Title: Sizing up black death and white death: how plague and TB interact with lung defenses and may have driven human evolution
Welcome to the fifth annual seminar series supported by the IDASTP (Infectious Disease Across Scales Training Program) and the MP3 Initiative (Molecules and Pathogens to Populations and Pandemics).
This weekly series of seminars and discussions on infectious disease research and control across scales will be presented by visiting Emory speakers, Emory faculty/postdocs and IDASTP students. Seminar and discussion topics are chosen to provide a broad overview of the current status of the field. Attendance of seminars will allow attendees to keep up to speed with developments in the field, and also provide a weekly opportunity to meet with peers and faculty in the IDASTP program. We encourage anyone interested in the infectious disease across scales research approach to attend.
Hi everyone um my name is Maria and it’s my pleasure today to introduce Dr Robin tanam for today’s seminar uh so Dr tanam began his studies with a MERS in biotechnology and then a PhD in developmental biology in Paris France and now he leads a research team here at
Emory where his research focuses on understanding how our bodies respond to pathological stress his lab primarily studies the cells that make up the innate immune system seeking to develop novel Therapeutics that may improve the cell responses to acute stresses like viral and bacterial infections his team has done extensive research on lung
Diseases incl including cystic fibrosis covid-19 and tuberculosis and together together today we will get to hear about some of that work so please join me in welcome welcoming him and we look forward to your talk thank you everybody it’s a pleasure to be talking to this one full varied audience
Um for you guys today I prepar a brand new set of slides with my left hand okay so you’ll excuse me if there’s no fancy animations or but I try to I’m French so I try to inject a little bit of Art in there not from me because I’m very full
Pier or musician but from other people um and also I wanted to show that we you know we’re we’re in March um it’s this is the uh um the month a few years ago 1882 when TV was first seen under the microscope by Robert P we’re going to
Talk a little bit about this so World TV day is happening in a couple of days so a lot of events here at so really engage you to uh look at the you know the Flyers uh there’s a lot of advertisements for the event here uh
Around uh and also in the lobby I think um so look at the video panels and take advantage of the opportunities and the wonderful people that are going to be there at this occasion um so because this is the uh the program that’s you know uh insiding us to think about
Biology across scales I thought you know what better than white death and black death to think about this together so there’s going to be a little bit of culture little bit of anthropology um and a little bit of infectious diseases which the three things that I just cited I’m a complete uh
Neight in I’m just an amateur right it’s going to be a little bit of long physiology and Immunology which is really what I’m what I’m good at or I think I’m good at um okay so let’s get right to it there a few of the financial disclosures I’m I’m always supposed to
Bring but I wanted also to bring some personal disclosures because I this program is also about you know traines thinking about how faculty came into their jobs and got interested in in what they interested in and uh it so happens let me see if I can get rid of that little
On top probably have to startop sharing for a bit and reshare so bear with me okay I think we’re back and this thing should disappear right about now yes okay um so 1973 a lot of you guys were um Senor par um when not born I was 11
Years old I was a big fan of soccer uh and this is when my uh dad was here was a an infectious disease doctor and internist in one of the big hospitals in Paris he was always a very joyful person and you know super energetic and you
Know uh some of my grand students will say maybe you know I take from him a little bit um but uh for a few months he came back home uh completely depressed because he was basically seeing young people die without any opportunity to do anything
About it and it was really one of the first friend uh in his career or Frank in his life as a doctor I I saw him that depressed and sort of you know down coming back home and we’re fortunate in the uh in Paris to have the pastor
Institute my dad was a malaria doctor um and he was taking care of some of the students International students who were coming in Paris in the um in the um international house that was there um so he had contact with the p Institute so one of the few things he
Did with other colleagues around Paris was actually feeding the team of um and Professor Shan and with some patient samples and L and behold after a few months of painstaking work looking at samples under Theon microscope see the probably one of the first photos that
Were ever taken of the virus by Char and this is uh Now history based on this discovery this group some reason Shaman didn’t get a share of the prize I don’t exactly know why but Mon and and C got got a Nobel Prize for this and I guess
You know now that I have kids who are at the age where they don’t want to talk about their dad it’s time for me to bring my dad and actually was quite an influence on on on what I did being a medical doctor often times you know came
