TWiV 815: MIS-C with Moshe Arditi and Ivet Bahar

this week in virology the podcast about viruses the kind that make you sick [Music] from microbetv this is twiv this week in virology episode 815 recorded on october 8th 2021 i'm vincent dracaniello and you're listening to the podcast all about viruses joining me today from fort lee new jersey dixon de pommier hello vincent and everybody else um you know i always looked out the window to tell you what i think the weather is like but actually it's it almost feels summer-like outside um a little bit high humidity for this time of the year there's a gray overcast uh patchy clouds trees are starting to turn um starting to think about thanksgiving already crazy it's very nice to see very nice day today yes yeah it is yes also joining us from austin texas rich condit hi everybody hey richard uh 86 degrees is sunny headed for 92. they keep promising us that this is going to let up but i'm so i'm having difficulty managing my expectations but it looks like maybe a week or so out they're talking about 70s but they lie you know they do yeah there's a profession that they get paid to lie monkey except you know i don't think it's really lying with intent no no they're just wrong they're just wrong the weather man can never lie they're just never right also joining us from ann arbor michigan kathy spindler hi everybody here it's 71 degrees light drizzle may clear up that's the same as 20 celsius we have two guests for you today who are going to tell you a really cool story about covid so stay tuned uh from cedars sinai medical center in los angeles moshe arditi welcome to twiv thank you vincent um uncharacteristically cloudy in la and 66 degrees here and from the university of pittsburgh school of medicine medicine yvette bahar welcome to twiv thank you very much it's a pleasure uh so it is here also uncharacteristically nice 76 degrees beautiful day in pittsburgh boy we span the coast in in in between as well today yeah we got everything today east west north south how about that no complaints folks we got it all right actually i want to i want to i want to issue a correction before we get too much mail or anybody gets too offended the weathermen are uh incredibly accurate most of the time okay and i appreciate that we just notice when they're not right right exactly because if you know scientists are wrong a lot right but most people don't notice except us um so our guest today let me tell you how they came to be uh moshe and i have been emailing for quite a while um we've been complaining to each other about uh how the variants have been described in various ways uh and so then um they he and yvette have have uh published this wonderful story that you hear about today so i said come on and talk about it so that's what we're going to do today but i'd love to first hear your histories because in the pre-show we were talking about it and it's it's just uh so cool tell us you know where you're from and uh where you were trained and how you got to work with each other perhaps moshe maybe you could start uh okay so um i uh i'm originally from istanbul turkey you know and i went to a french high school there all boy catholic high school uh and then um uh um i went to medical school after that in istanbul finished and left in 81 i worked at yale university for two years on surfactant you know used in premature uh rabbits for two years and then went to university of chicago to do my internship and residency training in pediatrics then to chicago my favorite town where i did my well stayed in chicago at northwestern to do an infectious disease fellowship in pediatrics and then moved to l.a i worked at la children's hospital and then i moved to cedar sinai which is affiliated with ucla as as faculty affiliation and i've been here 23 years so i've been working on lps signaling and toll-like receptor signaling um role of these innate immune molecules in atherosclerosis and vasculitis and since a lot of people tease me that i as a pediatrician i work in adult inflammatory diseases i've been also working on kawasaki disease vasculitis for the last 20 years so so that's in a nutshell that's how it is and and and we can tell you how we met with yvette which which you know maybe i'll let her tell the story yvette tell us your story okay so it is uh amazingly similar because i was born and raised in istanbul too and also went to a french catholic school for all girls of course that was very fashionable then in istanbul these were really one of the best high schools and then uh moved uh continued all my studies in turkey actually i got married i had two sons and i just did everything undergraduate masters and phd everything in istanbul and then became a professor there right after my phd uh for it uh the university i graduated from which was the most prestigious brazilian university then and in the chemical engineering department so i started as an engineer and i was a professor there for 15 years until i moved in 2001 to the university of pittsburgh and so it's very simple 15 years in istanbul 20 years here and in my career i of course started as a chemical engineer i never liked the engineering stuff i uh quickly channeled to material science first polymer physics and chemistry and polymers from polymers i switched to biopolymers and then gradually computational biology because in turkey you know the best thing you could do to be more competitive worldwide was to do simulations we had the best you know simulation infrastructure uh and then came the year and i i worked every summer for nine years at nih just doing research in the meantime in the utah year turn of the millennium as you all know that was the real breakthrough with the human genome but at the same time you know first published by uh francis collins and craig mentor and that was the time where bioinformatics computational biology really became very important and lots of new opportunities so i joined pittsburgh to start a new center center for computational biology which which soon became a department department of computational assistance biology which i have been sharing since then and i also started the joint program with carnegie mellon in computational biology you know how carnegie mellon is very strong in computer science and engineering and physics so i found lots of colleagues there with whom i could collaborate and found this very strong computational biology phd program now what i do is mostly modeling and simulations as we're going to talk about and i like to use structure so it is like engineering but at the molecular levels trying to understand how proteins function their machinery and how we can modulate their function you know by binding small molecules i do lots of drug discovery so and then of course with advances in data you know lots of databases in biology we do lots of data mining machine learning type of computations so my lab is essentially to we are tool developers you know we simulate everything on the screen and we collaborate with uh people like moshe who give us stimulating questions and we try to solve them so that's where uh we that's how also this research on stars go to spike started okay moshe so you guys were both you both educated in istanbul and what happened in between well we you know wait for i'm sorry good good so we we didn't even know i didn't even know that moshe was here in the united states and a few years ago all of a sudden he sent me emails asking are you eventual zone you know using my maiden name because that's how and i i say yes i am but who are you so i couldn't remember so that was really uh i don't know how many is more than four years for sure that we had we have completely lost touch but we used to play together in the streets i was the uh actually goalkeeper of the team we used to play soccer and then many other things he was the only girl who was on the team great great story it's lovely so you you connected before kovit i presume right a few years before coffee drive okay all right so i'm not quite sure how to start this story today there's so many pieces and maybe you have a better way but i thought maybe we could start with misc multi-inflammatory syndrome c and telling us you know what it is and then taking your wonderful story from that so so and it's exactly how it started you know uh uh yeah i mean this collaboration um you know i mentioned that i also have been studying kawasaki disease for over 20 years you know i i i go to japan frequently i've met dr kawasaki almost every year until he died last year at age 90. and it became a passion to me uh through my training to treat karus occupations in children and also work with a there's a wonderful mouse model of kawasaki vasculitis uh which you know my my lab has been lucky to be funded by nih for 20 something years for that so so when when stars cove two came and and and in you know march or april 2020 we started to hear about these bizarre cases in children first in uh france i mean england uh and then uh bergamo italy and and and other other european countries about this hyperinflammatory syndrome in kids that that that that uh follows sarskoff too that had some findings that are reminiscent of kawasaki disease such as conjunctivitis rash you know and um and mucosal oral mucosal changes which also are present in toxic shock syndrome uh and and they started to label this as kawasaki disease-like and it went further to even to be called that this is it you know sarskoff too is causing kawasaki you know and then this is kawasaki disease you know so it it really bothered me so much uh that uh this was wrong because you know since then we learned so much more that these are two different diseases demographics demographic differences the older kids are you know and then laboratory differences clinical differences were so much you know you know clear that there were two different diseases of course they may use similar inflammatory pathways that many diseases you know trigger um so so i became very uh vocal you know in writing or or or trying to tell that this is a different disease and if anything messy which is characterized of kids having multi-inflammatory organ system involvement with hyperinflation that follows the infection two three four six weeks later it's more like a you know it's presenting more like a toxic shock syndrome why because you know it has the components of of of multi-organ systems such as acute gastrointestinal acute gastrointestinal findings uh abdominal pain vomiting diarrhea myocardial in in you know dysfunction neurologic findings up to 38 percent kidney uh injury in addition to all those other things which we don't see with kawasaki disease but we do see with toxic shock syndrome so and toxic shock syndrome is caused by super antigens most people think that only bacterias have super antigens but then i realize there's a remarkable literature on viral superantigens and and and and the diseases that they've been associated with so so i got in touch with yvette because i knew she was doing computational uh uh studies looking for fda approve other drugs to to repurpose those drugs for it for sarskov too and i said to her that do you think the virus or the spy protein has a motif that may be like a super antigen uh and and the response was amazing to me and that was what is a super antigen so so when when yvette mentioned that then i will leave it to her now and i sent her uh papers about staph enterotoxin b icb or tssd you know the the typical staph and strep super antigens and diseases that and the and the structure of those of those proteins and a week later i get a phone call from her and i'm going to leave her tell the rest okay so so at that time you know we were already doing some research in starscope too like a spike glycoprotein and at that time i was very intrigued by the fact that you know there is between the s1 and s2 subunits of the spike there is this cleavage site and there is this insertion that's very unique to source code ii and i was wondering why what is it so special about it and i was you know at that time i was trying to see what is unique about this uh sequence and i