TWiV 1359: SSPE, the Long Shadow of Measles

0:00This Week in Virology, the podcast about viruses, the kind that make you sick.

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0:14All right, that's it. That's the best I've ever heard. From Microbe TV, this is TWIV. This Week in Virology, a special episode recorded on July 30th, 2026. I'm Vincent Racaniello, and you're listening to the podcast All About Viruses. Today we are recording at the annual meeting of the American Society for Virology. We are in Minneapolis, Minnesota at the University of Minnesota. And joining me today here in Minneapolis, Breanne Barker. Hi, great to be here. it has been a very warm and sunny meeting but also a meeting that has had some fabulous virology so i'm glad to be here absolutely amazing science at this meeting and amazing people too don't forget that science is all about the people who do it so we have two local guests they're both from the mayo clinic which is in rochester not too far about an hour Or from here on my left, Roberto Catania.

1:27Welcome. Buongiorno, Vincenzo. Buongiorno. Come stai? Molto bene. Anguillo. That's it for my Italian. And also from the Mayo Clinic, Kalpna Yadav. Welcome. Thank you. Thank you for having me here. I practiced that name a lot. Do you like the way I pronounce your name? Yeah. that's good is that the way you would say it? yeah okay before we do some science a couple of things if you like our programs we have 10 science programs at microbe tv and if you enjoyed them we'd love your support we are a 501c3 non-profit we live on your donations so please go to microbe.tv slash contribute and don't forget there are stickers here afterwards come up say hello get a sticker.

2:22We should have enough for everyone. Now, you all know what TWIV is all about. It's about educating people about viruses. Not just you, right? You're the virologist. You know a lot of this, but you learn. But there are also people who aren't scientists who listen to us. And I want to shout out John there. Raise your hand, John. So John is not a scientist. He lives around here. He fixes computers for a living. So I guess you could say he's a virologist. But he started listening to TWIV during the pandemic, got turned on. He comes to my live stream every week and he registered to come to this meeting, which is not cheap.

3:06So that's an example of the reach that TWIV has. So welcome, John.

3:17Thank you for picking me up at the airport. All right. So now on to our guest today, we're going to talk about a disease, a post-measles disease called SSPE. So, Roberto, what? So subacute sclerosing panencephalitis. What is this? Well, let's explain the name. Subacute means it's not acute. So it comes many years after the initial mesothymic infection. Sclerosing, because it basically puts your brain in a sclerotic way. And then it's panencephalitis, so it's in the whole brain. All right, so but it could be persistent instead of subacute, right? Yeah, I mean, right, I mean, yes, it is persistent.

4:17It is persistent. The name spells out subacute. Okay, so what exactly is SSPE? Well, it's an horrible disease. It's basically children who are less than one years old have 1 in 600 probability of getting it. Older children is 1 in 10 ,000, but the result is the same. It's always lethal. And you die by slowly losing your neural functions. These children get progressively into a vegetative stage and they die and it takes months to happen. How long after measles infection does this develop? Long, years. We recently had a case in which it developed 20 years after the initial infection. Usually one stays 5 to 10 years, but cases with 20 years exist.

5:30So why does early measles infection so dramatically increase the risk of SFPE? So what we have seen is children who are below the age of one year, they are much more prone. And so specifically what happens is what we feel, we do not know how the virus reaches the brain, okay? There is no known receptor for it. In younger children, the blood-brain barrier is not that functional. It is not fully developed. So the possibility is that it is like the virus moves through that and then they get it, right? But it is a persistent disease. So the virus, we do not even know when it enters the brain. The neurological symptoms occurs years after infection.

6:41So this is one possibility of not getting this disease in younger children. Also, they are not fully immune competent at this stage as well. I'm just curious of you out there. How many of you have not heard of SSPE? A lot. So you're going to learn something today. I mean, I didn't knew SSP before I started working on it. I knew about acute measles and the complication of it, but I had never heard what deadly disease this could be. Right. So that reminds me, Breanne. Yes. What did we forget? We forgot histories. I was going to come back. Let's start. I thought we would go around and do that at the end.

7:33We could do it at the end. Okay. That's fine. Not to interrupt. Yeah, so quite a few people don't know. So actually, one other question. Is SSPE only a result of measles, or are there other viral triggers? It's per definition only the results of measles. Okay, so you said it was 100 % fatal, right? Yes. Nobody has ever survived. I mean, this is difficult to look at, but now one can basically, well, 40 years ago, 30 years ago, 20 years ago, nobody survived. Now there are children which are basically kept alive for years in a respirator. You can keep people alive as long as you want. But they are completely debilitated, so it's horrible.