And my brothers and sister the three of them are all medical doctors and I was under little one at home right so I was always asking why and they were very often not able to say why they were able to say how they were recognizing the disease and how they were treating it
But not necessarily how would happen and why so I decided when I was a little one that I would bring the why to the to the dinner table okay so my job was really to try to figure out what was what was happening so um starting to work on uh biology pretty early
Um I think I can to the next to screen your yeah uh so I was kind of introduced uh by my student host but we you know uh 10 years later I went into bioengineering and lung physiology I got two masters that year and then went to developmental biology at College
Of and then I decided actually my wife uh to be decided that if if I she move me then she would never move me from Paris so she said okay let’s go and spend two years in California I said okay California sounds good so we went
And when I was at the gate my mom said you’re never going to come back I said oh this Indian mom right so I said oh come on Mom like and she was right I actually never I me I went back from time to time never
Went back so it’s been 25 years actually that our family is in the United States so 1999 went to Stanford uh spent a couple of years doing some physiology in a dark lab doing patch clamping and you know looking at um atop physiological um sort of tracings of cells and U you
You’ll learn why I did that at some point um but then I switched uh I was really interested in mology genetics so I switch to the herberg lab and the herbergs are famous because they invented the flomer and they also have the patent on humanized antibodies so they made Stanford very
Rich uh they also made themselves very rich although it didn’t really show because you know they had worn out closes and you know they were sitting on the ground I mean it was really an interesting lab but they were maintaining a lab with lots of post dogs who were essentially allowed to do
Whatever they wanted and for some reason they like me so they were Frank ofile they had some spent some time inor Institute as well uh so I did spend quite a lot of time with them actually um they allowed me to uh put together my little team within their lab
And then in for five years I was sort of a baby faculty in Pediatrics and also in in Psychiatry at Stanford so I worked on I did some clinical trials on autism and c c was COPD when I was in genetics I did some work and I did a lot of human
Work as well so I was still dabbling into a lot of different things and for again people from my lab who are here who know me they’ll say I’m still completely un focused but it’s all right I mean I think you know we’re in science not to get paid handsomely but to have
Fun so uh kind of you know we trade money for Freedom so that uh the lab CA know this year so we do quite a lot of things we we are about you know 15 or so and today we’re going to be talking about our working TDN
Play uh so I’m going to organize it around three uh main sort of topics first of all a broad introduction about U white death and black death tuberculos and pl um I’m going to I don’t know if you guys remember remember that series with um Tony Curtis and um uh Roger
Moore tells my age I think proba you guys probably didn’t really hear about these people right I mean they were two famous actors he was like a rich guy and a sort of a guy coming from uh you know from the the Poor Side of society and they were
Um it was I was actually pretty uh was pretty bad at the time I guess I realize now they were kind of I mean they were womanizers and they were kind of you know cracking you know crime uh Mysteries they had really nice cars but
The beauty of this is that you know the the starting sequence you had basically the the screen Stitch into two and you had the upbringing of the two characters like you know for a minute and you could see the guy who was born with a silver
Spoon in his his mouth and the other guy was starting nothing and at the end they were basically teing up so I try to organize some of it this way um so the basics first White death tuberculosis consumption disase scrofula B disease these are different names for it tuberculosis because it forms
Tuberculous Visions in the lung consumption because it eats up all of your energy and your lethargic and basically can’t do much once you have it why death because um because you’re anemic um with with tuberculosis the extremities become white so that sort of dianous like quality to your skin and in
The 19th century was highly prized among romantic artists uh thesis you C up scrofula lymph nodes that are buing out and po disease um this uh refers to the um deformation of the vertebrae that are affecting people with tuberculosis the reason why all these names are there is
Because for a long time people didn’t know they were the same disease they had no idea actually for probably you know the the the largest uh amount of time people were thinking TV was hereditary uh TV could be um cured by having the king you know touch
You so there was a there were lots lots of very interesting myth about this until uh in 1982 that uh doctor from Germany who was not very sort of well considered by his peers so he had been sent in you know in a in a rural area in
The forest he was taking care of folks who were um working with with sheep and uh he basically got exposed to a lot of people who had ANS right because the uh is in the is in ship hair his wife offered him a microscope uh for his birthday I think when he was