read a paper by jean-pierre on you know the significance of this region that it resembles some uh neurotoxins and could be targeted et cetera things like that so when moshe contacted me i said do you think it might be similar a super antigenic region there might be there and and of course i asked what are super antigens and learned that for example bacterial toxins are super antigens to those small molecules that elicit this excessive response cytotoxic adaptive immunity and i said okay there are some sequences indeed that i've seen in the literature short sequences similar to bacterial toxins and other toxins actually viral toxins as well uh what viral and super antigens let's see and then we started to do a more careful analysis and maybe i can show you if you slice sure sure okay so for example uh one of the things the ba yeah like background you know super antigens now we know i learned that they can bind tcr's uh but also at the same time mhc2 molecules in contrast regular antigens where you have a peptide super antigens are themselves proteins and there is here one of the super antigens that have our attention sp staphylococcus toxin b which binds the beta chain variable domain of c tcrs so when we were modeling the structure and this region we noticed you know when you do a pdb protein data bank blast and you find similar sequences uh we what popped up was uh is actually this staphylococcal antitoxin b let me show you uh here so the the this stuff eb has indeed a super antigenic uh region uh segment that is sequentially very similar to that of source ii not starts called the one 2003 but what was even more interesting is that it has a what is called a palindromic character so you can align it you know parallel to each other but also in the anti-parallel way and then you have even a longer segment that apparently is similar to seb now not only the sequence more strikingly we also have the structure of that segment you know in a cv and it starts called the spike and you see those these are positively charged amino acids located at the same position or i'm sorry you have you know lots of similarities in the structure and now we said this region this region is definitely sequentially and structurally very similar to a bacterial toxin seb that was the starting point the discovery of that sequence that closely mimicked a segment of the bacterial toxin acv and then we said okay does it bind to the tcr of course it does so that is that is located here and this is how it finds the tcr and we have lots of you know basic residues on the uh spike and lots of acidic residues on the tcrv beta chain in particular so we were very pleased to see that yes it does bind also the uh tcr should i continue i have a question i have a question so well many but let's just have one so the the super energetic is relatively short right it's sort of like a it is a peptide that would be presented in uh mhc2 as you say right more or less the peptide uh you know usually mhc2 presents the peptide alone right it is not attached to a protein so what happens is that in the case of a super antigen we have a peptide let's say again in this case about 20 amino acids 24 but it is also surrounded by other parts of the molecule that may assist also in further binding so and that makes you know the affinity much higher and as a result you have a much larger number of tissa receptors that are being expressed or t-cells themselves that are expanded as you can see from skewed tcr representations so here this is showing as an example you know that is the uh region you know superantigenic region here but there are extra interactions in the vicinity including a you know additional molecule intercellu which serves for intercellular adhesion which further stabilizes this interaction so it is the fact that it's part of a protein makes it uh you know higher binding affinity so would it be interacting as part of the virus particle or on the cell surface if it infected cell it is on the spike as you know it's part of the spike and it is somewhere in the middle as i showed here you see yeah so it is uh we you know i had it is sketched somewhere the way things interacted here okay here is the host cell here is the stars curve two this is the spike this is the spark and the way it interacts with acetone the green eye is h2 and then there are i i didn't show here but there are the proteases from the host cell that cleave the spike so the s2 timer remains here uh bound to the virus and then undergoes a structural change to become primer you know right and trigger the fusion process and then the s1 trimer after cleavage is just in this extracellular region so it may bind directly a kisa receptor or the t-cell receptor itself may approach the virus so there may be multiple ways so you think it has to be released from spike s1 has to be released in order to be a super antigen right i don't think it is a requirement uh because it's still exposed okay but when it is really you know shed into the s1 and s2 timer it gets more exposed so there might be a higher probability of interaction so i want to uh clarification does um does the t cell receptor engage this super antigen in a fashion similar to other ligands that it engages or is this a special interaction yeah no it doesn't have a slight event yes it is very interesting because the way the we you know we reported there the interaction of our super antigenic segment with the tissa receptor was mostly with the beta chain and with a bunch of acidic craze on the beta chain variable domain of the tcr and this is exactly actually how a cd itself also interacts with tcr's and we're going to get there because that's how we also came up with this idea of designing an antibody inspired by what was already known for ecb yvette maybe we can show the super antigen slide okay so that is also you know you have the t-cell and you have the antigen presenting cell normally this is the antigen presented by mhc class 2 but the super antigen it doesn't even need uh oftentimes the mhc class two but it may also uh you know serve as a glue between them it is it has a much higher affinity binding affinity to the t-cell receptor variable beta chain variable domain of the beta chain a lot of people listening probably don't know what a super antigen means right yeah and what's the consequence so maybe in the context of the bacterial protein what does it mean and what happens yeah super antigen is like an antigen but it has super activity so antigen would be triggering this adaptive immune response right tcars detect what will be binding now what happens is that in the case of a super antigen the response is excessive so for example the number of tcrs that are being expressed or the t cells that are that are expanded are a few orders of magnitude larger compared to an antigen and this excessive response you know gives rise to a cytokine storm moshe can explain even better than me okay yeah i mean like yvette showed in the cartoon you know if it's a traditional uh peptide uh presented you know after a antigen presenting cell presents the peptide in the groove to the t cell receptor you know those are the traditional antigen presentation and you end up with 0.01 to 0.001 or percent of your t cells that are specific to that antigen superantigen bypasses that pathway attaches from the side to the tcr and mhc class 2 and now suddenly can activate 20 30 40 percent of your t cells suddenly and with a major release of cytokine you know this this super antigen term was coined by pipameric in 1991 i believe and initially from the memory uh memory mouse uh uh tumor virus yeah yeah right yeah um so uh and of course that's what causes flesh-eating bacteria to uh toxic shock syndrome and tampon tampon-induced uh uh you know um shock you know and additionally traditionally has been associated with bacterial uh but but we know we know now that uh there are so many uh viruses like like i just said mouse memory tumor virus and and rabies virus uh hiv gp120 is a is a as a super antigen you know ebola has it shown to have a super antigen and and of course ebv and most interestingly human endogenous retroviruses uh uh have been associated with uh that been shown to have super antigens and that's important because we will get into this maybe super antigens not only can cause this massive release of cytokines that may send you to shock with cytokine storm but repeated exposures to it can also cause autoimmunity and and this is what we think what's happening in missy you know um is kawasaki's a super antigen disease yeah so you know vincent that has been this did debunked you know like it's been like when the 20 30 40 years ago 30 years ago they found that maybe it's a staff super antigen post event that those studies have not been you know uh uh you know replicated and although there's a minority of people that think majority of the people think it's a traditional antigen of virus or viruses that have not been discovered yet so yvette maybe you can take it to do to do next uh okay so now you know think about it we found a segment of the spike which is sequentially and structurally very similar to this staphylococcal anti-toxin b which is one of the typical toxins that causes this toxic shock syndrome all right and for acv there is a huge literature you know this has been a system that has been widely studied and also studied by bettina reese actually at stony brook who has i'm sorry bettina fry latino fries story i i don't pronounce correctly so she has identified and let me go back to my presentation again to make things easier for you so she she identified three antibodies let's see where it is okay here it is so this is from her work and i can use full screen so you see you can see here uh a cb in the middle gray and she identified three antibodies fab 20 b1 63 and 14 g8 color coded here that bind seb that are known to you know neutralize seb and then we when we examined more closely we found that one of them 63 binds exactly that segment which is similar to our super antigenic segment on the spike protein so for the listeners who might not be watching those three antibodies bound to the seb in different regions exactly exactly exactly corresponding one of them binds to that segment which is similar to the spiked glycoprotein superantigenic segment right so because after all again as we mentioned that the segment that binds is short like an antigen but it is part of the protein so these antibodies block uh the super antigenic properties right that is that's what uh betina then uh reported the original phrase from in this 2014 paper have they been used therapeutically so apparently i i was told pfizer was interested and then at that time they humanized the monoclonal antibody then a ceo change and the project was dropped okay so when we look closer the way 63 that particular antibody interacts with sip we see that it is interacting with those uh acidity basic amino acids lots of lysines here lysines that are sequentially homologous to the arginines in this uh secretogenic region of the spike and then of course we tried we we verified if you wish that 63 this antibody also bites our spike and indeed we've seen the same amino acid acetic acid amino acid of the uh antibody interacting with the basic amino acids of the spike exactly at this region where the cleavage takes place so now okay binding does it really it doesn't uh imply uh you know a functional impact of course but then moshe's uh his collaborators they also did the experiments to show that there is indeed in a you know a decrease in effectivity in a 63 the fab those dependent manner so that are this has been now published in a uh sort structure and then uh we started to think even deeper should i go on or just wait okay so i think it would be great just to reiterate this finding so you have this monoclonal antibody that was known to bind to the seb molecule another superantigen and then you showed that it could block infectivity for sars cov2 in two which shares a segment common with scd right so there is you know the binding epitope on starscope to glycoprotein is almost identical to that on seb not only