast are probably well aware, these types of conditions are perfect for diseases to break out and just spread like, wildfire. Since about 1900 or so, before the earthquake, San Francisco had been battling bubonic plague, and things were just starting to seem under control when the earthquake struck.

Soon after the earthquake, rats swarmed the wrecked city, sparking this renewed fear of this deadly disease. And there is a lot more to the story of rats and bubonic plague and racism and discrimination in San Francisco that I'm not going to get into in this episode. But one of the things that came out of this threat of plague after the earthquake was the push for more research on the ecology of this disease of bubonic plague. So the director of the U.S. Public Health Service Plague Lab, George McCoy, decided to investigate some of the reservoir animals for plague in North America, particularly ground squirrels. curious whether the plague bacteria they harbored was in any way different from those and rats.

So to answer this, he went out trapping in Tulare County, California. At this point, the causative agent of bubonic plague, Yersinia pestis, had already been described. But McCoy was having trouble isolating this bacterium from some of his ground squirrel samples, even though they had symptoms of plague. Ooh. Like these swollen lymph nodes, like lesions, like, yeah. And so eventually, after tinkering with the culture media recipe, McCoy and his colleague Charles Chapin were able to isolate a new microbe from the squirrels,

which they named bacterium Toularence after Toulare County. Wow. Eight years later, in 1919, a researcher at the U.S. Health Service named Edward Francis was sent out on his first field assignment to study an outbreak of something called Deerfly fever in an area of rural Utah. Francis set to examining each person who was sick, taking samples from them, trying to grow microbes from the samples to figure out what was making them sick. And it didn't take him too long to figure out that the likely causative agent was bacterium tularens. So he called the disease tularemia.

Wow. Straightforward. Yeah. Well, yeah. I mean, there also was a little bit of this unfortunate situation where Francis got to know the bug all too well. Yeah, he picked up tularemia from someone who later died of tularemia and you know the rest from the first-hand account. But his illness, Francis's illness, kicked off what would be an unlucky trend among tularemia researchers. and many of them would get sick with the thing that they were studying over the next years, decades, really.

So I want to read you a quote from the same paper describing Francis's illness. Quote, all of the men, six in number, who have been intimately connected during the past two years with the laboratory investigations of tularemia, which the public health service has been conducting, have contracted this disease. such a record of morbidity among investigators of a disease is probably unique in the history of experimental medicine. Fortunately, there were no fatalities, end quote. Wow. Yeah, and then this paper goes on to describe how some of these researchers that got tularemia had worked with deadly pathogens for decades and knew all of the PPE tricks and whatever. Some of them worked under rougher conditions in terms of like a field lab and others were working in like state of the art labs and still

they got sick which yeah it's just so infectious yes you can take as many precautions and still there's like such a high risk of getting sick i read it's also especially in laboratory conditions because even just opening the culture flask you're potentially aerosolizing things so yeah Yeah, yeah. Yeah. It's impressive and terrifying. Yeah. So at some point in between taking all of these samples and recovering from tularemia,

Francis had also carried out extensive testing to try to figure out where this bacterium was hiding out in nature and how humans got exposed to it, which, as we learned, is like a number of ways. So not a simple answer. Yeah. Francis isolated the bacterium from jack rabbits and ground squirrels and also showed that deer flies, mouse lice, and bedbugs could play a role in transmission to humans. His extensive and groundbreaking work on the disease would later inspire the genus name to be changed to Francesella. Oh, love that. Yeah. But the cases of deerfly fever that Francis was sent. to investigate in 1919, didn't mark the very first outbreak of tularemia in humans, of course, because as is so often the case, once Francis and his colleagues published their findings, other likely past cases or past outbreaks of this disease came to light.