35 or something like that pretty late rumor um and he was looking at basically the samples that he had collected from patients and then that’s how he found and so when he found and perhaps after that he caught the attention of the people he was given a a bigger position
And he said I’m going to go after this disease disease consumption so he lock himself up for about six months apparently because he was trying to figure out a way to grow this pathogen in uh in a Petri dish which took him a lot of time and for those of you who are
Have experien with TV it’s a very difficult pathogen to culture but in 1882 he was able to find it and apparently it was one of the most uh most amazing um presentations done by the scientist was not a natural he was reboring he had like a he had a voice
That was high pitched and so so on and but apparently everybody in that audience that day you know thought it was the the most incredible thing that they had heard and indeed um he Pro proved that this pathogen was responsible for all these different symptoms and he inspired generations of
People to spend their time in dark rooms either with the atop physiology apparatus or with a microscope and the geman alexer few years later in P Institute in Paris I did exactly the same thing uh and iolated the the pathogen Viria peses uh that’s responsible for the other play were talking about today
Blank de also called peses PL pestilence blue sickness great mortality and so on called or U both of these uh of these pathogens have had you know high impact on the uh on on on the collective you know uh Consciousness and culture so let’s look a little bit at their
Deaths MTB in 2022 according to wh um we have about 1.8 billion estimated infected individuals in the world that’s about 25% of the human population 10 10.6 million showed symptoms of sickness and 1.3 million died the historic death though I mean obviously you know people didn’t sign a
Death certificate uh since Antiquity but um the estimation is at around 1 billion uh what’s interesting about TV is that it’s been with humans uh ever since we’re humans and even before we work so we go uh we’ll talk about this a bit later but really when it exploded it
Was in modern history during urbanization periods uh especially in Europe during the between the 1600s and 1800s where it’s estimated to have caus about 25% of Old Death obviously TD hasn’t gone anywhere uh it’s ongoing it’s uh especially uh you know it’s very um concerning scourage in the developing world and
World wi among the poor and for the last 40 years it has found an ally in HIV so um the course of disease is dramatically aggravated by by H so it’s been a res Resurgence of of TV cases because of because of this uh Pesce is different in many
Ways it is still here and hasn’t gone anywhere there are reservoirs all around the earth reservoirs generally of you know small mammals that are um in burrow and Dr Waller here specializes in the uh the uh the reservoirs in in the American West so depending on the years we can
Have like you know few cases here and there in recent years there have been between two and four or five th000 cases generally due to outbreaks uh in the uh Democratic Republic of the Congo especially Madagascar in Peru and then rare isolated cases in the US China um
Generally at least two three cases 10 cases in in the US per uh per year a historic death doll again very difficult to estimate but estimated about half of what was called TD and i i p this um this graphic from uh the alliance for vaccination I thought it was pretty well
Done they were basically looking at um history seven delious um pandemics and you can see that PL is represented by try to activate the point too slow too slow this one is this one is the plague that happened during Antiquity the Justinian plague um this one is the huge one black death that
Occurred the 14th century in Europe and Asia and then there’s the third day that happened mostly in China um in the 19th and 20th Century so you can see the this one in particular uh the estimation is 200 between 75 and 200 million people who Di
Right because of plague and so it was estimated to have cause about 60% of all death by the way interrupt me at any point you have questions okay I just the is I’m I’m no TV or no PL specialist so might not have the anwers for that but I I’m reading and I’m
Getting myself educated um in terms of the origins this is pretty interesting so there was this theory that MTV was derived from microbacterium Movis when you know humans started to domesticate cattle but genetic information uh really have debom this Theory the MTB complex which is shown on the left hand side has
Nine MTB lineages and that has has also Movis and M so these are the cattle and uh and goat um pathogens and we know now that humans can be infected by Ovis and cattle can be infected by tubercul by micrum tuberculosis so we can infect our animals and they can
Infect us as well what we know is that the MTV complex has been with OMS since uh the first migration out of of Africa so it’s been coevolving with us and in fact different lineages of um TV are coevolved with different human subgroups Okay so that’s something that we have to
Keep in mind when we do experiments in our lab with like one particular strain and cells from people that you know are from groups that might not have coevolved with that pathogen also uh because of you know the acceleration of human movements uh in the in the last
1502 200 years what’s happening now is some of these trait that have evolved in the human population are protected against one inage particularly but not against a new one that might have been introduced by a new population okay um the right hand side is sort of a an interesting representation of the
