TWiV 1071: Giant viruses and virophages with Matthias Fischer

Vincent visits the Max Planck Institute for Medical Research in Heidelberg, Germany to speak with Matthias Fischer about his career and his research on giant viruses, virophages, and their protist hosts.

Show notes at https://www.microbe.tv/twiv/twiv-1071/

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This week in virology the podcast about viruses the kind that make you Sick from micob TV this is twiv this week in virology a special episode recorded on December 5th 2023 I’m Vincent racken Yello and you’re listening to the podcast all about viruses today I am in heidleberg city in Germany I’m here to attend the giant virus meeting you’ll be hearing a a twib

From there as well but I thought while I was here I would stop by and see uh my guest who is here at the max plank Institute for medical research Matias fiser welcome to twiv thank you very much it’s a pleasure having you here I

Have been wanting to have you on Twi for many years and uh I I thought of of having you on at the at the um giant viruses meeting which is later this week but you said you’re too busy and you want to be able to focus on the meeting

So we would do it here instead well since you coming anyway to heidleberg before and drive down with us so um while while I’m here this is the Institute and then there is also University of heidleberg right next to us exactly where there is some biology

And we’ll do yes a podcast there as well uh but let’s start uh with you is tell us your history I know you’re originally from Germany right I am German exactly I grew up in a small town in the uh very eastern part of Bavaria uh called Paso

And uh then I moved to University in bid which is the northern part of Bavaria MH and there I studied biochemistry so how did you know you wanted to study biochemistry well um I think I got excited late High School the last two years we had a fantastic biology teacher

So shout out to Mr burgle if he’s still alive uh he really got me excited in uh genetics and molecular biology and I thought what’s the best way to get there either biology or biochemistry and then I favored biochemistry and applied and got accepted and that’s what brought me

To bids so at the University biochemistry and that’s a four-year program I presume right uh it was a bit longer than that it was uh 5 years MH um we still didn’t have the bachelor Master distinction it was a diploma that we got in the end okay so it’s kind of like a

Bachelor Masters combination exactly all right so at the at the end of the five years what did you do well um towards the end of my biochemistry studies I got the chance to partake in an exchange program with the University of California for one year which was a fantastic experience which campus was

That uh that was in Berkeley Berkeley lovely yes very lovely and it was also my first Peak into virology so I became fascinated with viruses during uh the years in bid but unfortunately there wasn’t really a chance to start a project that dealt with viruses um so moving to Berkeley was a fantastic

Opportunity to see if that would be something I could do my PhD on so at Berkeley you took courses right I took courses I also worked the lab of Floyd vman on bacular viruses okay as an undergrad researcher which was a great experience and that confirmed me in my

Decision to pursue PhD in neurology afterwards okay where did you do that so the question was uh where to go what topic to pick um first of all I did like the west coast of the American continent yeah it’s nice that was enticing so that’s why you didn’t come to my lab

Because I’m on the East Coast right and also at the time I read a paper by Curtis sutle from University of British Columbia about the diversity of viruses in the ocean and that was a topic that I had never encountered before what year was this roughly that

Was roughly 2003 so that paper that he had published where he has a a figure of staining seawater with cyber green yes and you see lots of virus particles in it exactly had that been just recently published it was a review article um I think it came out in nature around that

Time but yes it did have those cyber images cool and it also had a lot of numbers in it right showing that there are 10 million virus particles on average per milliliter of sea waterer which we didn’t realize before he did that experiment right and of course

Nobody knew what all these viruses were so I thought what they what they infected right yes exactly most of these were known to be bacteria fages but again the exact nature of the hosts and the viruses was not known so I thought this would be a really interesting area

Right right and so I applied to his lab and I was there for a visit and checked out the environment and seemed very friendly and so I ended up in his lab yes that’s how I started in Vancouver where I stayed for six years um it was a

Bit longer than a PhD would have taken me in Germany um but I think it’s both owing to the fact that uh degrees take a bit longer in the American system you have to take courses first and also the nature of project um was really not

Designed to be completed in 3 years so what I was presented with was a new virus that had isolated a couple of years before I arrived mhm from the Gulf of Mexico and infected a heterotropic flatulate so a microscopic eukariotic organism um but not much was known about

Either the host or the virus so these had been already described in Curtis’s lab before you got there yes there was in The Host okay um already at his time in Texas so he was uh in Texas before and then moved to British Columbia M and

Since then not much else had been done on this virus host system and it seemed to be a large virus at the time the family that was most likely um to be a candidate family for this virus were the fot day which was a family of alal