sequentially but also structurally right so evidently something that binds one of them would bind the other so binding was fine but it was also we also showed that it reduced effectivity yeah so this must have been a really exciting finding of course okay it was particularly exciting because the existing monoclonals you know that that we use in patients we were told that you have to use them very early because it only works to block uh viral uh product you know like reproduction and entry but it's it doesn't really work in the later stages of anti-inflammatory stage this this potentially theoretically would affect both both parts both you know blocking viral viral infection as well as if the super antigen tcr is shown to be functional and playing a role it may block that as well so what you're thinking is that maybe the inflammatory disease not mis but other inflammatory diseases in covid might be in a a reflection of some super antigenic uh interaction right yes and that you know for example adults that go into you know some of them akiko's work with yale for example have shown at some some uh patients have prolonged a cytokine storm you know that goes on and and is it possible that this is playing a role yeah you know scb is very interesting uh uh of course this is all theoretical and and and it needs to be proven but by age you know 16 you know or 60 80 of the population have anti-scb antibodies uh but but 20 of the population cannot make anti-cb antibodies and then you lose your anti-acb antibodies these are known from toxic shock syndrome studies so is it possible that after 70 or 80 years of age apparently people use their anti-scb antibodies is it perhaps why it's more severe disease at that age so these this this is a one possibility the other was was very intriguing is the ivig has been used in both missy and also in some studies for adult severe covet and there are some trials still going on ivig is full of anti-scb this is why toxic shock syndrome's therapy is ivig plus steroids you know um so this is another theoretical thing that we're working on you know uh so that's that's why this is this was important so some of this discussion gets me wondering about the uh kinetics uh of this uh disease because uh misc i think you said uh can show up pretty late after infection in children and likewise the inflammatory the severe inflammatory syndrome shows up pretty late in uh adults and i have thought of this as uh pretty much after the most acute part of the infections are over so the question arises in my mind uh is the super antigen effect sort of a hit and run long term thing or do you need to have super antigen present in you know something like a stoichiometric uh amount at the time that the disease is induced what are the kinetics all right so so this is this is the question i get all the time you know uh and and and and so so the kinetics is that you know we're working these are observations right now and hypotheses that need to be completely completely understood better i mean i mean i feel like we're building we're building a ship while we're sailing you know that's how that's how the whole disease has been and and miss c is the same you know we found as we go so but but the way i can envision is that the super antigenic motif particularly when s1 is shed and particularly when you know david waltz uh uh uh uh you know from brigham has shown that circulating s1 levels directly correlate with disease severity in adults like who goes to the icu and stuff so so one aspect is that perhaps these super antigens that are shed in the s1 that have become more more ex you know exposed are playing a role in cytokine release acute that's one part then kids would miss c how do you explain that they're coming back four weeks six weeks later if this is an acute disease and their acute disease is just very mild sometimes even just like a exposure and nothing but then they come with hyperinflammatory syndrome as an autoimmune kind of like a mechanism almost right like like kind of like group a strap and then four weeks later you develop rheumatic fever kind of thing right and there i think the hypothesis has to be either a autoimmune interaction that the superantigen is inducing not only the t cells that are going crazy but also polyclonal b cell activation that eventually turns against itself and and may explain all this auto antibodies that us and many other people have reported now in missy this is one thing the other thing is that in misty patients there is another paper that we published with alessandro fasano from uh and laurel juncker at jci that shows that these kids continue to have virus in their stool up to four weeks six weeks and they have increased gut permeability and they're leaking perhaps some of these s-ones indeed they measured s1 level in the miss c patients and it correlates with disease severity even at four six weeks later because of gut permeability so while super antigen may cause a acute cytokine release in some patients adults or others it may also cause this late onset autoimmune kind of things that we're seeing perhaps even even in long covet in addition to to miss c but these are all theories that that needs to be proven so another question that i had was about uh potential predisposing factors and why it's only a fraction of people who show up with this i know you've done some work on this but i've raised the question and i noticed in particular a sentence from your pnas paper saying that uh speaking of misc uh and this was i forget exactly one but no such cases have been reported in china japan or south korea that made me wonder whether there was a genetic component or something like that absolutely and maybe maybe yvette can show the slide about the hla hla finding that uh event if you have that that slide you know so i don't think i have it uh no it's the four slides i send you uh uh but you may you know maybe you didn't include them but uh so so this is the tcr uh 11 2 skewing and then the hla skewing but anyway so what we have published uh in in in a jci paper is that um there is obviously a t cell receptor skewing so you can say okay you found this super antigen and of course the reviewers said the same thing right well how do you know it's doing anything you know i mean is it really causing any functional like does it was it there just like for for structure or is it doing a uh how do you know it's playing a role in the disease um or super antigenic role even so we had to come in the pns paper in the adults that have hyperinflammatory syndrome and show that they do indeed have t-cell receptors skewing 24 1 or some other a couple of them and that was in that paper in in a subsequent paper in jci we showed that in kids with miss c there is specifically t cell v beta uh 12-2 that is that is uh skewed or blooming you know so that is a signature in a way of a super antigenic immune signature that t cells specific t cell receptors are are skewing yale group has shown the same thing and a french group has shown the same thing so this is now repeated in three cohorts that t cell receptor 11 2 is skewed in that paper we start the paper by just saying hla associated t cell receptor skewing so we had i think five or eight kids with missy and among those with severe missy to our surprise all of them had a unique trio of hla uh a finding you know i think you know um um so it was a2 uh uh b35 and and c404 i think it's in the paper so so this three alleles you know of hla one is somehow helping the superantigenic motif to be presented to do to the tcr and this is the first clue in my opinion that there is some genetic predisposition this is why 60 70 percent of cases are either hispanic or african-american in this country and then african-american african origin in europe now i was very happy to see a med archive paper from nih that just was came out two days ago and it's in the abstract as well that the same three alleles are shown in more than half of their misc patients so so this is a clue that why this is such a rare disease you know so so would you expect then that this superantigenic region of spike might bind better to that particular tcr can you can you approach this structurally yes actually that's what we've done also and you know we first the first the data we got from our collaborators in germany was that the you know this subset of tcr's that are observed to be overexpressed in adults with severe coveted 19 and then we checked whether you know those tcrs would be binding and the pns paper already contains that later on then a similar type of study for tcr skewing was done with the children the one published in journal of clinical investigation and that's where you know the particular tcr v beta chain 11-2 was found to be distinctly overexpressed and then we have also shown how the interaction you know we have all those results in those papers how the interactions with the superantigenic region and this particular vibra chain are very strong now there is one more thing though i would like to add uh there you know we a very interesting study caught our attention last year uh where uh it was published in science by matthias at all so what they have done is the following they have uh screened 15 mars you know amino acid segments of 15 uh peptides let's say or 15 amino acids on the glycoprotein so they took each of them and they probed their t-cell reactivity and they observed this in patients that have not been exposed to sars co2 so so these are i have again a slide here but i can explain so what happens is that there are many segments actually on the spike that showed a very high teaser reactivity so the explanation is that some of those peptides are already shared with previous stars viruses or common cold viruses and there might be some people who have gained some kind of immunity you know and that might also explain the differences between individuals i seem to remember that some of the variants have amino acid changes near the this fear and cleavage site does does that make any difference in terms of being a super antigen do you know so you just read my mind you know we are going to continue on that time okay so yvette there was one one slide you showed about the prr you know the the the the poly basic side binding to the tcr uh if you if you get the uh um you know uh the uh uh the binding uh comp you know like structural binding that you showed earlier at the beginning and number 13 i think yeah that one yeah and so you see in the middle p681 and all the mutations were just like outside of this but when the delta mutant came p681 becomes you know r right you know like uh and so because the the motif armor this motif that we discover is becomes even more as more basic even more basic so even more basic means that now you can have you know attached to the acidic fury and much more therefore you cleave you have much more cleave i think several people you know jason mclean and others that you invited i think have talked about this that that delta variant may cleave much much more therefore two things happen you make more s2 and you know more infection and perhaps more virus levels and perhaps that explains the transmissibility increased transmissibility but what people are forgetting is there's also more s1 and more s1 is shed this is like almost like a viral toxin kind of concept you know in in what eva harris you know when i talked about in one of the twins that you had you know like ns1 from the flemi viruses that are being released so we proposed that s1 is like a and also viral toxin that is being released and uh so now here's an observation so that requires to think that delta is causing much more severe disease if that's hypothesis is correct and i think there are at least five papers that are showing that uh there's more hospitalization you know with with delta i mean no clear paper shows that there's more severe except hospitalization but there is a very interesting observation i want to link to mystique so you know i want to go back to this concept you know where actually at least on my end everything started that was uh you know we were focusing on this region of the