World where uh the the geographical areas are shrunk or um just blown up depending on the number of cases and you have also in the pie charts the different types of dages that are responsible for the different cases okay so this definitely shows that India in particular has you know a lot of
Cases of of TV central Asia there’s quite a lot going on in Africa and even though it’s it’s here in the US it’s in South America it’s in Europe as well we can see that these countries are much less effective questions no okay keep going one quick question so it’s kind of interesting
That the jav Sumatra Boro the arelo there’s so there’s so many cases there they AC cross all of the islands and yeah I was also surprised by this uh but yes it’s it seems to be a cross but when you look at the does it really connect to India no
And and if you look at the V it’s in2 primarily um that’s where the wall line is so you get you know more sus and yeah I know it’s a map you’re going to bring up the ball but you know you have and you have monkeys so like an evolutionary divide
Across thatle arelo going far back but it’s like the whole thing shows up yeah no absolutely this is and yeah definitely when you look at theine you can see that it’s it’s very distinct that paper yeah both both of those are in the correct gap on the wall of my
Office it needs another map this map I mean I thought was really cool um so I I I wanted to bring it up here it’s actually a pretty good uh review um so people obviously with modern genetics have been able to go after uh TB and try to detect TV
Remnants of of humans that were buried and at this point the oldest human case of uh TV uh stre sens was found few years ago when folks found a village that was submerged um in the East media Mediterranean so you know close to Israel in this cycle at and they found
Three cases in among I think 60 or so um individuals that they were able to to check uh a woman and her infant baby and then ad uh man and they found also traces of um part disease the formation of the vertebrae in the man and in the woman
And the infant they actually showed U pulmonary TV adions so let’s uh keep going but it’s just to tell you that there’s no one TV in the world we have to deal with different images and they most most likely have different uh you know different ways that they they infect us um
Pesties so pesties arose from your tuberculosis around 4,000 years ago this is again looking at molecular genetic clocks so there’s a lot of uh I would say confusion in the field as much as there is discussion whether the molecular clock pesties is stable enough to be able
To properly date the appearance of the different um uh lineages so this is actually coming from a paper that talks about that this Ean in coming biology 2023 talk you know they expose really well the problem molecular dating and how some of those assumptions that we make are actually
Not born out um experimentally so the clocks might be off you know by by several hundreds of thousands of years but you can see pretty clearly here that there’s uh you know three main waves and uh the second pandemic which is the one we talked about the blood
Death you know with all this this this imagery of the you know the daughters with the with the crowd like you know mask and so on in Venice like that that type of thing this happen here is is the same um strain as the as the modern
Pandemic this one is a j pic during Antiquity and we know now that there’s cases in the Bronze Age this is when festis was uh was basically introduced um in cents we’re going to talk a little bit more about it this is really he got me started and interested
In okay so little bit of a cultural introlude here um obviously there’s been a large impact on culture from both pathogens and I picked a picture from one of my favorite painters on the on the left hand side you guys know who it is Maybe art class interrogation here the
Faces and the the monochromatic eyes migani yes mod okay actually I you because his name soani was a um was an Italian artist who actually lived in moas like in in Paris at the time where C was where all the poor artists were going Picasso and others M actually died of
TV all people who are on the right hand side of that picture I believ to have succumbed to the disease you guys might not be familiar with is basically the French shakespeer uh the Bron sisters the three of them yeets uh and we also have people on the
Right who wrote who had very powerful either opera or novel characters or you know affected by TV who didn’t die of TV as far as we know whose wife died of TV and H go and by if you guys like you know goth stuff you know edar is the is the father
Of goth and he he had kind of a morbid um attachment for I mean he liked his wife obviously but he kind of had a morbid attachment for the fact that she had TB so when she was coping her blood like he had some lines in his text where
He’s saying you know the crimson color of her of the blood that she cut was like you know um contrasted with the with the the whiteness of her skin so there was this sort of R Romanticism around TV at the time in the you know in the Cal
Circles y for example even said that he wanted to catch TV because he wanted to look good with the ladies I mean that’s in my words it was much more poetic than that um and he he eventually died of TD at 26 so there was there was really this sort of um interesting