The oldest of these dates back to 1818 and comes from Japan, a disease named Yato Bio, hair disease, that appeared in people who had handled, rabbit meat. In the 1890s in Norway, an illness called lemming fever was described. And this is maybe a stretch, but there's also a description of a tularemia-like disease in lemmings in Norway from the 1600s, like 1653. But even in the U.S., there had been outbreaks or at least individual cases of deerfly fever prior to Francis's investigations in Ohio, Utah, California, probably other places. This was clearly not a disease that was new to humans, nor was it limited to North America. After it came out that Francesella Toulorinces can cause disease in

humans, cases and outbreaks began to be reported all over the globe from Japan, where in 1926, a widespread disease was linked to rabbits and concluded to be caused by Francesa Toulincese to Russia, where four outbreaks between 1926 and 1929, involving over 1,100 cases were determined to be tularemia. Wow. And in these outbreaks in Russia, flooding had driven water rats, which I'm guessing are European water voles, which are actually voles but look like rats. Anyway, this flooding had driven them out of their holes, and the Russian government offered rewards for every skin to try to reduce their numbers, which led to

a lot of exposure by killing all these rats. Yeah. We also see tularemia popping up in Turkey, Canada, Austria, Sweden, Italy, and many other regions. And over time, a pattern began to emerge in who was most likely to get infected, basically people handling wildlife, hunters, trappers, cooks, agricultural workers, and naturally war. Similar to what I mentioned earlier, in terms of of an increased rat population following the 1906 San Francisco earthquake, war also created tremendous opportunities for Francis Lelotilliances to thrive, largely through increases in rodent populations. For instance, during World War II in the Soviet Union, a huge amount of arable land was not cultivated. Harvests were delayed or destroyed, buildings were demolished,

and poor sanitary conditions all resulted in a ton, a ton of increased contact between humans or rodents, with an estimated 67,000 cases between 1941 and 1942 in just one region. What? Uh-huh. Along the eastern front, there may have been tens of thousands of Russian and German soldiers may also have been in front. affected during the war. And because this is a pathogen that infects wildlife, the increase in human cases and rodent populations also meant that Francesella to Lorenzis subspecies whole arctic, of course, became more established and disseminated in the environment, causing a long-term

persistence in high caseloads. Wow. Okay. I read in a paper that in the 1940s, there were an estimated 100,000 cases annually of tularemia in the Soviet Union. Ay, aye, aye. I know. I know. I was probably helped along by exposure roots, like breathing in dust that had been contaminated by dead rodents or their poop or contaminated water supplies, like basically all the things that you would expect to see increase during times of war. Fortunately, sanitary conditions improved in later decades, plus, Plus, there was that vaccine that was developed and was widely administered, like mass vaccination campaigns in the Soviet Union.

I think 60 million people ended up getting vaccinated between 1946 and 1960. Wow. Yeah. And by the 1990s, annual cases there had decreased to 100 to 400. Wow. Yeah. Yeah. But I'm getting ahead of myself there.

The incredible increase in both the number of cases. and the distribution of this pathogen prompted more research into Francesella Tullerensis throughout the 1930s and 1940s. It's ecology, its clinical picture, exposure roots, the role of arthropod vectors like ticks, other animals that could infect, and so much more. And we already know from Francis's research in 1919 that this pathogen could be a dangerous one to work with. And so what do you think happened once more and more bacteriologists turned their attention to it. Oh. Yeah. More and more

cases among these researchers. Francisella Toulerenses had earned a reputation as a deadly microbe that was disturbingly difficult to avoid in lab settings, so much so that in some countries, researchers just flat out refuse to work with it. Other countries, however, saw a silver lining.

Oh, dear. The potential of Franceselotulerensis as a biological weapon. Working in its favor are the following. There are seven, so buckle up. Number one, it's highly infectious, like you said, as few as 10 to 100 bacteria needed to cause disease. Number two, it's easy to find in nature

because of its wide distribution. Number three, it's easy to make a lot of. Number four, it can be aerosolized very easily as lawnmower-associated outbreaks have shown. There were like started out on Martha's Vineyard. There's been some in Colorado. Like, yeah, it's really horrible. Terrifying.

Number five, it can spill back from humans into the environment and stay there for a long time, continuing to pop up. Number six, only a few antibiotics work on it and resistant strains could, you know, in theory, be easily engineered. And number seven, no vaccine is currently available. As early as World War II, countries such as Japan, the U.S., the USSR, and probably many others, devoted a lot of time and effort into determining whether or not Francisella to Lorenzis could be developed into a suitable biological weapon. And this wasn't the only pathogen considered, of course, but it was given really high priority for those reasons. for those reasons I mentioned. And some of this quote-unquote research involved just straight-up torture, right? Injecting people with tuliremia.