starscope to where there is a prra in search right in the segment and this is uh followed by the cleavage site rs now all other family members actually mers has also a segment here but um many other sas of two family members they don't have uh so this is an insertion so that is uh that's extremely reactive you know you see there are one two three arginines here in the delta variant there is one more arginine coming into place so such a highly basic region is extremely reactive so it would but now i think uh what moshe also brought up is the reactivity to with uh the antibody might be increasing but also we have the reactivity with the furion or the protease that does the cleavage at this position right so when we were trying to interpret the results how the antibody is inhibiting the virus or it's uh the spike the glycoprotein from from infecting human cells then we also started to think more closely about you know what is happening we know that we are talking about this cleavage site just the vicinity the near neighborhood and we know that uh okay 63 this antibody similar to 16 which has been discovered for sev 6b3 is reducing viral entry that's our interpretation from of the experimental data but we are talking about the s1h2 proteolytic cleavage site at the same time and then we now look more closely what is happening there so the spike itself uh it's the same exactly the same region where the tcr and the antibody binds it also binds this uh human protease or furin you know tian prss2 or fury they both bind at the same position and they also you know exploit those uh basic residues to have a very tight binding high affinity and then if this is the case there is a competition between the antibodies 63 and those proteases that all try to bind this insert pr the vicinity of this insert right and then when we then we started to calculate what's the binding affinity and it turns out that when you calculate the binding affinity between the spike and those proteases versus the spike and the antibody we found that the antibody binding affinity is comparable to that of urine one of the proteases the other one has a weaker binding propensity so in this image where i i have shown both the 63 and young campy rss to the protease bound to the spike of course this never happens because i just superimposed them virtually because they are competing exactly for the same site so one possible way that we have observed less impactivity in the presence of 63 is that that region then was at least partially blocked by 63 and there were a few were furious molecules or proteases binding there so we came up with this hypothesis that you know 63 will effectively compete with proteases that interfe that's interfering with the proteolytic cleavage which is essential for the fusion peptide to be released and for you know entering the host set yeah so so i want to go back one minute to the uh the delta mutation so and i can i can answer uh uh instance question six 681 mutation you know like p becoming r um so i just said that one of the consequences would be that there will be more cleavage and then there will be more s1 uh when there is more s1 you would expect to have more severe disease the only thing i can tell you from the miss see as a clinician is that since delta the uh waves started we have seen tremendous amount of pediatric cases that shoot up you know like shut up you know like really you can go to the cdc missy website and you can see cases of pediatric cases and the misc cases exactly follow each other in the prior prior uh surges with the alpha with the you know with with the uh alpha beta and the other other variants but with delta we're now seeing severe young kids coming with severe pneumonia to the icus and not missing so you could see that the curve that cdc has on their website shoots up the pediatric cases but the misty is down so the my hypothesis for that it fits together with the pa what we're seeing here as a clinician we don't see much missy anymore we keep seeing acute severe disease which we didn't see before what was the history of we see very mild disease initially and then six weeks later four weeks later severe messi now very severe disease at the beginning and no missing in my opinion that's because of perhaps the 681 is doing something that mutation and pushing the the more uh uh uh shed spike that is causing more initial severe disease and when you push so much th1 and so much severe disease perhaps the body turns off the autoimmune part for later because you're just like dealing with the acute disease initially more but this is a very interesting observation the opposite of what you would predict right opposite what you would have predicted yeah i assume there are no animal models of miss c that you could test all of this in right no no but but but we're trying to give spike to ma and then see what happens with repeated spike to see if there's an autoimmune autoimmune thing yeah so the question that was uh on my mind the whole time i was reading this stuff is what about vaccination uh why doesn't vaccination trigger a superantigen response uh or you know maybe there is something about vaccination something i think i wrote to vinson one day i think they david walt with alanna ogata published another paper uh where they uh measured circulating uh s1 after vaccination and they have found that you know in the first eight days there's a small amount 50 microgram you know 70 80 microgram you know of of circulating s1 after vaccination for the first vaccination and the second vaccination they couldn't because maybe antibodies you know interfere with their elisa that may play a role in you know maybe the headache and the side effects but but it's not enough or sustained and you probably need the rest of full viral disease to really cause this and not just like one spike or for a few days or something and that's the only explanation i have so one other thing is you know if you look at the literature all the structures claudium structures that have been resolved for the spike they have replaced this prra segment mutated it because this is a highly reactive and flexible region that doesn't land itself to structural stabilization so uh i i'm not sure but we may want to check whether in the vaccine the sequence that is being used did they keep the prra segments which is uh you know highly super antigenic or not i need to i i think we need to check that's a very good question though i think i know this you know uh because i talked to jason mcloone about this and and i think the prra uh uh motif was uh a change mutated in the johnson and john in the johnson and johnson vaccine and the novovac vaccine not the other ones oh interesting interesting yeah but the the the mrna vaccines have a c-terminal two prolines added right what does that does that interfere with the uh the site if you're inside at all or is it distant from it the terminal will be at the s2 it's too far okay c2 okay but before before we uh uh you know i don't know when you want to wrap this up i just want yvette to to show us in my mind what is the most interesting observation she made which are the neurotoxins but i i think we ran out of time well you you were uh welcome to to stay on it's i just was being respectful of your time um okay so sure i can show very quickly uh you know when we did the analysis uh because you know we didn't know where to look at in the very beginning so we scanned all the sequence and uh you know that was a study from the lab of uh jun wu and others in the year 2004 that's published in viral immunology uh after sars the first star pandemic and they were they looked at uh whether they had there were any superantigenic toxin-like or adhesive uh molecule-like segments in sars uh one you know the first one and then uh they did identify that a bunch of motifs including a few neurotoxin motifs uh here highlighted in green now we checked whether those motifs were conserved in star score with two and then we found that one of them actually uh is very you know highly conserved and quite long actually you know it's not a short segment it's quite a significant portion uh of uh between residues 299 300 and 299 and tyrosine 351 of the spike and the end of it one end of it here uh the c terminal end is very exposed like the you know the receptor binding domain or the internal domain of the s2 subunit or entire spike so we were very intrigued by this neurotoxin motif as well which might be relevant to these effects you know we observe in uh in the in the central nervous system especially in the long covet case and then we wanted to see whether the the tcr's that have been identified to be overexpressed expanded in patients with a severe covet and in this case we are talking about adults whether those tcrs could also bind this neurotoxin motif and it turns out that they bind this region even stronger than the superantigenic region so that is not another you know motif neurotoxin-like motif shown in green here where the tcr's will be binding as well and this is uh certainly you know undergo in progress but i just you know mentioned the science paper of matias at all where they have identified in people who had not uh been exposed to sarsapoto some cross-reactive epitopes from the spike and it turns out that that particular neurotoxin like motif uh shown here turns out to be one of the most highly reactive uh segments on the glycoprotein so we we are right now pursuing this line of research to better understand the role of this particular segment which is actually partly concerned between the two stars and has been uh you know verified here to be cross-reactive uh even in uh you know in patients who have not been exposed that so i think uh maybe uh moshe if you would like to add anything else but i think i think what we're doing is that we are very excited about this milky way we have these uh uh uh neurotoxin motif that yvette just showed and we made a recombinant protein and and uh doing uh uh uh you know doing experiments with the blood-brain barrier opening and and going through i mean people have shown um that uh s1 uh spike protein opens up the blood-brain barrier and so it's not inconceivable that these uh shed or or neurotoxins can pass through the blood-brain barrier and may may lead to some of the neurologic findings that we see in uh in acute covet neurologic findings i think i think that's really interesting i just want to finish with one thing that you know when i started to look into this and the role of uh super antigen i i came across a paper in 1982 i love these old papers you know so so so so so so david uh aschenbah from seattle who was an obstetrician who wrote this incredible paper and you could take out toxic shock syndrome in the title and you can put long covet in there you know and then the title of the paper is persistent neuropsychological sequela of toxic shock syndrome 1980 to 82. and he describes you know 16 or 10 or 12 women who go into toxic shock syndrome and then a year later they are describing a syndromes of like uh neuropsychiatric uh uh of headaches not a concentration enough or or you know cannot really uh ability to concentrate it's almost like you're reading the long covet you know from today and i thought it was very interesting you know for to me i wouldn't call that very old you know i'd call 1939 in old paper 1982 was when i started at columbia you know it depends on your perspective so what you're describing sounds like the brain fog that is the term that people are using now exactly for the for the long coverage yeah yes do you have any sense for what the peptide might be hitting in the cns to do this or is that something you're interested in finding out we are that's too early to do that kind of stuff you know but uh now i have one last question which is th this uh amino acid sequence must be an accident that it has some other function it needs to be cleaved by furan's right to improve infectivity so it's an accident that it causes the t cell receptor amplification and so forth right because that would be of no benefit evolutionarily speaking for uh viral selection right well super antigens are