8:31So how long do these patients live? So I guess if you're on a respirator, you could live forever, right? That's the point. But if you're not, what's the longevity? Well, the case in which we have recently studied is it took about 14 months from the first symptoms to death. That's about what happens. It's maybe a little bit shorter. Again, if you are in a country with good medical care, you survive longer than if you don't have good medical care. So this SSPE occurs in every country with measles? Yes. Okay. And what is the best way to prevent SSPE? Vaccination. Sorry, I didn't hear you. Could you say that again?

9:23And vaccination.

9:28I'm going to put that on TikTok. That's a good one. Don't you think? I mean, it's... Okay. You've mentioned that the SSPE patients were immune compromised, or were not completely immune competent. Can you talk about what ways these patients are immune compromised? Sorry, I must not have been clear. There is no immunocompromised. These patients are not immunocompromised. Some of the younger patients, I do not have a completely developed immune system. These patients are perfectly immunocompetent. Okay, got it. Although the younger kids are less competent, right? Yeah, the younger kids, because their immune system is still developing.

10:17But all the patients in SFP, these are fully immunocompetent. So you get antibodies against measles. Are there other genetic associations in the patients? Well, there is another disease which comes into non-perfectly immunocompetent people. This is called measles inclusion body encephalitis. And yeah, it has been described in humans who do not have one, do not have, are not immunocompetent either genetically or because infected by HIV. So that's basically a shortened, compressed symptoms of the SSVE patient, but they occur faster because these patients do not have a good immune system. Yeah, the MIB, usually it occurs within one year of getting of measles, and then you are not that much immune competent because of HIV.

11:25Some studies have also listed that males are at higher risk as compared to females for SSP, but there is no clear distinction between these genetic factors. So I understand there are four stages of SSPE. This was mentioned at the measles meeting last week. Can you tell us about those? Looks like you don't believe that. Right. And you can always categorize disease. But, yeah, basically, since we are speaking to a broad audience, yeah, it gets progressively worse. You begin, you progressively lose several competences, which is to walk, and then you cannot speak, and then you cannot rest... Breathe?

12:20Breathe. Sorry. Possiamo parlare italiano, no? And then you cannot breathe, and then you die. So it begins insidiously, right? I understand that you can see kids in school, they start to perform poorly, right? Yeah, yeah. In the kids, it is the starting sign that there is a decrease in their functional ability. Then there is effect on eyes. So it comes like vision is affected. And then, so these are just the starting sign. but then you do not specifically know it is because of measles or because of any other disease until it is much more, like it moves much more in the brain and then there is myoclonal, so there is that you have difficulty to walk, difficulty to do anything.

13:23At that stage, when you take a child to a hospital, still it is very difficult to differentiate between other neurodegenerative diseases. So there are a set of criteria where the clinicians will do, and then ultimately if you have a high antibody type, they will detect that. Yeah, that's what I also wanted to know. So if you have a child who is exhibiting these symptoms, how would you diagnose it finally in the end? Yeah, well, again, this is the dramatic part. It's just it is not diagnosed until almost the end. I mean, it's just, I mean, especially now that people or clinicians do not think of SSP, it's not diagnosed until it is too late, basically.

14:20Yeah, so for the diagnosis part of it, I mean, there are other things which comes first, and then if they do not get a true candidate for these neurodegenerative symptoms and these things, then they will ask. This is usually the case that if, did you get measles in your younger life? or do you have a history of vaccination? If the family says, no, we don't, or this person got measles, then that is the hit that, okay, let's do a PCR or an antibody title, which is highly increased in CSF as well as in serum. And then there are others. So it's a criteria called Dyson's criteria, where you have two major and three minor qualifications which need to be qualified for measles.

15:21So it's basically a diagnosis of exclusion. If it's nothing else, then they ask measles. And you said antibodies in the CSF. So if you just had acute measles, you would not have those antibodies. So we, of course, always think about measles in other tissues. How does the virus get to the brain? The answer is we don't know. But there are two possibilities, the hematogenous way in which the virus will be delivered by an infected lymphocyte, or then through the olfactory epithelium, and then through the olfactory nerve into the brain. and we have recently some evidence that this is, at least in one case, this is the way in which a virus reaches the brain.

16:18So again, replication, mesos replicates in the olfactory epithelium, gets picked up by a neuron and then it basically seeds the brain. We think that happens during acute infection and then there are 10 or 20 years. Are there receptors on the olfactory neurons? There are no receptors on the olfactory neurons, but there is a process which we call Nectin-Elicited Cytoplasm Transfer, which, as the name says, can transfer viral... Well, we have formally demonstrated that it can transfer viral infectivity from epithelial cells, which express Nectin-4 through neurons which express Nectin-1. So what is the connection between Nectin-4 and Nectin-1?