One of the most publicized was the horrific torture carried out by the Japanese Research Unit 731 operating in Manchuria. And the U.S. used human, quote-unquote, volunteers in the 1950s, who were infected with Francesella Tullerensis using different exposure routes, especially at. aerosol in different levels of bacteria. And so this is how we know that the infectious dose is 10 to 50. I read that in several papers, and it's disturbing how all of the papers that I read literally just say, human volunteers. That's what they say.

Yeah. So I don't know the circumstances of what that volunteering looked like. Were they given a consent form? Were they given full disclosure? about the risks associated with this. I mean, 1950s? Almost certainly not. No, I know.

Definitely not. Yeah, I think it just sort of, the fact that it's just like, and they were volunteers. Right. It's just like brushed under. It's like, oh, we learned this from human volunteers. Like, what? Right. Sorry, back it up.

More detail, please. Yeah. Yeah. Yeah. Mm-hmm. Yeah. But interest in this pathogen as a potential biological weapon continued to rise, and of course with it was increasing concern about its actual use. And so this actually led the WHO to develop

this model that you talked about earlier, Aaron, to estimate just how bad an attack using the pathogen could be. And they incorporated things actually like meteorological conditions, decay rate of the bacteria in the air, antibiotic sensitivity or resistance, infectious dose, case fatality rate, et cetera. And they estimated that if 50 kilograms of an antibiotic resistant strain of Francesella to Lorenzis was released in a metropolitan area with a population of 5 million people, 250,000 individuals would become incapacitated and 19,000 would die. Yeah. And I say incapacitated just because like you said earlier, Aaron, there's this really long period of recovery with relapses in later months. And the CDC also performed its own cost estimate. I love that it's always cost. Always. Which is, you know, equate human lives to monetary value. I mean, is that not America for you? Yeah. And in 1997, They estimated that it would cost $5.4 billion for every 100,000 people exposed in an aerosol attack.

Oh, wow. Yeah. Oh, wow. I mean, now that we are equating human lives with money, that's really expensive. Yeah, it really is. Yeah. Only smallpox and anthrax were estimated to be more expensive, actually. Wow.

And although the U.S. officially ended, its bioweapon development program in the early 1970s, research on antibiotic and vaccine-resistant Francisella Toulerencis as a bioweapon allegedly continued in the Soviet Union until the early 1990s, although this has not been confirmed. But to this day, Franceslla Tullerensis is on the very short list of Category A select agents by the CDC, which are organisms that, quote, pose a risk to national security because they can be easily disseminated or transmitted from person to person, result in high mortality rates, and have the potential for major public health impact might cause public panic and social disruption and require special action for public health preparedness. And it really is a very short list.

Anthrax, botulism, plague, smallpox, some viral hemorrhagic fevers, Ebola, Marburg, Lassa, Machupo, and tularemia. That's it. That's it. I did want to point out one thing about that list. We have covered almost every single thing on that list. I know. We're still missing Lassa and Machupo. Lassa and Machupo. And that's it. I know. So, wow. Wow. I know. And Marburg very recently. Yeah, exactly. Just a couple episodes ago, actually. But yeah, I think that just underlying. how seriously people take this bacterium and for very good reason. And because of this, and because of all the other really fascinating aspects of the biology of tularemia that you explored, Aaron, research on this pathogen is still an incredibly active field. Yeah. And we're learning so much more

about this deadly microbe every year. So, Aaron, what can you tell me about tularemia today? day. Oh, I can't wait to get into it right after a short break. So like you mentioned, Aaron, tularemia, Francesella Toularences and all of its subspecies, has really only been found in the northern hemisphere. But in the northern hemisphere, it's reported very widely throughout North America, Europe, Russia, into Japan, China, throughout a lot of Asia, not really reported in the southern hemisphere, although at least one subspecies has been found in Australia at least one time. I don't know. But throughout its range, tularemia is generally considered an emerging or re-emerging disease.

That is that over the last 20 years, it's being found in expanded geographic ranges, popping up in places that we didn't know that it was, either because it wasn't there before, or because we just hadn't found it there before. Hard to say which. It's being found in new host species. Same qualifiers. Was it just not there or had we not found it? And it's popping back up in locations that it hadn't been seen for quite some time.