generally thought as virulence factors to help uh the the microbes to do the disease well but that is true yeah but ladies virus super antigen is used apparently to bring the virus from where the virus is in the muscle all the way to the nerve endings you know it plays a role by activating specific t cell receptors so i have no idea why why the origin of this might be or what what the role of it is yeah i just you know it doesn't to me it is my particular view it doesn't make sense it doesn't seem like it would be selected for to cause this misc because it's late and it has no impact on transmission which is a you know a major selection for so i would look at it as an accident especially since sars1 doesn't have it but who knows anything else you wanted to mention that was really it's a really cool thing oh is there any implication for treatment so should we look at everyone's hla1 and say okay you are at high risk for misc and be ready to treat them would that be one approach well one thing i read was that covet 19 adults they were already an hla type study you know like who would get sicker but for kids this needs to be you know repeated and and in other cohorts i'm aware of like two other cohorts that are finding similar hla finding but once once we confirm this you know that that might be that may give us a clue you know which which patient may develop more severe you know hla i mean disease you know for uh yeah it seems to me that the antibody would be a good treatment right almost all of the antibodies right now they target the rbd the receptor binding domain yeah and you know whenever there is a mutation there you may have an effect uh you know evasion risk for multiple antibodies not 63 on the other hand and there is one more antibody actually called 4a8 they bind another region and they have now shown a reduction in effectivity so i think uh using this antibody in cocktails my together with rbd binding antibodies might be a good strategy so of course to try this you need to titrate in in appropriate animal models i mean if you use an animal model where you give lethal virus and then you give this antibody you may not necessarily see a suddenly reversal of death but but to look at the pathology or level of pathology in the lung might be might be the way to go perhaps to try this and we're trying to work to have collaborators to help us that those experiments fascinating story um really nice example of how you can start to figure out pathogenesis right uh what i like is this mechanisms it starts with an idea yeah that it's just an idea that i probably would have discarded and gone to lunch you know uh and then experiment after experiment and paper after paper using different approaches turns out to support the idea okay so it's a it's a great story it's a great journey right still in progress and we're still uh continuing yeah that's right all right moshe our dt from los angeles thank you so much for joining us you're welcome and yvette bahar university of pittsburgh thank you both for joining really appreciate it and good luck keep it up bye-bye thank you for inviting us thanks good talking to you pleasure all right great good story i think it's cool i mean i don't know of any other pathogenesis where they're starting to sort it out right misc looks like they have a mechanism right that's good i was reminded of their story when they started to refer back to the streptococcus and the you know the disease is an autoimmune disease that uh has a lookalike molecule someplace i was at rockefeller where that data was first discovered by zabriski and framer and i remember everybody getting very excited about that because rheumatic heart fever could be now explained by waiting to treat and then all of a sudden you get another disease which is even worse than the scarlet fever that the strep throat that you have to begin with so so nothing is unrelated staphylococcal enterotoxin b seb that she said that it fast a lot you might have missed it scb seb and that's the super antigen and um which triggers tss right toxic shock syndrome yeah exactly and the other thing that maybe people got lost with so the t cell receptor normally would recognize a peptide presented to it by mhc right and so this super antigen is really good at recognizing the t cell and somehow amplifying certain ones so that they're way higher basically yeah basically the way i see it is is it it activates those t cells right okay which means that they divide and proliferate and they also send off all kinds of cytokines that's right and that's what that's when they talk about skewing that's what that means is you've amplified a certain population of t cells that the super engine reacts with which is another terrific thing because they basically predicted in their model that something like that should happen and then they go look at the kids and sure enough uh they have a whopping fraction of their uh t cells the kids with miss c whopping fraction of their t cells are of a certain type uh that react with this super antigen amazing i just i i don't know if it's actually where's s1 right i guess it's being shed at entry so it's got to be coming from virus particles attaching to cells oh yeah this one is shedding off right because there's a lot of questions on the biology that need to be addressed but in one of their papers they said you can't change the sequence because then you have no infect or less infectivity if you change that if you're in sight and then you can't dissect the two properties that's i wonder if you put it into another virus oh that's gain of function sorry but you could put it into and if you had an animal model for another virus say an animal virus that doesn't affect people put it in and see if it triggers mis or some inflammatory syndrome that you wouldn't see right so vincent i noticed that they didn't bring up the issue of blood type i was going to even raise that but is that an old story now that's not being adhered to anymore or are there certain blood types that are more susceptible my understanding is that that was no longer held up on further examination the connection with blood type and severity yeah um but uh what is the frequency of this i wanted to ask them does anyone know the misc kawasaki no no not kawasaki misc like well i don't know we should have asked them that it's not very common but i just love that you may have a mechanism to explain it right immunological molecular and isn't it great you look at this and you see it looks like a super image and wow that must have been cool that day right [Music] anyway it's a great story that's why i wanted them to tell it right let's do a couple of emails oh you have a public service announcement kathy yeah it's something that i only just found out about but we lost an important adenovirologist bill wald he died in june and i only just found out about it last night so bill wald has pretty much he spent his entire scientific career at st louis university uh having been trained in manitoba so he was canadian and uh he was about to retire in august and uh vancouver island in canada but so uh what i want to tell you about them uh we have two links one is um the obituary from the um from the web and also a journal of virology article that a number of people who uh were with him at st louis university uh wrote together so it's it's just a longer really nice tribute about his life so he was an adenoverologist um and he was e3 basically if you wanted to know anything about e3 and human adenoviruses bill wald was your guy and um one of the things said that he was really generous with uh as a citizen he generated over 250 viral mutants and all kinds of anacera and monoclonal antibodies and was very happy to provide them to anybody and i was the recipient of that back on um some of the kinds of things that he did um e3 is conserved among all the adenoviruses i mean it's it's always there and yet it can be quite different from one adenovirus to the next and the early things that the rap about it was that it was dispensable well it was dispensable for growth in cell culture and bill argued that no it must be important for something in the virus in pathogenesis in the natural host and so he really worked to characterize that um there are a lot of nice tributes uh both in this journal of virology article and online um he was known not only for his scientific achievements and leadership at st louis university where he rose through the ranks and became the chair of the department he was a supportive mentor caring person outstanding teacher and a dear friend to many of us um he was a favorite golf buddy a passionate running coach he he ran marathons and this is something i didn't even know about him until now um so he will be missed by a lot of people and had a really positive impact on the field remember harry ginsberg used to say that too it's dispensable for herself but must be doing something yeah yeah e3 really important and and yeah so uh too bad it's one of the genes to take out in vectors right to give more space right and and that you know and so there were two ways that bill sort of addressed that and one was let's figure out what all these e3 genes are doing and the other was if we can take it out then maybe we can use it in as an oncolytic vector and um so he had a lot of connections with working on cancer and things like that so yeah it's a day when you could focus on one gene well one multiple genes oh yeah six or eight for some of the human adenoids but still to focus on one region your whole career people did that all the time i don't know if you could do it anymore yeah and publish papers with two or three four authors yeah yeah yeah oh and his people were all very loyal to him so the postdoc who left my lab um was with him from 1996 till 2020 when i think he saw the writing on the wall that bill was going to retire and and he changed labs but all those other co-authors on the jv article i think many were with him for years and years yeah yeah i met him a few times all right rich can you take the first email there sure hal writes first of all thank you for your excellence i am a 64 year old relatively healthy and fit internal medicine physician practicing in southern maine my second vaccination was on january 20th recently just this week i contracted sargo v2 uh this is day five and nothing more than an annoying cough mild fever and a runny nose for a few days i'm almost back to in quotes normal yay vaccines work my question is do i truly need a booster fully vaccinated plus covet more than likely with delta variant in that order i know there's no negative outcome in getting the booster but is there truly a benefit in this scenario if so what is it and when would be the best time to get the booster shot well i'll give you my spin on this and others can weigh in i would say first of all and most important i don't know okay and i don't think anybody knows we do know that there are studies that say that if you've had the disease and then get vaccinated you have a superpower okay that you are immunologically cooler than either infection or vaccination alone okay and i would presume that the reverse is also true that if you are vaccinated and then get sick that you have a superpower uh but there are no data that i am aware of so i don't know uh your your thinking is all right sounds to me if i had to guess i would say that at this point a booster shot although no harm done is superfluous so a superpower that's different from a super antigen right yes we got the super episode today i yeah i would agree with that but i like that hal has uh thought about this and also you know he says i contracted the sars cov2 virus good for you and yay vaccines work they do yeah and this is what's gonna happen over time over the years as we have said many times before uh my my belief my prediction is that the virus is not going away uh and you know depending on what happens to the vaccination programs um i would kind of expect that all of us if we live long enough are gonna uh even having been vaccinated going to get boosted by the virus itself okay so there you go dixon can you take the next one