17:12Nectin-4 would be the measles receptor, right? This is the measles receptor, and it is expressed in epithelial cells, including the epithelial cells of the olfactory epithelium. And yeah, those are innervated by neurons. And yes, when the neurons pick up pieces of cytoplasm, they also pick up genomes and they may transport the genome to the brain. And again, that seeds an infection, but there is no receptor in the brain. And yeah, it's probably the infection smolders for months and years until something happened, and this happens in a population of genomes. And in fact, in that case, we know that there are two genomes which have complementary function which then seed the rest of the brain.

18:11I mean, part of the problem is there's no animal model, right, at all. Correct. I mean, measles does replicate in primates. We have used the resource macaque system to study the acute infection of measles, but when we have acute infection in every animal which we infect, we can basically monitor what happens. If we work with SSVE, we may have one in 10 ,000 animals or one in 600 which get SSPE, so the cost will be enormous. So basically you've never seen it in a non-human primate? We've never seen it in non-human primate, yes. I would assume you'd also have to look to keep those non-human primates around over a long period of time.

19:05Right. Yeah, yeah. I mean, you have 600, and then only one will get, and you also don't know, when that one will get that disease, right? Right. That sounds really challenging. In reading about SSPE, sometimes I see mention of the collective infectious unit. So can you tell us what is a collective infectious unit and what is its relevance to SSPE? Yeah, the collective infectious unit, It's a concept that viruses are not... The viruses which do not spread through particles, the viruses which can spread by fusing cells, often make large populations. And if you have hundreds or thousands of genomes, basically you can pick up...

20:04So begin to distribute functions on different genomes. And then you will spread these genomes. And again, this is probably very important for SSPE. Just put the genome in one place, the human brain. And then the genomes begin to, well, the mesovirus RNA polymerase, like the polymerase of any RNA virus, including polio, will introduce one or two or three changes at each replication cycles. And again, if you have 1 ,000 people or 1 ,000 genomes which can contribute to functions, the probability that two with complementary functions will be able to spread without having to recognize a receptor is much higher.

20:58much higher. So you need a population of genomes in order to effectively have components which can contribute to the spread. So it's basically complementation. It's basically complementation. So I heard from Patrick Sinn that this happens in the respiratory tract that whole sheets of cells come off and those are what are transmitted. So would that be a collective infectious unit then? Yeah, yeah. I mean, we think, again, this is not proven. Patrick may be proving that in the next few years, but we think that what is exposed by somebody who has measles is mainly just big chunks of respiratory epithelium with hundreds of cells.

21:52Each cell will have hundreds of genomes. So when you get hit by somebody who is sitting behind you or in front of you and has measles and contributes to the impurity in the air by coughing, you could get hit by hundreds of thousands of genomes. And the macrophage in your lung will try to eliminate them. And they may eliminate 99%, but a few will be still available, a few hundreds. And if the right combination of genomes is there, then you start infection. And to add to this point, measles is highly infectious. So these large centers which are dislodged, the reproduction rate for measles is 12 to 18.

22:44That is, one can infect 12 to 18 persons. That is how it happens. So I've always thought that measles is expelled in the tiniest of respiratory droplets that can travel all the way to the back of the room. But these sheets are not going to go very far. So this sounds like a paradox. Yeah, again, Patrick's seen as an NIH grant to ask these questions. But what I think is important is that while there are these evidence or this fear which says that if somebody enters in an elevator a few hours after somebody with measles, it will also get measles. I think that what happens is that while people were going to the pediatrician and five years old may not be as careful as other people and may touch his nose and touch the bottom on the elevator.

23:50And so it can be fomites. And so, yeah, you're correct. I mean, large chunks of cells will not fly away. but possibly this is not the only or not the main way in which Mesos is so contagious. So there are still virions released from the respiratory epithelium, right? Yeah, but it's just with Patrick we measure that and it was just so little. It's not much. And it's about the same amount of particles as the number of cell-associated particles, which we can measure. But again, it's difficult to measure. I mean, this is the particles which are released for this well-differentiated airways epithelium, not from a human.

24:44So when does the virus enter the brain during acute measles? Is it early or is it late? Anytime? We don't know. Yeah, we do not know when it enters. Either it enters during the acute measles or it stays there in the lymphoid system or the epithelial system, just hiding for a long period of time and then moves to brain, or it just moves during the acute phase and then stays in the neuron for a longer period of time. We do not know that. But there is no infectious virus in the brain. Is that correct? Yeah. The only way in which you can basically re-isolate virus is by overlaying sensible cells to piece of the brain, which you have gained from the patient.