And this is true really throughout its range. And throughout all of the Northern Hemisphere, it's not an even distribution across various countries or territories. or regions. This tends to be an infection that's more common in rural areas of various countries, but it's not entirely clear what all of the different determining factors are that go into when you're going to have, say, an episodic outbreak in animals or an epidemic in humans or even sporadic cases. And part of that comes back to that we don't really know. what the environmental reservoirs are. We don't really know what the conditions are that facilitate

this spread per se. Yeah. It's it's so weirdly patchy. Yes, very patchy. And like I can only imagine how many variables would go into a model that would begin to try to estimate where and when and how and yeah. I love thinking about it though because it would be such a complicated model. The other thing, thing too is that it's very patchy in terms of identification and reporting, right? Every different country or even different regions of different countries might have different things that they're doing to both actively surveil or passively surveil for this disease in animals and in humans and maybe are reporting it differently on a country by country level, right? One quote from a paper that I really liked that kind of sums up why it is so difficult to really understand what the kind of global prevalence and incidence of this disease is sums up like this.

And I quote. Thus, a correct assessment requires extensive trapping of the primary mammalian reservoirs of F. Toulrensis, such as rodents and lagomorphs and of vectors, ticks, flies, and mosquitoes. In most countries, such epidemiological investigations are not made currently since they are very time-consuming and expensive, end quote. Well, there you have it. There you have it, right? We don't know. We're not doing it. We need a one-health approach, and we mostly don't have one. Yeah, yep. But we do have some things. So let's go over some of the numbers that we do have, shall we? Mm-hmm.

In the U.S., the most recent official, like, morbidity and mortality weekly report on this, which sums up data from 2001 to 2010, reported 1,208 cases in the U.S. in that time. So that's an average, a median of about 126 cases per year. Now, on the CDC website, you can also find much more up. to date data from every year since then. So from 2010 to 2020, the numbers seem to have gone up. Again, I can't tell you if this is statistically significant because the reports are not out, but just the raw numbers that exist tell us that over the most recent 10 years, the median

number of cases is 214 compared to 126 the year before. And the range also is on the higher end. between 149 and 314 cases. So overall, greater numbers every year. Interesting. It is interesting. In that time frame, the year with the greatest number of cases in the U.S. was 2015, where there were 314 cases reported. Over 100 of these were in Colorado, Nebraska, South Dakota, and Wyoming. These are states that many years do see some numbers of tularemia, but this was a huge increase in those states compared to like the prior 10 years combined.

So this is part of what I mean when I say that this is an emerging and reemerging disease. We're seeing sporadic cases here and there in places where maybe it existed, but not necessarily to the extent that we see today or in some years. I'm curious about those strong year-to-year fluctuations because it makes me think about like, okay, our rodent populations going up and was it a really strong, you know, rainy year the year before where there's a lot of whatever, you know, more nuts of a certain kind. Oh, Aaron, Brian Allen would be so proud of you, you disease ecologists, you. But yes, that is one of the like possible thoughts on an explanation. Is it there may have been increased rainfall, which promotes vegetation growth and potentially pathogen survival in the environment and then leads to increased rodent and rabbit populations?

Again, very a la lime disease. Yeah. Where you have these very complex cycles that really require a very integrated approach to be able to understand. But even more complicated because it's not just one or two or a few species that we have to look at. Right. Right. A vector and reservoir and et cetera. So that's the U.S.

In Europe, the European Centers for Disease Control and Prevention also collects data on tularemia. It's a notifiable disease. But each country, each member state of the EU, has different surveillance systems and different degrees of public awareness. But let's go over some numbers, shall we? Between 1992 and 2012, over 18,000 cases were reported to either the World Health Organization or the ECDC. The majority of these were in Finland, Sweden, and Turkey, like the highest numbers overall. And then there's a more recent paper from 2021 that reported that in that year, just over 800 cases of tularemia in humans were reported across. 26 member countries.

That was an increase over 2020 and an increase over the average of 2017 to 2019, though in 2019 there was a large outbreak in Sweden. So the total number that year was over 1,200. And then, Aaron, just because you mentioned Russia so much and those numbers back in the former Soviet Union, I did find one paper that reported in, 2019, only 42 cases reported in Russia. Wow. Right?

Yeah. Way better. Those are some much, much better numbers. Yeah. Yeah. But in addition to this geographic variation, the other thing that we see with tularemia is seasonal variation, which isn't surprising since we do have a lot of arthropod-borne infection and environmental transmission, really. So it's Northern Hemisphere summer months that tends to have the highest number of cases. But this, of course, varies, right?