Um I don’t know how to call it like maybe part Trend maybe was a coping mechanism I don’t know exactly what it was because it was definitely a disease of the poor there was this saying in in Europe that you know TV was killing you know 90
Out of 100 four people it was picking like you know one wealthy man and one wealthy woman here and and killing them as well uh but I think some of these Romantics were almost actively seeking you know infection because they had this uh they had this excuse to be lazy I
Guess because they were consumed by the disease but it was I mean it was not a funny was any experience um this one you guys recognize the painter yeah and um so that’s inspired by the uh the big plate the the two or 300 year PL
That happened in Europe in in the Middle Ages bachio wrote the the camon was a it’s a really amazing book about a play obviously I’m French have to say C you knowest even though laest is it’s about plague but it’s really more you know a cultural sort of uh criticism of of
Uh group Behavior I guess group think uh Daniel the also wrote a great book on plag and Shakespeare interestingly except for a few verse in MTH in other places although he lived through the plague uh didn’t really uh sort of um you know dedicate any single work to
This maybe it was just too present like nobody wants to sing about covid-19 right now I guess so uh interestingly his only son Hamet Shakespeare died at 11 of of the pl people who died of the plate generally die like this so it’s hard to say that person died of the plague I
Mean you know when when plague is is is rampant people have to be very and there’s you know often times I think a lot of lot people died the cause of death was was not necessarily but uh these two great painters tishan and H also died on the
Plague in ity in Germany right around that time I wish I had half of the talent of mod it’s one of the best fures out there um Okay so we’re going to look a little bit at the at the biology now and then after that some of the some of the
Cell bio and maybe some of the more modern stuff that we can think about when think about those diseases so I’m going to spend a little bit of time on this um so don’t hesitate to stop me you are probably pretty familiar with it uh already but uh for for TV the infection
Route is through sharing of air that’s breathed by patient so there’s TB in the in the droplets in the aerosol so if you go in you know crowded places Crow buses or in places where TV is endemic there’s a risk of catching a tv and that’s one of the reasons why I
Think TV was thought to be hereditary is because if you hang around with people who are TV well you’re going to get T right so so there was this uh this notion there was also the notion that you had you went into the you know the mountain or you were isolated and you
Got better and or you could actually avoid TV well it’s true as well right I mean it’s kind of the U the isolation idea so the first thing that happens when TV comes in that is going to go into the long it’s going to get to encounter micro FES that are there micro
Pages are residents in the long their job is to pick up trash and pick up stuff that uh the mucus is not bringing up right so the other the scavenger cell they’re there to do the the housekeeping on the surface of the L so the CTV they pick it up what TV is
Able to do is able to escape uh death inside of the micro FES so it’s blocking the ability of the microf to acidify the K it right we know that in a fraction of uh people who are infected TV is clear at that point okay so some humans have
Sterilizing immunity against TV but we still don’t know why or how Okay in most people that is about 90% of people who get infected TV is going to into the formation of what we call granuloma where bunch of infected micro pages are going to get G together there probably some population Behavior that’s
Promoted by infection by the bug and not just population Behavior such that uninfected microf FES can come and get infected in turn but also other cells of the immune system com in that are not necessarily infectable by TV and they start to form this concentric um
Structure that is a a mature Roma where you now have at least you know 10 or 12 different cell types organized generally in sort of concentric way with m in the middle um and a lot of people actually start there this is called the lat States okay uh but generally you know 10
To 15% will um go on to develop active TV in that case um the the gr will just get into forms called Cas Gran where the micro inside start start to die uh there’s PR TV that’s in the middle that structure gets uh destabilized and at that point the person can sh te
Okay any questions feel good put everybody to sleep not yet okay does the molone that it puts out have any role in this just thinking so like two questions one leprosy is also M bacteria and and there’s a lot of natural or immunity to
That is TV on its way to that is there a long L period or is that a really naive question no something question alone I think it’s a question that’s that’s uh that’s actually quite interesting we don’t understand how how TV is able to escape in certain people and in most
People is actually you know a l infection um the thir is that you’re looking mostly at um an immune susceptibility in hosts that allow to should Escape right so infants other people people with HIV the and and there is also so now a set of people who are known to be
Susceptible to microbacterial infections in general so non tuberculous microbacteria candida as well as the agent of leprosy those people are hypable to TV we’re going to talk about it in a minute but we know they have polymorphisms or mut you know lots of function certain immune Pathways what we