25:43And then there will be cell-to-cell transmission. But it has not been possible to isolate virus from the brain. If you look back at the literature, there are some indication that this has been possible, but it turned out that those were often contaminants. Yeah, the overlaying method, it won't give you productive virus from these brain isolative patients. So I'm just trying to figure out how the virus gets in the brain, and how shortly afterwards is infectivity lost, right? We don't know. Sorry. Same answer. Okay. So you have analyzed the brain from a child who had SSPE to identify the sequence of events that occurred.

26:32Can you tell us a little about that brain?

26:37So this patient, there was a case who got SSPE, this individual, and then his brain was donated and then we got that brain. So he got measles early in childhood. The symptoms started around when he was 20 years of age and then after the first symptoms within within 14 months, he died. So this was 20 years of persistent measles virus in his brain. And then, yes, we did some facial dynamics of how measles evolved in this particular brain. Well, with sequence, we were in the unique position of having a frozen brain. It was It's not a fixed brain, it's the whole brain which was donated to the CDC.

27:40And we got RNA from 15 pieces of the brain and we were able to analyze with current technology. So we covered the genome a million of times in average. And that allowed our collaborator at the University of Washington to reconstruct the phylogeny. So again, if you have, it basically reconstructs the history of how the virus, the sequence of mutations which were accumulated in the virus. So are there specific places in the brain that the virus went to? And is there an order of that travel? Yes. It's basically what we say to our collaborator is to look from one piece of the brain which was different from everything else.

28:29I mean, what we already knew from the initial analysis is that there were two genomes that were co-spreading in this brain. But we say these two genomes must have been... So the site in which the infection started must have a different population of genome than anything else. Because the sites where the infection started were seeded by a seed. And everything else was seeded by two genomes. And the location where the infection started was the frontal cortex, which is innervated by the olfactory nerve. And then at this point in this frontal cortex, there were already three important mutations in the attachment and in the fusion protein.

29:26and when single point mutations in the matrix protein was added to these three, then the genome with this point mutation and another genome were able to spread everywhere. With the concept of this complementation, as Dr. Tanya told, starting in the frontal cortex, it had a different set of mutations which were present at almost 100 % of the frequency. And this is what we say that these are the driver mutations for the brain spread. And then what happens with this genome population, it acquires different sets of mutations, and then it diversifies into two populations, genome 1 and genome 2, which has a different set of mutations which are complementary to each other.

30:23And in one genome population, genome 1, it has the specific mutations in the matrix protein, which when it got the virus, genome 1 got this mutation, then it has some advantage. And this moved out from the frontal cortex region to the parietal and then the lower regions of the brain. So you basically got 15 pieces of the brain? You didn't get the whole brain, right? We did get the whole brain. We removed 15 pieces from different regions of the brain. And then you sequenced those. You did deep RNA sequencing, right? Yeah. And it's, I mean, Paul wrote, we should mention Paul wrote at CDC, which was at the measles meeting a couple of days ago.

31:15And yet, I mean, that's an interesting story because, again, We see one SSP case per year, about, until now. Maybe worse after that. But Paul at one of these meetings tells me at lunch or at dinner, we have a brain. You have a brain, I have a brain, we have a brain. No, we have a frozen brain from an SSP patient. And then I say, well, okay, good. Are you sure that it's an SSP patient? Yes, we did a PCR. And then I say, well, just pick two pieces of brain and we will do some analysis and see how much virus is there. And then there was 10 % of the reads of the cellular read were viral. So in these two pieces of the brain, the virus had taken over 10 % of the transcriptome.

32:20Then when we did more pieces, there were between 2 % in the in-brain and 20 % in the forebrain. For the context of it, in earlier cases, the amount of REITs which you get is 0.1 to 1 % only. So at that time, we were pretty excited. Not to say that, but a lot of infection. That is very impressive. We have to be grateful to the parents who donated. I mean, that must be very difficult, but the advancement in our understanding is enormous. Yeah, absolutely. So from this, I heard you talk the other day about this, so from the sequence you can track the movement of the genomes through the brain, right?

33:14Yeah, so I mean with the analysis with our collaborators from Washington, they did quite an impressive work of putting how the virus enters and then how it moves from different regions, acquiring these specific mutations in the fusion and the hemagglutinin protein, and then plotting all the sequences of it moving, like the whole trajectory of virus movement. So is there a hypothetical order of mutations that the measles virus had to acquire in this situation? Well, we have quite a well-defined... I mean, let's mention Will Hannon and Alison Feder, because this is their work. But Will Hannon was a PhD student, and Alison Feder had worked with HIV.