oh you gave me the long one sure no it's a short lamont writes what i find interesting there is a documented transmission change of breakthrough infections in fully pfizer vaccinated individuals what i sort of expect is this will be abused to continue to argue that the vaccines don't work with delta and we that's a follow-up to the comment that was just made so this is an emerging infectious disease very short it's called the research letter breakthrough infections of e484k harboring saurus kov2 delta in lombardy italy um which um was the legion really hammered in initially if you remember the beginning that's right that's right um and the last twist that i released one of my guests uh worked there and studied it firsthand so this is an interesting case it's it is um someone who got infected and then his mother they're all vaccinated and then the mother who's vaccinated got infected and then the somebody else close to them and they all the genome sequencing suggests that it's all the same virus that they transmitted to each other so they're thinking these vaccinated people were transmitting it to each other yeah i i mean it's a couple of people i agree and i don't know what the bigger picture is but of course yeah a small study like that will be used to say the vaccines don't work for sure but no one died no one died nobody died that's right um i think it worked uh yeah the patio fatigue headache my algae dips near um fatigue none required hospital admission yes a cold ran through the family it did yeah yay vaccines work that's it yeah to quote another proof kathy can you take the next one yes jeff writes hi i was trying to explain the immune system to my 12 year old son in simple terms i don't think that there are really any simple terms for the immune system which is what makes it so fascinating but anyway i came up with what i think is a pretty interesting metaphor of musical recordings and they're being played the idea is that there is a memory the stored music which has no specific playing volume but a spectral analysis would reveal many combined frequencies each with a relative amplitude when played there's an overall amplification that can be set regardless of the recording's inscribed amplitude this playing amplitude expresses all of the memories at their relative amplitudes then we talk about immunomodulation it is the external overall amplitude that we're talking about and the t and b memory is the spectral decomposition the tnb memory inscription process is similar to our recording of music the system records on the record a response to what is going on in its environment although we don't usually represent music in terms of its spectral decomposition there's not reason that we couldn't and if we did then the tb immune memory system would actually work similarly to that way of recording music anyway i'm not sure how far this metaphor or analogy could go but i thought it was fun at the time what i wanted to ask you though after all this is what is the best book on the immune system for a 12 year old for under 150 so for instance janeway is out although i could probably get a previous edition cheap cheers jeff so um if your 12 year old could understand this analogy with spectral analysis combined yeah right amplification and so forth um then kudos to him and to you for knowing that he could understand that because um it i think it's a pretty complicated analogy it is but um anyway um maybe it works and maybe it works for some people who think more about music in in physics terms which reminds me i have the chance to go to another saturday morning physics about music in the near future um right to do that um so uh the book that we've suggested in the past that i have and i refer to is about a quarter inch thick eight and a half by 11 format paperback by lauren samparak called how the immune system works and you want to get the sixth edition because immunology is always changing and you want to have the most current one so how the immune system works nice so uh susanna lopez she's not written anything that would do the trick has she yet she needs to tackle this one i think she might have said she's working on it yeah she's she's written some things that kind of get it at some aspects of the immune system but and then yeah i don't know it seems to me that her books are targeted more younger yeah the younger age group um but that could also work for understanding immunology it's true yeah the other answer is as soon as we understand the immune system that book will be written but that hasn't been done yet right all right this next one is from johannes twixtors i'm a little behind in listening so i'm sure someone already told you but just in case and twiv rats more coronaviruses from august 29th you were talking about a ligation method that leaves no traces and that you didn't know of one gibson assembly would be my obvious example as i use that in the lab all the time and all you need is for that is fragments that have overlapping sequences of 20 to 30 base pairs and an enzyme mix containing a five prime exonuclease that generates long overhangs a polymerase that fills in the gaps of the annealed single strand regions and a dna ligase that seals the nicks of the annealed and filled in gaps and voila no traces of ligation because you do not have to use restriction sites if you synthesize or pcr amplifier fragments and no recombination scars like in gateway cloning yeah i forgot about gibson yep have a great day from perth australia okay let's do one more round rich adam writes greetings vincent and everyone i love twiv but i gotta take a very slight exception to your discussion of star trek red shirts in twit 802 which was in every other respect a terrific episode god a star trek booboo this is terrible how many times has it been said on twitter when discussing statistics check the denominator if we apply that principle to the star trek red shirt phenomenon we get a different story than the usual narrative by the way the usual narrative is that if you show up in a star trek episode wearing a red shirt you're doomed those are the characters that wind up getting killed uh while there's actually a book written about this a novel about red shirts while it is true that more red shirts engineering communications and security personnel that's their uniform is read died in the three seasons of star trek then either gold shirts command positions or blue shirts science and medical staff if we look at the population of the enterprise we see something else by the way i've heard rumors that there were some sarge some star trek shows after the original series but i suspect that may be fake news anyway by raw numbers the deaths break down as red shirt 25 that is 58 of total deaths gold shirt 10 23 of total deaths blew eight 19 percent of total test the star trek enterprise technical manual states that there were 239 red shirts on the enterprise 55 gold shirts and 136 blue shirts this means that the death rate by shirt color is red shirt uh roughly 10 gold shirt roughly 18 percent and blue shirt roughly 6 percent that means the safest position statistically is to be a blue shirt science officer next is to be a red shirt engineer security person and the riskiest position or highest death rate is what the gold shirt command officers credit for this calculation is not mined but goes to mathematician james grimes some of you some whom some of you may know from number file or singing banana it's a new one to me i gotta look that up keep up the great work i love twiv and all the microbetv offerings thanks for all the knowledge and entertainment sincerely adam well we stand corrected uh and i love the data it's uh marvelous that's it that's what does it i so i don't know anything about this but i was on some kansas medical center show and one of the doctors said this and so i just passed it on here on twitter and i think you guys may have agreed or something well there was a there was a i think one of the reasons this came up was that there was a a photographic meme going around for a while that's right with four star trek crew three of whom were wearing masks and one of whom wasn't and the one who wasn't was was a red shirt right right right okay all right dixon now you get a longer one now i get a longer one georgia writes hi vincent and crew listening to shane croney's responses to your questions and impact of timing of boosters i wondered if i might apply that to my situation with the shingles vaccine i got the first shingrit shot at the end of august timing for the second shot has identified as two to six months based on the discussion in the above episode do you think it might be better to get the second shing shingrich uh sigrid uh injection towards the later time frame is it fair to extrapolate response to covet 19 vaccinations to the shingrix vaccine as far as timing of the booster is concerned some background i developed shingles of the trigeminal ganglia on the maxillary branch v2 early in july after i finished a 10 day course of acyclovir 800 milligrams per 5 5 times a day the shingles resurged and expanded to include the ophthalmic branch v1 and i took another course of acyclovir and my eye doctor put me on a 90-day course of 1 000 milligrams of valacyclovir as soon as i finish the acyclovir i need i read up one at the cdc on shingrich how come i can't say that word shingrik rix and confirmed that the use of antivirals wouldn't interfere with getting the vaccination alas i was left with some nerve damage but i haven't given up on the hope that it might eventually improve love all the microbe tv shows and listen faithfully i'll practice that word over the week sorry if they say two to six months then you can go anywhere in that range that's a pretty broad range though isn't it yeah and i doubt if there's any data that says that uh any uh particular interval is better than yeah any other i wouldn't necessarily uh uh um translate experience with one vaccine to another okay so whatever i would in your circumstance i might want to get boosted as soon as possible yeah that sounds it sounds like i'm sorry about your situation that sounds like a pretty awful uh experience that's right that's right for a while the shingrix uh there was a shortage of it and so i was faced with i had gotten the first dose and i was toward the end of the six months or maybe just outside of that before i was able to procure a second dose but now i think that's long since eased up so yeah i think i got my second dose at seven or eight months just because i uh forgot at any rate behind a little behind the scenes here there's a good uh i love this sentence that um read up on cdc on shingrix and confirmed that the use of antivirals wouldn't interfere with getting a vaccination um and the deal is that the shingrix vaccination is a protein subunit vaccine so there's no virus involved so an antiviral is not gonna and antiviral is not gonna deal with that uh did you guys have a strong reaction to shingrix no little little stiffness in the arm not bad no okay uh kathy you're next yes christos writes hello i love your show keep communicating science you are very unique in what you're doing i want to hear your opinion on the use of tcid 50 to determine virus titers either with in vitro assays or in patients i keep seeing it on sars2 papers and to be honest i hate it i feel like quantification of infectious particles should be measured only in plaque forming units tcid50 mixes up cpe general pathogenic effects synthesia and so forth it doesn't seem right for viruses like sars2 am i wrong here's a neat little paper describing two mink outbreaks cheers christos okay so i will tell you my take on plaque assays versus tcid50s they're both using cytopathic effect and in some cases maybe cincitia or whatever to measure um a platforming unit or um some kind of pathogenesis that allows you to score a particular well uh in a tcid 50 assay they're both quantitative and if you just state your units consistently in tcid50 units or platforming units i think it's fine uh one of my colleagues here doesn't like plaque essays and says that tcid50 tcid50s are better uh it may