Don’t know currently is how 90% of the people uh good latency and we don’t know how about maybe 5% of the people are Mally infected and are able to clear so there are some super resistors which at this point we still don’t understand at least you know I
Haven’t seen convincing data that you know tells me we have we have a handle on this but the same way as when we look at people who are at risk of developing disease when we look at patients with HIV the type of immune barriers that go down that make them more susceptible so
That perhaps can help us understand how to boost certain um parts of the of the immune system in in people uh in the rest of the population I think understanding the folks who are super resistant will be really interesting as well so it’s it’s def research that needs to be
Done um the pathogen is very different in that it’s absolutely acute and interestingly it’s one of those things where nothing is happening for a day or two and then or help is ose and you die within a day or two so it’s really uh a pathogen that’s not adapted to humans we are
Not um the habitual host for pesties we’re just accidental hosts because pesties cannot really use us to stick around and you know and live it live its life right what we know now from genetic studies molecular studies of sporadic cases for example couple of years ago in
Libya um a few years ago in in Madagascar is that you’re looking at a low local strains that seemed gone for years and suddenly reappear with a human case at the genetic level so really humans are absolutely accidental hosts uh and there are a number of of small mamals bwing
Borrowing Ms from General that are all across the world that are allowing this these birg to survive yeah the um when they’re trying diagnosis now what what shows them besides just doing test whatever what makes this different so uh so generally currently the index cases or most often in history
The index case that is the first time the first person that gets infected generally gets infected by a flee right so the free is on one of these mammals it’s riding these mammals to get the blood pesties get into them and pet this develops into the salivary glands as
Biofilms and when the flee starts to try tries to bite the next Mel it’s actually unable to exper Survivor so it’s going to expel bofum going to vomit the bofum of pesties in the next host right so that’s the index case and generally what happens with this is that the either the
Infected micr patients picking up that pathogen in the skin or neutrophils or the pathogen itself through the the movement in the lymph it’s going to go into the KN node so very quickly you’re going to have some neosis of the KN noes the Boos right Black Death those those
Black sort of JY Ino or or um you know um the that are either in the inguino region or in the groin those um are easily know can be easily SP okay just within within a day or two you have those but also what’s kind of interesting with pesties is that it’s
Really wimpy as a pathogen so there’s a bunch of really good antibiotics that we have now so if you if you are in this preinflammatory phase either acquisition through flee which is really most of the cases or when there are human you know epidemics let’s say what happen in the
The DRC for example people can acquire Tes through the iros droplets then it’s then the the clock is scking much faster that pre-inflammatory phase in case of lung infection lasts for probably 48 Hours maximum so you’re either treated U you’re either detected and treated then or essentially there’s a 100% death rate
That so uh generally they will have typical fever um you know headache like the typical infection um you know set of symptoms that are really I mean there’s no differential diagnosis that I’m aware I mean obviously the food test is negative you go into the doctor like oh I have some for
Fever they do all these tests right that are the common things but sometimes they just send you home say oh it’s cold we’ll get over it so what makes them say that diagnos well a lot of people die because ex because of that exactly and
And I think um fortunately I this is one of those pathogens where you know Public Health experts are trained across the world to know where the uh reservoirs are and to know where you know suddenly when somebody shows with some weird um you know bacterial type of infection
To you know at least put them on the antibiotics that pesti is so wimpy that it’s it’s you know it’s going to be killed and and after that do the diagnosis so I think I think a lot of people are getting you know the the antibiotic treatment uh as as as
Prevention because it really doesn’t cost much and P this has no resistance to it um hand online sure so the head online what’s the question um what is the uh pseudo so pesus evolved from pseudo tuberculosis and I was wondering what uh pseudo what kind of disease pseudo tuberculosis
Causes I thought it caused your cenosis or some kind of gut infection but I can’t quite yeah it’s a good pathogen it’s a good pathogen that can infect uh a lot of different species uh it’s uh it’s common in a lot of mammals it’s also in birds so cism is
Nonth it’s a non special it’s a non specialist it’s actually infecting across across species yeah um the notion is that and we’re going to go over it a little bit have time um the notion is that uh it it jumped from potentially from horses um into humans or Ps into humans