34:16And for that reason, she had all these bioinformatics programs in place to reconstruct the history of the spread of the virus, basically in temporarily differentiated virus from the same patient and use that backup to reconstruct the evolution of the virus. But yes, in these particular patients, there were three mutations in the attachment and fusion protein, which were already there. And then this matrix mutation occurred later. So we can even reconstruct the sequence, but we do not think that it should be the same sequence everywhere. It's just what do you need to have are mutations which diminish the activation energy of the fusion apparatus of the virus.

35:22But what was critical is this matrix mutation. Maybe I'll let Kalpana say what the matrix mutation did, because she has really sorted out how it works. Yeah, so for SSP, we had quite an understanding of how these mutations in F and H hemagglutinin protein, which are responsible for lowering the activation energy for the virus to fuse, So giving it advantage. This metric mutation was like, it was different because what it did was it, first it gave an advantage for the virus to move. So we were like, why does this specific mutation at position 50 occurred and provided it. So the first thing which I started was to check if this mutation occurs in other SSPE cases and just looking at the sequences which were deposited in NCBI that if the position 50 of the matrix was hit or not.

36:41And it was striking that 50 % of the cases has this change in SSPE. So 50 % of the published literature of the cases. in SSPE has this position 50 change, either to serine or troline or to leucine. So it was changing from phenylalanine. So that gave us a hint that, okay, this position is really important for the virus to spread, at least in these 50 % of the cases. And what we saw in our analysis as well that it was. Then what I did was to look at the mechanism of what gave this mutation adenovage. And we saw that it is specifically interacting with actin. So it provides the virus or cytoskeleton movement to move to other cells.

37:47So this is a specific act in interactors. Also what it does is it moves the whole fusion apparatus to the neurites, so the long branches of the neurons. And we have some indication that at synapses, these are incorporated. So matrix is what doing. First, what it did was it gave it a hyperfusogenic phenotype. So in the field of measles, everybody knows that the wild-type matrix, it inhibits or it down-regulates fusion. It makes the virus less fusogenic. But this mutation, what it does was, it was just the opposite. It was hyperfusogenic. So that means it moved quickly to other cells. And then in neurons, what it did was to put the whole machinery of the virus from one point of the cell to the synapses for efficient transmission.

38:56So essentially, since there are no receptors in the brain, the genomes are moving cell to cell by fusion. And so this change in matrix, as you said, increases fusogenicity. Then there are also changes in the fusion protein as well. What do they do? So for this specific case, what we saw that we had these mutations in the F protein, so truncation specifically in the cytoplasmic tail of L. What it does, it inhibits that fusion restrictive function by the matrix protein, so making the virus more hyperfusogenic. But in this specific case, what we also saw that there is a recalibration of fusion, that means because there was two genome population which was having the same phenotype as hyperfusogenic.

39:59And at this point, what we know that the cells need to maintain an optimal level of fusogenicity. I mean, if there is just a lot of fusion, that particular neuronal cell will die, and then it will be a dead end for the virus, right? What virus does, it maintains that fusogenicity level. So what we saw was the frequency of one genome having a hyperfusogenic mutation increasing in a particular region of brain than the frequency of other genome which had this hyperphysogenic mutation in another, say, F, decreasing. So we saw this increase and decrease in frequency of these genome populations everywhere, from the frontal cortex to the lower regions of the brain in cerebellum, in brainstem.

40:57And this is what we think was just modulation of this virus. This was an intelligent virus modulating everything just to do it over the whole brain. So you also saw some changes in the H-protein tail. What changes were those and what does that do? For the H-protein, so in the field, major emphasis have been on matrix and F-protein because we know that this is fusion which happens when F is there. For the H protein, we identified a mutation, and it was present in all the regions of the brain. It was a change at the eighth codon from isoleucine to threonine position. And so what I did was similar in different cases, SSP cases, how many of these SSP cases has this particular mutation, and a lot of has this mutation.

42:06And if we combine it with our F50S mutation or the change at matrix protein, approximately like 10 SSP case has this combination of mutations, the same mutation occurring in matrix, in fusion, in hemies, glutin. So for this particular mutation, we know that it provides a hyperfusogenic phenotype. So by looking at the trajectory of the virus, what we saw was where regions where the genome containing this matrix protein and the fusion protein was lower, the frequency was lower, the frequency of this mutant came higher, just to, I think, complement the function of the other mutations. Yeah, I think this is the idea.