depend on your virus what you're used to and so forth but really in my mind they're measuring the same things but now let's hear what vincent and rich think well i i don't do tcic d50s but not all viruses will plac so sometimes you have to do a tcid50 if you want infectivity and i noticed that companies tend to use tcid50s a lot because i think you can do more high throughput with tci 50 than black assay is hard to do in a high throughput but i agree with they're both measuring cpe um and you could even do both and make an equivalence of the two if you wanted for your particular virus i agree we we had i have done only plaque assays except for i had a a student once we were studying a pox virus of seals and actually isolated this thing and it wouldn't plaque but uh it would cause a cytopathic effect i found it uh to me it's always been cumbersome because i'm familiar with the tcic 50 as you've got to visually inspect all these wells and decide where the cytopathic effect is but i think there are sort of staining methods that you can use where you can use a plate reader and in that case it would be a piece of cake and i think some people use tcid50 because it's easier yeah if you can do that kind of thing so but i agree i think they're both measuring virus replication so that's the key and you know as cathy said some people like one some people like the other it's fine there's something satisfying about a plaque because you can sort of relate to the notion that a virus did this a single virus set this off but that doesn't really tell you uh everything you need to know about the population of viruses that you stuck on the plate okay um because plaque assays you know are themselves not uh perfect in quantifying all the potentially infectious particles in the in the solution so from that point of view they both are a kind of a relative measure of what's going on but they're both measuring infectivity so cool this paper is very nice that that uh it was sent to us here uh by christos about me galbraith stars cov2 outbreaks on mink farms in germany um greece and it's very detailed it's cool tracks it really well by the way they killed all the minks in the farm banks in denmark and netherlands after the outbreak i also learned that on our latest twiv last one is from bev you'll probably have lots of people telling you this but just in case dogs eyes refresh at a faster rate than ours do so what we see as a moving screen is a flickering mess here's the first link i found on it so we were thinking about whether dogs see tv and uh this article in the nest is do dogs see the tv the same as humans dogs see a whole new picture when it comes to tv because of the flicker rate yeah so what do they end up seeing they don't have the same visual acuity um with the advent of high resolution broadcasting hopefully television producers have tapped into the canine market dog tv a channel devoted to programming for dogs launched in 2012. it broadcasts a mix of relaxing and stimulating content designed to reduce stress boredom and loneliness while dogs are alone in the house i my neighbor who has like a dozen schnauzers they they rescue them their tv when i go to my car i can see the tv and it's on 24 7 to entertain the dogs you know you could go out any time of day and it's on so they see a flickering mess i see but clearly some dogs are mesmerized by tv yep well flickering mess could probably be pretty entertaining could be all right it's time for some picks and i am really looking forward to hearing the next installment of dixon's top 10 comedians well this is number four as i recall and uh he should have been number one but i didn't alphabetize them or anything i just randomly picked them mel brooks is by far the most versatile of all the comedians that i've become attached to and my that it tickles my funny bone every time this man says something it's usually funny uh and he intends it to be and he's quick clever a remarkable individual he's made movies he's done stand up he's uh selected incredible casts for some of his movies and this is a compilation of his life basically it's a pretty long youtube documentary on mel brooks and he starts out by dancing with his wife and singing um sweet georgia brown in polish and he and the documentary ends with the same stand-up except that uh his wife is now sitting in the audience and he has to go get her she doesn't want to do it and he drags her onto the stage and the moment they get started she doesn't miss a line she does all the steps correct it was just incredible they were a wonderful couple there's some very touching and warm scenes from gene wilder as uh he recollects all of his experiences with mel brooks and carl reiner of course figures prominently in this as well one of the best lines i thought i've ever heard from him was when he was being interviewed by carl reiner as the 2000 year old man and of course they sent him first to the mayo clinic to make sure he was 2 2000 years old and he says well well i'm not quite 2000 years old he says in september 16th uh i'll be 2000 years but i'm not quite there yet so let's not push it he was even funny at that level um so carl renner asked him once he said you know it must have been rough being 2000 years old when you first started your life there were no medicines there were no doctors he said what did you do for illnesses he said what do you mean what kind of illness have you got in mind he says well what if you got diarrhea what would happen he says well you took clean peaches that was instantaneous out of nowhere the man was and still is um the fastest thinking funny man i've ever heard so that's that's my pick i'll have to have a look at this it looks good oh you'll like it you'll like it you know another quick one was joan rivers she was really good i don't know she was excellent she was i don't know if she's on your list but i liked she was really rapid she could have she wasn't you're absolutely right in fact someone put an old clip of her on the johnny so johnny carson apparently got her started yeah but there was a disconnect yeah well then when she when he was retiring she wanted him to give her the show and he didn't so she was right i watched this clip of her where she came 20 years after her first appearance and she was so quick and saying funny things it was amazing yup totally agree cathy sorry sorry born melvin kaminsky he's 95 years old he was a corporal in the u.s army served in the battle of the bulge exactly melvin kaminsky kathy what do you have for us so i have some watercolors that are a virtual exhibit and i want to read you um something written by the artist i'm a painter photographer who spent 12 years at the art students league in new york studying with mario cooper and dale myers i am a member of the sama gundy club in new york city these are representative of some of my recent watercolor paintings that i entitled germination i live in fort lee new jersey with my wife marlene bloom an accomplished artist who paints in oil on canvas to see my photographs please go to depommyphotoart.com so what you have now figured out is that these beautiful watercolors are by dixon and i didn't even know that he had this talent or this hobby uh and they're just they're just fantastic well i love so yeah how this art show came about and and you're doing watercolors yeah well um it all started 12 years ago no that's not true i was i always used to love to draw as a kid and i think that's what drew drew me to uh no pun intended to the to the visual aspects of biology i loved all the diagrams and the colors of the different tissues etc um i collected stuff out of nature and uh used to observe them in little jars and stuff just like other little kids did then when i got to be an adult i reached a point in my life when i i needed to fill a gap that was missing for quite a while so i decided to take some lessons at the art students league which is anybody can walk in that door pay 56 dollars for months worth of lessons from world famous artists and without any um trepidations of fear of being overly criticized because you don't know how to do anything and i sat in mario cooper's um class for a month without painting anything i watched everybody else you sit in this big square room and there might be 30 people in there and they're all busy painting and they're getting paper out and everything and i'm sitting there like i've never seen any of this before it's like you know entering an operating room and you're going to do brain surgery and then they expect you to do it the first time you go in there you can't do it and i see this kid six years old sitting on my left and there's a woman in her late 80s sitting on my right and they're both feverishly working away and i've got this blank piece of paper and mario cooper sits in the middle of this square and he goes around and he looks at everybody's work he's got this little pencil in his hand and if you've done something good he gives you a little penciled star at the bottom left hand corner of your paper and if you've done something bad he just keeps walking he doesn't say anything he just keeps going and he says or he'll say something like well i think you've done enough painting on that one but you know he'll move on but he's got these he had these wonderful insights uh which really were quite applicable to lots of other things uh and he said for instance he has the class he is what's the darkest place in the room and everybody's looking around for the darkest place in the room he says well you don't have to look too far he says it's actually your eyes if you look at your eyes not the pupils but the irises around them you can that's the darkest place if you look into the pupil it's even darker so when you make your eyes and they went on to explain how to do eyes at any rate so i i started out painting flowers and i you know i was very bad at it i mean i was really bad but i must tell you here's what kind of a teacher he was the first time i put paint on paper it didn't matter what it was and i forgot i didn't even save it he came over to me specifically he looked down and he put a little penciled star at the bottom left-hand corner of my paper he says you're not going gonna know if you're a painter unless you paid a miles worth of painting when you get to the mile then you can look back and say well i didn't make much of an improvement here i think i'll take up golf you know but but i i kept improving i guess and um all these iterations of the germination series started with pictures of flowers and those are all stamens of flowers that morphed into these crazy things and his wife dale meyer who took over his class for him after he passed away it was a very sad event of course um she looked down at me i was painting flowers up to that point and all of a sudden she looks at these things and says well you've certainly stepped on the edge of a cliff now haven't you and i i just kept doing i'm still doing them i i i love the feeling of paint on paper and the effect that it has i don't like messy artwork like oils my wife loves them they stink you have to wash your brushes every night you have to put your oils in the refrigerator so they don't dry out all kinds of things with watercolor you can go to a river you can take some of the water of the river you can sit down next to the river you can take your color watercolors and you can paint a picture of the river using the river as part of the painting which is what isaac always which is what um winslow homer used to do so i um i just love doing this i'm sorry i use this to escape i this is my escapism as you can tell i've escaped in some bizarre places are you still painting water coloring dixon i haven't i haven't uh i've done more photography recently than i have painting but um i know but i gave you one vincent and i was amazed that you actually liked it and uh no so it's this one here um yeah that's the one again which i have a copy of it hanging in my office at columbia i absolutely love this i just think the red ball the little things coming out of it the yeah there's a biological underpinning to the paintings that i guess that'll