At the time in the in the Bronze Age what’s interesting about this uh although you know TV was infected micro infecting micro pages is infecting the L cells micro pages and when neutr fields are present from the beginning they can clear has this if neutr are not present and come a couple
Of days later they clear the host so it’s a biphasic response where early neutrophilia is completely protected and late neutrophilia is completely Leone a really really interesting case where and we still don’t understand how this kind of U you know complete Rage of the of the lung happens yeah um so when
You’re saying if are there you mean if they have another type of infection yeah so we know for example that and we know from the covid-19 literature now that children between zero and two two and a half have more neutr in their long at Baseline have a type three interon sort of system
Between the eum the micro and neutr Fields that keep more neutr Fields present because they’re better at picking up virus whatever stuff that kids get exposed to so when you don’t have antibodies yet it’s good to have scav like nonspecific scavenger cells so we know now from experiments in animals
As well that if you induce a tiny bit of neutr inflammation an adult animal you don’t you cannot get ptis infection in the LA okay so it is a that’s actually the reason why I got into that and I’m going to give you your five box at the at the end because that’s
That was planted this one um so the H resistance traits and I said 10% of infected people progress to AC TV so there are host genes that regulate clearance and latency there are a bunch of resistance traits that have been proposed um I think the pathway that
Have been the most worked out is the gamma interfer pathway gamma interference also used as a way to detect uh when people have you know been exposed to TV you can take their blood and expose that to antigens and then you can see whether is interfere on production by um
Pathogen specific T cells in the blood so those cyto I2 I 10 23 are sing loop with g t and n are also important for you know boosting the killing of TV the micro there’s also this um molecule called en it’s it’s an iron transporter that’s expressing micro
Features this one has been shown to have EV Bol specifically response to one lineage in West Africa and now that there’s been some changes in in population movements of population that alio is actually not protecting against the new Lees that are around so uh so there’s some some interesting
Coevolution um story there but again the main cell that I think is that the Crux of TV post interaction humans withow micro for pits um the safety pressure must must have been enormous right because we we talked about 60% of people in Europe and Asia dying of uh
PL 30 to 100% legality so people can resist bonic uh the Bic phase but the ponary and septic phases are fatal so there been a number of trads that have been proposed to be comparing some resistance there this protein called piring which is responsible for the disease familiar Mediterranean
Fever it’s a it’s an autoinflammatory disease that’s affecting people in the Mediterranean Basin in Turkey in the mreb and it’s a gain of function mutation of that protein called pying which is a regulator of the inflam so it’s basically a molecule that regulates the amount of i1 data that you put out
It’s one of those very strong alarming of the immune system and it’s one in particular that says I’m dying bring the neutr kill okay so that gain of function mutation of iring has been shown to actually promote resistance to peses but when you have twoos you have this autoimmune disas this autoinflammatory disas
Interestingly also the ccr5 data to that people know well in the HIV literature was also thought to be selected in terms of population genetics by play ccr5 is a scavenger of cyto that attract neutr so when ccr5 is absent there’s more cines that accumulate to promote neutrophilia
That has been shown pretty nicely in a number of papers so this is where you know MV and HIV intersected PL in h seem to intersect as well with regards to that receptor the main cell that’s of Interest here in the long okay I have a couple of minutes
Where I want to talk about well you know what we do about this um and the the open lines for research so one thing that that was published in in a few years a few years ago by several sets of groups looking at um evolution of language also uh looking at just ancient
DNA and looking at ancient poy um the there was this convergence of evidence from those different areas of of of poo studies showing that this population theia step ERS from Anatolia came uh all the way uh uh so from about here came this way through Europe and and went down and what’s very
Interesting is that you can find them because of their Ceramics you can also find them by the genes they left behind and in certain areas especially in the north but not in the South you see the Ceramics everywhere but in the north there are Hypes replaced pre-existing
Hypes within two or three generations so people thought it was either a genocide or a or some other way that the jeans sweep was so dramatic uh but there’s very little evidence that the Yas were anything but ceramic makers so unless they kill people by breaking the pots on their
Head I think there’s something else at play and we know now that they brought PES with them because PES came from horse they were the thir population among humans to have domesticated horse and they had such um you know uh I was about to say intimate relationship with that didn’t sound good