43:03Again, there are F and H, and F and H, well, H contacts the receptor. F physically makes the fusion, is a trimer. Matrix grabs the tails of both F and H and keeps them in check. But depending on what you do on matrix, and this was the big surprise, we had suddenly this mutation in the brain. Matrix usually keeps F and H in check. And this mutation stimulates fusion. This mutation came up only at 10 % level at the beginning, at a very low level in this initial population. But this initial population was 90 % F-tail deleted. And when the virus then spread through the brain, when M, when the mutation facilitating fusion in matrix went up, the mutation inhibiting facilitated fusion in F went down.

44:08There is this idea of the equilibrium and you can only do something like that if you have two systems, if you have two genomes and you easily complement one with the other because the mutations are on the different genomes and And yeah, if you have one genome, it's like humans with one genome will be lost. Poliovirus with one genome, let's hope that it doesn't allow to have two genomes in it. Otherwise, we are in a bad shape. So this is a perfect example of evolution, right? The virus gets in, there are no receptors. So spreading cell-to-cell bioreceptors is out of the question. But still, the polymerase is copying the genome and making mistakes, and those that make these changes to fusion that you were talking about, they're selected, and that drives cell-to-cell fusion.

45:09Is that basically how we can look at this? That's a great summary. Very sneaky. It is. It really is. Okay, Brianne, let's go to number 32. All right. I'm jumping all over the place. That's okay. So what causes the brain damage in the end? Is it a fusion? Are only the neurons involved? Why do we see this brain damage? Yeah, I think the point is that we don't see brain, you don't see symptoms within for a long time just because the virus spreads without fusing, spreads in a very discrete way. And then what Paul Rota told us is that, well, we also saw that there is only minimal amounts of virus in the in-brain.

46:06The in-brain is where the respiratory functions are located. So basically what... And again, we have part of the brain in which 20 % of the total cellular reads are viral. This is about the same number of reads which are viral in an acute infection, in a lytic infection of hila cells. So there are probably not many functions in the frontal cortex left when the patient dies. The virus is very sneaky. Basically it is able to spread without being recognized just because it has this thermostat on fusion. And we don't see much fusion in the brain. There are not cells which are near each other which are all infected.

47:08It's often individual cells which are separated by urines. And the concept of taking the hindbrain at the last because it controls all the respiratory and dysfunction. So if it is taken first, I mean there will be an instant or death will be there within a few weeks, two months. But this virus, it takes over all other regions and all other functions and then takes the hindbrain at the last of it. But I'm not understanding how. So it's just all the viral proteins are contributing to the demise of the cell? Is that not fusion? That's what I'm getting from you. It's not just fusion.

48:03It's not good. It's the other protein. Well, even measles, even during the acute infection, we have some data from... We don't have data from humans, again, but we do have data from macaques. And we do have data from ferrets infected with canine distemper. And what happens is that these viruses can, even during the acute infection, replicate at very high levels in lymphocytes. In ferrets which are infected with canine distemper, and this canine distemper expresses GFP, we can basically take out, look at what is in the blood, look what is in the organs, and in the local lymph nodes. A week after infection, more than 50 % of the lymphocytes fluoresce green.

49:04So this virus is able, it maintains the function of the cells extremely efficiently. It doesn't want to kill the cells because it is not good for a viral infection to be very lytic. All right, so we don't know how it's causing symptoms, basically. That's the answer. Yeah, well, again, causing symptoms, yeah, it's by one after the other taking over regions of the brain which are responsible for motility and so on. But we don't know, or again, the virus really has become evolutionary, very clever in not impacting cell function, in not inducing apoptosis, not inducing anything. It is basically a completely stealth infection for weeks, months, and years.

50:05And when the virus is done, when an acute infection is basically taken over most of the immune system and causing immune amnesia or in a persistent infection in taking over the brain, then it's too late. All right, I don't get it, but let's move on. I still don't understand what's causing it. Why is it so slow? How about that? Can we understand why the disease is so slow? I think why it is so slow because it needs to accumulate those mutations. It does not have a receptor there. So it needs another way to take over those cells. And what these mutations does is it provides that lowering of the activation energy threshold to take over those fusion and move to other regions.

50:58So this is what we probably think because these mutations we never see in an acute measles virus. These are mutations which are always seen in brain. So the virus needs time to accumulate those mutations. So for the SSPE patients, are there any therapeutic options? How are those patients treated? Okay, so for these patients, these are just, so there is no known therapy, right? There are antivirals which will just give symptomatic relief. There is vitamin A supplementation because individuals are affected. So the eye keratoconjuctivitis and other stuff are there. So vitamin A and then there is, you know, same remdesivir, but no approved therapeutics.