come to the incubator one day and be on the walls here for sure kathy thank you so much for picking up i am so thrilled that you shared these with us and i think everybody needs to stop listening to twitter right now so look at this site so this is actually thank you to the rest of the picks so now i'm an adjunct at fordham and this is the art department at fordham that actually asked the faculty the adjunct faculty whether they had any art that they wanted to show and so i've i've had actually two shows this is my second show so i'm very proud of that i thank all of my art teachers for that there's an exhibit in the in the lobby of our building hammer building at columbia and you had a bunch of paintings in that as well remember five years in a row in fact that was a lot of fun cool that's fun thank you rich what do you have for us uh i credit grant mcfadden with this one um it's just a it's actually a little news clip from a service called global news uh that describes a new way to probe hurricanes with a a a machine called i don't know if you want to call it a machine called a sail drone and there's a company i think in california that makes these called sail drone uh which is uh basically a big surfboard with a big wing type sail on it um it's not all that bit actually not all that big maybe 12 feet long or something like that but obviously uh amped up with all sorts of electronic stuff that i imagine can help it navigate to where it wants to go and they sailed this sucker into hurricane sam and it took pictures and recorded all sorts of other metrics and i'm just astonished first of all that this machine can survive the rigors of a hurricane we're talking 50-foot waves and uh well in excess of 100 mile an hour winds and so this has pictures of the sail drone some sort of fluff with pictures of hurricanes but then some pictures of that the sail drone took itself inside the hurricane so i thought people might be interested in that it's way cool but to me that the drone um is a little misleading because well at least i think of the drone as being something aerial that's you know coming down and shooting pictures but this is sailing right in there in the water it's a very cool looking machine how it stays a right you know does it ever capsize but it must be self-writing or something you know yeah nice my pick is a book called a shot to save the world by gregory zuckerman it's subtitled the inside story of the life or death race for a coveted 19 vaccine and this hasn't come out yet but i have a copy here because uh the author uh emailed me said he liked twiv he listens to and he said i'd love to hear your reaction so this is very cool this is uh about all the people in the mrna vaccines i think chadox and maybe a few others there's a list of people in the front which is very cool it includes a number of people cast of characters he's got moderna uh he's got bioentech he's got uh pfizer he's got oxford with sarah gilbert um he has um then he has a thing at the end academic researchers he's got cat catalin kariko drew weissman and others jason mcclellan is there government scientists who do you think might be on that uh yeah tony fauci barney graham john mescola kizmikia corbett anyway it's mostly about the people well that's great this guy and of course that's the key to good science writing right so he went and interviewed everybody and uh starts a long time ago i mean it starts in a parking lot in kansas where the head of bioentech is trying to raise money for his company years ago you know but you get to know these people like the head of bioentech and his wife they both run the company uh they they're just workaholics they sleep like four hours a night that when they go on vacation they take five computers with them and they boxes of pre-prints that they read and all this and they let their kids go swim in the pool so it's about the people which is interesting because you don't hear much of that and you know the science is sprinkled in it but here the part i love is about kuriko catalin you know we've already talked about the article saying you know she had a rough time at penn and this is someone in in the neurosurgery department at penn who became a rare supporter she was absolutely brilliant but she challenged people and that was off-putting to people especially those who were insecure she was a pain in the ass she didn't give a about getting a gold star from anyone one day kariko was told to report to the department head everyone's complaining about you he said calling her destructive kariko who had five foot eleven towered over swain stood up to challenge her boss who's everyone and what's their complaint call them now if i made a mistake i'd like to hear it he wouldn't pick up the phone and call anyone so it's that kind of stuff i love and it's about everybody that he's got stuff on everyone well they're just humans right and they have their own yeah so i really like it um i'd love to get him on and chat about this he's a he's a writer for the wall street journal uh investigative reporter he usually writes about business and the economy and stuff like that investing um and uh he decided to do this love to know why and i think it's really interesting if you know as as david cuomo said the best way to write about science is about the people but this is really mostly about the people uh you will hear the science and how it proceeded and so forth but i like it it's good great i thought you were going to say that you had it because he had asked you to blurb it but it's already published by the time he sent it to you so it's it's it's coming out october 26th um so this is a pre-publication right and all the blurbs are already on it oh yeah the blurbs are already on yellow oh that reminds me um so it comes when you get these samples it comes with a public publicity sheet right which it gives you bullet points that you could talk about on your show and um [Music] and then they have blurbs on the back of the book yeah so who's on the back here they have malcolm gladwell is one of them and then newspapers but there's one bullet point here that i like zuckerman the author says the virus likely emerged naturally spilling over from the animal world and he's skeptical of the thesis that it originated in a wuhan laboratory i really like that the vaccines are among humankind's most unexpected achievements and are the result of decades of dedication creativity and frustration so i think he gets it right i think he gets it that's good yeah they're going to be a whole bunch of these books yeah you should check this one out we have two listener picks catherine writes dear twitter i was interested in dixon's comment about the most recent ipcc report dixon what's that hear the mutants oh you're muted oh environmental intergovernmental panel on climate change okay in the time you're still not unmuted but i was able to google it in the time i'd like to recommend project drawdown and give us a link plus the book which is a great resource it ranks various climate solutions by impact to help understand the most important things to do to help stop climate change it makes you feel better to work on solutions okay dixon so check that out project draw down thank you sincerely catherine just an energy efficiency engineer charles writes ave twivam viers those who are about to plaque salute you that's cool or tcid50 right i must confess that i am quite far behind on twit aside from the few i've attended in person at asv meetings i only started listening in earnest a few years ago currently a vast gulf of time separates us as i work my way through your extensive archive your broadcast started around the same time that my adult career as a virologist began as a graduate student at colorado state university it's been fascinating to follow the virological highlights of the past 10 years as my career has progressed along with your program thank you for documenting the weather including your experience during hurricane sandy which welcomed me to my postdoc in the laboratory of eckerd wimmer not sure if this has come up for my listener pick of the week i would like to suggest arrowsmith by sinclair lewis oh yeah as phage therapy comes back into the limelight it's important to recognize that this idea is over a century old and even reached public consciousness in this early 20th century novel about a microbiology graduate student and his irratable german professor i would also recommend another book from the 1920s called microbe hunters written by paul decreef these books were highly influential during my childhood and influenced my decision to become a virologist this is charles brandon stouth yeah i love those books those are all great yeah yeah absolutely yeah so aerosmith has a connection to the university of michigan because paul decree who is the uh author of the other book microbe hunters um was a student with frederick novi who founded our department and vincent i don't know if you remember hearing about this in the lecture for the milestones and microbiology uh that you came for but um uh decreef collaborated with sinclair lewis on aerosmith and he gave him not only some of the scientific background about phage and bacteria and so forth but also the important insight into the sociology of the scientific environment so that that's our connection to it here at michigan i remember that yeah i remember that that story uh during the milestone ceremony yeah that was cool yeah i have a my mother was an english teacher in high school and she uh used to teach this book and i have her copy all marked up in pencil with things underlined and things she wanted to highlight it's really a treasure it's great um so so someone this week talking about you know [Music] following things with twit someone this week said you know the twibs of the past year and a half are a great record of the pandemic in a way because they're every week and we talk about it and people could go back and and they said you should archive it somewhere because um you know the copies in my basement won't last forever it's it's true it is an archive of the pandemic right we've been pretty much documenting it yeah i was reflecting this morning on uh all of the uh ideas that we have had along the way that have proven wrong [Laughter] so if you uh go back to uh if you go back to the beginning and then listen through and see the evolution you see you know that uh we were cluelesser than than we are now and uh it's been a tortuous journey but it is a record that really you can't find anywhere else yeah three two three times a week by virologist chatting for two hours yeah that's right some may say it's a record they don't want because it's too much but no you don't get to choose that all right that is twiv 815 microbe dot tv slash twiv you can send your questions and comments to tuiv at microbe.tv and if you like what we do consider supporting us microbe dot tv slash contribute dixon de pommier trichonella.org depommierphotoart.com that's one i haven't given in a while that's true thank you dixon thank you vincent and you you should mention the fact that without you i wouldn't have those websites so thank you so much for your collaboration my pleasure dixon and i we have something else to do i think you asked me i forgot yep okay no problem kathy spindler is at the university of michigan in ann arbor thank you kathy thanks this is a lot of fun rich con did meredith's professor university of florida gainesville currently in austin texas thank you rich fair enough always a good time good rich i'm vincent racqueniello you can find me at virology.ws i'd like to thank the american society for virology and the american society for microbiology for their support of twiv and ronald yankees for the music you've been listening to this week in virology thanks for joining us we'll be back next week another quiv is viral [Music] you

Channel: Vincent Racaniello

Views: 10,408

Keywords: virus, viruses, viral, virology, COVID-19, pandemic, MIS-C, hyperinflammation, coronavirus, SARS-CoV-2, superantigen, T cell receptor

Id: OrIciWwK5E4

Length: 125min 20sec (7520 seconds)

Published: Sat Oct 09 2021