Across all of Europe and between Europe and North America, different states in the U.S., report cases year-round, others not so much, etc., etc. But that's at least what we know of the epidemiology of tularemia across its distribution. I do think that one of the things that's most interesting, scary about it is that we do seem to be seeing these increases, right? And how much of that is just better surveillance versus true increases? We don't know. We really don't know. Right. And it seems like there's still so much that we don't know about the ecology that getting an answer to that is not going to be possible without more.

research. Exactly. Speaking of more research, in addition, I think, to this one health approach and a better understanding of not just the incidents and prevalence in humans, but in animals and the ecology of this infection and all of that, I think that that's a really important part of the future research that is being done, that needs to be done. But the other part of this, of course, is the vaccines, of which we don't have one. currently, not one that's licensed.

There was a vaccine. It was a live vaccine. It was effective. It was based on the whole Arctica subspecies, but had at least some efficacy against the more virulent tolerenses subspecies. But part of the reason that it was never fully licensed in the U.S., at least by the FDA, is in part because we did not,

and still don't understand the mechanisms by which this vaccine-derived strain was attenuated, was made to be even less virulent. Ah. And because we didn't understand that and we still don't really understand the virulence of this pathogen, how does it make us so sick? Why does this one make us so much sicker than the other? There's a lot of concern that this could easily revert to a more pathogenic strain. Mm-hmm.

So for long-time listeners, you might remember from our vaccines episode that there's a lot of different types of vaccines that exist and there's pros and cons to all of these. With live vaccines, which are a live virus, these are a strain of virus that gives us a very robust immune response, really good, usually long-lasting immunity, but without any illness, without a real infection. per se. But with live vaccines, there's the possibility that these vaccine-derived, attenuated, less virulent strains can gain some of those virulence factors back and then actually cause disease. And we see this on occasion with things like the live polio vaccine, for example. And that's why across the globe, we really don't use that vaccine in most of the world. because polio is no longer prevalent in most of the world, the risk-benefit analysis has changed. So we now use an inactivated injected vaccine for most people that are getting vaccinated with polio.

When it comes to tularemia, the risk-benefit analysis is already going to be very different because this is a rare disease, right? So the risk of using a live virus that has the potential to revert to something more virulent is already, like that calculus is already different than something that's very prevalent. Does that make sense? Yes. Yeah, no, it does. So there's a lot of research being done. And in the U.S., especially since 2001 when the anthrax letters came and were a thing and the fear of a bioweapon attack kind of increased again, there had. been a ton of research on alternative vaccines, alternative live vaccines, killed vaccines, component vaccines, and all the different types of vaccines for tularemia.

We still don't have one. All of the other vaccine types so far just haven't come to fruition in a way that has led to a vaccine coming to market, essentially. But I do have a great paper. it's a little old now. It's from 2015, but it kind of goes over what we had so far and where we may go from here. But that's tuliremia. So much more to it than I thought. I know I say that a lot. But yeah, it's, I underestimated it. Won't do that again.

Yeah. Certainly not. I want to keep an eye on Colorado numbers in the next few years. See if this rainy spring will have any impact down the line. Oh, I'm so curious. We'll have to do an update episode, Aaron. Sources? I have so many because I think I just like pulled snippets from a thousand papers. I'm going to shout out three right now, but there are so many more out there.

For the history, I really like to paper by Siostet from 2007. called Tularemia, History, Epidemiology, Pathogen, Physiology, and Clinical Manifestations. And for the bioweapon aspects of tularemia, there's a great paper by Oistin at all from 2004 called Tulleremia Bioterrorism Defense Renews interest in Francesa Toulogelorensis. I read that paper too. I liked it a lot. Yeah. I had for the biology a couple of other, also older papers, but they were really nice. One from JAMA in 2001 that was called Tularemia as a biological weapon, medical and public health management. That was a fun one.

Uh-huh. I read that one. And then I had a whole bunch of papers updating the epidemiology in the U.S. and in Europe and across its range. We'll post the sources from this episode. and every one of our episodes on our website, this podcast will kill you.com under the episodes tab. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Leona Squalachi for all of the wonderful sound mixing.

We appreciate it so much. We do. Thank you to exactly right. And thank you to you, listeners. I hope you like this episode. Yeah. Hope you learn something new. That's pretty much our goal.

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