52:12It is always lethal. I get every month or so emails from families of children who get SSP and who ask for some intervention because nothing works. With Kalpana we have a project to make antisense oligonucleotides, which can be delivered to the brain and which can correct, which has been shown to correct other neurological diseases. But at the moment we cannot offer anything. We really want to raise awareness of this disease. And one way to understand what this disease does to children is while there are some testimonials of parents of children who have SSPE who explained, well, we didn't vaccinate these children because we were told that measles is not a real disease.

53:26And now they sit near this child who is dying and they say, well, vaccinate your children. Yeah, I mean, you do not want to be that one family, right? With a kid which has no future and you know that he will die. So vaccination is easy and it is the best way to prevent this disease. So I would suppose that inhibitors of the polymerase or maybe even fusion might be working. But from what I got, by the time you diagnose it, it's too late. Right. I mean, again, early diagnosis is also something which will be important in this context. And yeah, I mean, again, if some measles is now happening in this country and it's happening when some children have already died of it, this was of acute disease, other children will get SSPE.

54:35It may be possible to at least have early diagnosis or propose to family of children who got measles to come back on a regular basis to test antibody titers in the cerebrospherinous fluid and possibly get the SSPE early enough that one will be in the position of delivering on a compassionate basis if the wars happen, these antisense oligonucleotides. So we talked earlier about the difficulties with animal models. Do you think that it would be possible to use other technologies like brain organoids to help address some of these questions? Yeah, so we are doing that. We are making brain organoids just for this specific function.

55:38to see how virus moves and how does it take over so that we know a little bit more about this virus because now it's just the brain. So it's an after effect of SSP and we get that and we study retrospectively. for brain organoids, it will be the future. Yeah, and now we have recombinant viruses which have individual mutations. They are identical to the wild type, but have these mutations which we deduce are important for SSP on an individual basis. We can begin to address these questions. So globally, there are many, many more cases of measles than we have in the US. What's the global incidence of SSPE, do we know?

56:37I mean, there are no data for SSPE, but globally what we know in developing countries, it's very high. So acute measles, so measles is endemic in all developing countries. And then SSPE is also a lot higher as compared to what we see there. Okay, let's go back to the beginning. Tell us a little bit about yourselves, where you were from, and how you got educated to come here today, Roberto. Okay, I'm from a beautiful place, in the lake region of northern Italy, which was taken over by the primitive cantons of Switzerland 500 years ago. So I'm the Swiss-Italian part. And yeah, I went to school, elementary, middle school, high school in Lugano.

57:40So I spoke Italian until then. And then I was interested in two things. One was molecular biology. These were the 70s, and it was clear that something was going on with genetics, which was very interesting. And the other was anthropology. And the only place where these two directions were strongly represented, a Swiss university was the University of Geneva. So in the French-speaking part, so I moved to Geneva. and then when I was in Geneva I started working on molecular biology and did my long project in a lab in which was also some work on viruses and quickly realized that viruses are a very simple system to work at with new, basically, molecular biology at that time, so more than 40 years ago, it was molecular virology.

58:46And at a meeting, I did speak with Hein Schaller, who was working on hepatitis B virus. And this virus has 3 ,200 nucleotides, and they just got the sequence. and I saw a possibility of just learning to do recombinant DNA work and work on hepatitis B virus with Heinz Schaller for my PhD studies and came back to Switzerland for my postdoc. And there there was Martin Billeter, who had a couple of clones of the mesosvirus genome and had this idea, well, we could do what we had done, I had done during my PhD to basically set up a reverse genetic system for hepatitis. So why don't you try to do that with measles, which, well, it took 10 years or so, but it worked.

59:49But there was also, the other reason was this SSVE. So this problem or this RNA virus, which can basically stay in the brain for five to ten years, and we didn't know, we didn't have any idea of how it did mutate to adapt. So again, this was 40 years ago. We got some data from these brain specimens from different patients. And now we can work and obtain basically one million. Instead of having one genome per brain, now we have a million of genome per brain that allow to come back to SSP and do this work. So have you worked on that, on measles, ever since your PhD? Yeah, after the PhD. So more than 40 years, yes.

1:00:47And you came right here to Rochester from your postdoc? No. Then I went after a few years in Zurich, when I was then basically a research associate. I went to Yale in Connecticut and learned about cell biology, working with Jack Rose and NVSV, and then went back to Zurich as basically an assistant professor and after a few years they and when I was looking for a position I was looking in Europe I was not using looking in the US but I heard in fact a colleague invited me to look at this new project of the Mayo Clinic which wanted to really a molecular medicine program in order to to start in the gene therapy field and in order to deliver genes for gene therapy one needed expertise in viruses and that is how the molecular medicine program at Mayo started just with this interest in the basic biology of viruses, but also an openness to apply viruses to the liver gene and make gene therapy viable, which at this point was, I mean, there was almost a resistance from the viral community to think about gene therapy and giving viruses to patients.