Um so they have such good relationship with their their horse that I think they you know there was a lot of Co Evolution happening there um they also brought with them the mutations of the C and we know that that by population genetics cftr is a gene that’s expressed in your
Longum different sets of mutations it’s causing the disease fosis present in in and patients with CF what you have is you have neutr sometimes it’s completely UNC to work so when you look at little ones with CF little babies they really don’t have anything there’s no virus there’s
No bacteria there’s already Nutri in no and so I spent a lot of my time in my career just figure trying to figure out how this works and behold what we found is that there’s there’s a new way by which get activated in these patients uh those RS are long lived and
They are imun modulatory and they release exactly the type of factor that es doesn’t like um so we call them grien because I already had you know black death in mind I was I was thinking okay well you know the green mutr will fight against black
Death um the big breakthrough in my lab a few years ago is that were able to actually make human neuts think that they’re in the lung and we can make them think that in the L of anybody we want because we just have to collect long from somebody these people expectorate put
That on top of of an Epal that we put in our in our little contration inro we take blood from that person and we can migrate you through and make them think they they in the lung so we’ve been able to show in CF patients in particular that we can
Reproduce their change in really of granules that can change the way that they killing certain bacteria but we know that they’re noton well but we think that they’re this really well so why um you know those those mutations AR in humors generally for resistance against a certain type of bug but you
Open the plant to the to to an assault by another one that’s going to exploit exactly the you know the opposite and we can see in vual that we can either that that phenotype with drugs now we we’ve scan screen a different sets of either RNA Bas or or
Or small based therapies we can use this phenotype or we can remove it so the the project we proposed to MP3 a few years ago was that there was a combination of climate in northern Europe and exposure to pesties that led to the selection of this tra climate
Because once you’re exposed to the cold you make mucus when you make mucus those bugs are stuck when they’re stuck they recognized but the secret both p and per is secret toxin that’s able to activate the cftr cftr is a flushing Channel and the psy toxin also inhibits this channel
Here so essentially when your PES this you’re trying to inhibit the secretion of mucus activate the Flushing you get this birth you’re not seen and then when neutr come it’s too late and they actually kill the you spray but if you’re able to not activate this channel the bugs are stuck the Nutri
Come they released with the mechanisms that we saw patients with CF and you survive okay we’re even thinking that this might have been a way by which those thosea might have even carried testies with them because if they’re exposed constantly to they don’t die they might actually have super
Spreaders the beauty with these follow we can also transmigrate monocytes and make them turn into long microfigures okay we can combine them with infections and so on so what we have in story now for the next few years um on the pet side with np3 and the continuation of this with Dr Mardi
Waller window we’re trying to understand how the CF trade might have protected against s it might have been selected because 25 to 30 million people in the world one in 25 white person is a carrier for mutations of the of this of the CFT uh we’re also interested in inducing this phenotype
Acutely to protect against acute exposure to pesticide p is is an agent that’s a lot of people are fearing in context of biot terrorism for MTV what this is one of the things I’m most excited about now that we have long condition micro Pages we have access to this DSR fre here
We’re working with Dr rang we’re going to infect um human primary long condition micro pages from people from different places of the world with the strains that they have cooled with and with the Dr Shady who’s a really good collaborator of ours as well we’re really excited to look at HIV MTV
Co infection okay so there’s there’s a lot that that’s cooking up in our um just a minute late I just want to make sure that I um acknowledge people in the the group we’ve grown to a pretty large group and it’s a a lot of goodlooking people there I mean fr
Fortunately it’s not just me right because otherwise you know I W be that great but yeah we do we do have a lot of really uh you know good and talented young people there a good mix uh and you can see you know it’s it’s nice to of people coming from
All over the world really so so that allows us to get blood from uh people from different places and look at polymorphisms you know I mean this some some sort of idea behind it um these are all of our collaborators Chris n Lance and John and Sophia is there as well on
The uh plate project s and JY are and Ray are collaborators on the the TV side and then um I want to highlight also de Anderson that who has um any more models of play with the AOS solation so bsl4 play models that were to use as well in some of our
Studies but stop there um sorry I didn’t leave any time for questions we have questions during so we’re all good yeah awesome of course if there are more questions and you have some time we can just hang around for those people want to ask questions abely everyone else