1:02:33So are you actually Swiss, not Italian?

1:02:39Yes, no, that's correct. Yes, again, everybody... What's correct, Swiss or Italian? Or both? I have a red passport, so that's a Swiss passport. Okay, okay. But again, culturally, all our books in elementary and so on come from Italy. Karpna, what about you? What's your story? Yeah. So I'm from India, north of India, a small city. Not that small, but Lucknow. Yeah, I grew up there. So my father was in military, so we moved quite a lot. But most of my growing years were in Lucknow. Then I did my bachelor's in veterinary science or what it is called DVM, doctorate of veterinary medicine and started working with animals.

1:03:42So I did quite a few years, didn't quite enjoy it, like treating animals and yes it was, I think it was not for me. Then I went to do master's and And then my PhD, all from India, so Indian Veterinary Institute. Worked with paramyxovirus in my PhD, so specifically Newcastle disease virus. So it's the same family as measles. And what we were doing was just for my project was to make a recombinant virus, which would be a better vaccine candidate in that area in those developing countries because NDV is endemic. So we were combining Newcastle disease and an immunogenic gene from other poultry virus, infectious bronchitis or other, to make a vaccine, and this is what I did.

1:04:40Then I took some time off. I had my older kids, so I took time off. And then I realized I need more research training. So I started looking in labs to come to U.S. for growing myself. And then that is where I landed in Dr. Cataniel's laboratory, working with measles. So how did you pick working on viruses when you went back for your master's and PhD? That is interesting. So there was a talk which I listened to. There was a seminar. And there was this lady which was talking so passionately about foltery virus, so infection bronchitis virus, and it was endemic and how they were really trying to make a better vaccine candidate.

1:05:41and I just went and talked to her and I was like, oh, she's cool. Yeah, that is. And just asked her if she has a position and then gave some exams and landed in her. Sounds like it tells us a little bit about the importance of actually interacting with people and mentoring. Yeah, and also, so maybe women in science particularly, if we see a role model there, like which is there, which is talking about you can do it, then you get that confidence that, yes, I can also do it, right? Yes, absolutely. Okay, we have two last questions. And the first one is, what would you have done if you had not been a scientist, Roberto?

1:06:37Well, I mentioned that before, anthropology. When I was a kid, I wanted to become an astronaut. It's not anthropology.

1:06:53Maybe he wanted to do anthropology of extraterrestrials. Yeah, maybe. All right, anthropology. What about you, Kapna? Maybe a writer. I write stories. You would write fiction? Yeah. Okay. So this second question was actually posed. I did a podcast at Breanne's University last week, at Drew University, and one of the students asked this question. It's so damn good that I'm going to use it, and I think you should ask it as a consequence. Okay. So for each of you, if you can give everyone in the world one message about viruses, what would it be?

1:07:37Vaccinate. Yeah, that's good. I like it.

1:07:47Help, no, you want to? You could do the same if you want. Yeah, I mean, people think viruses are non-living. And still there are so many viruses we don't know anything about. So these are small, intelligent creatures which make your life hell. So yes, vaccination and other forms are important. So this is a high school senior, right? Yes, yes. Rising high school senior. Great question. Well, she asked it of me. Yes. And then he stole my answer. So I had to stumble out to answer. I did? Yeah, you did. Well, I didn't know it ahead of time, right? No, you didn't know ahead of time. Okay. Anyway, that's a TWIV special at ASV2026.

1:08:33You can find the show notes at microbe.tv slash TWIV. You can send questions or comments to TWIV at microbe.tv. And if you enjoy these programs, we'd love your support. Microbe.tv slash contribute. I want to thank the American Society for Virology for having Quiv here again. We've done this for a number of years. I appreciate them letting us do this. Our guest today from the Mayo Clinic, Roberto Catanio. Thank you.

1:09:06They do like pronouncing Italian names. And Kalpna Iada. Thank you so much for joining us.

1:09:20Brianne Barker is at Drew University, Bioprof Barker on Blue Sky. Thank you, Brianne. Thank you. Thank you so much to both of our guests. I learned a lot. Thank you.

1:09:33I'm Vincent Racaniello. You can find me at microbe.tv. I'd like to thank the American Society for Virology and the American Society for Microbiology for their support of TWIV, Ronald Jenkes for the music, and Jolene Ramsey for the timestamps. You've been listening to This Week in Virology. Thanks for joining us. We'll be back next week. Another TWIV is viral.