Viruses large alal viruses um so that was the Assumption when I started that it would be a new foda virus infecting this Su Plankton um so I started characterizing the system and the first thing you do is you’re trying to amplify the virus by growing it on the host cultures um

Learning how to deal with the host itself growth conditions purification conditions and so on and very early on I stumbled across a big problem which was that the old lysates that were presented to me which contained the virus worked very well in establishing new infections and yielding new virus particles M so my

Goal was always to produce a new stock that I could use for the experiments with fresh virus but those stocks Never Killed the host so I got no fresh production of the big virus from this recent Stocks by the way what’s the name of the host the name of the host now is

Cafeteria Bor harde ah too bad they took Ron beris out right Ron berus was the previous name exactly it got reclassified okay yes and why is it called cafeteria um the most likely assumption is that it is a very voracious feeder right on bacteria so you can find it anywhere in the world’s

Oceans these are saltwater or Marine these are marine species okay exactly you call them heterotropic what does that mean that means they don’t photosynthesize they need organic material to feed on and that’s in the form of living bacteria okay and they they fyos the bacteria or they fyos them exactly

And they’re very important component of the marine food web that transfer all the energy and the carbon from the bacteria up to the higher trophic levels so the um virus is cafeteria beraldi no we still call it cafeteria Ron Banis virus so CR cro is name the virus okay all right so you

Were trying to grow stocks and that wasn’t working that wasn’t working and it was quite frustrating M because we didn’t have any information about the genome we had no protocols available so you’re basically starting from scratch by the way how do you titrate the virus there’s no black assay I presume because

These are swimming no we did exactly those cyber staining experiments and Counting them on slides under the microscope I see that’s how we figured out how many virus particles we had and you could never amplify uh the the tighter basically in your experiments not from the recent stocks exactly so

The old Li worked very well and that was always a bit of conundrum and you didn’t want to just rely on the old lysates cuz eventually they would run out right there was a very limited quantity of those absolutely okay so they were precious so it took us a while to figure

Out what the reason for this problem was MH but um so I have to also mention that at the time when I started which was 2004 that was also the year when the Mimi virus genome paper was published in science right and of course that caught

My attention at the time but we didn’t have any genome information about it yet except for a little snippet of a helicase gene that was just randomly sequenced from a random PCR and previously before the MIM virus genome was published it was most closely related to fona virus but after that it

Turned out to be very close relative to the Mimi virus genome so we already got a glimpse of where this journey might take us and you had some genome sequences already of CV as I said only a random Amplified piece of a helic case and that happened

To match oh because the Mimi genome was done at its entirety right yes exactly got it okay and that helic case had a hom in the MIM barus genome okay so we got a little preview of where this virus might fit but it wasn’t until years

Later when we got the first genome data about cro and I spent about one entire year trying to construct shotgun libraries the oldfashioned way M so you shred up your genome you put the pieces in little plasmids you clone the plasmids into bacterium and and try to

Purify and sequence them was that here in in idleberg no no it was all in Vancouver in Curtis’s lab okay and none of that worked so we tried the most specialized vectors we could get our hands on at the time but we obviously dealt with something that was called

Unclonable DNA so only very specific pieces um namely the the TRNA genes which occur in this virus were able to go into such vectors and be sequenced got it but for the most part of the genome we didn’t get any sequence from those experiments so one year in the lab

No results basically and then fortunately these new techniques for sequencing genomes in the high frut Mana came up and the first one of those techniques was called 454 pyro sequencing if you still remember it’s already been a couple of years and there have been many other methods in the

Meantime U but that was my Lifesaver because now we could get genome information without having to clone pie of the viral genome in and clone it in bacteria so we got I think around 50 conics so 50 pieces of the viral chromosome back from those 454 sequencing experiments and then I spent

The rest of my time basically piecing together those 50 pieces into one continuous sequence so it was like a genomic jigsaw puzzle and I did that by uh using random um combinations of PCR primers that were facing fa ing outwards from the ends of each each of those

Conts and whenever I got a product I could sequence it and then link two pieces together right so that’s how we ended up with the genome sequence and how what was the total length of the genome the total length was just under 700,000 base pairs um similar to Mimi

Virus no Mimi virus is quite a bit larger 1.2 it’s 1.2 exactly 1.2 megabases right right and so here we’re dealing with a genome of about 700 kilobases which is still a fair size for a vir yeah so you completed this in uh in Vancouver yes exactly correct but

Back to the problem why I couldi it right yes because that turned out to be a very interesting um side project which then turned into a major paper and again uh the Mimi virus system was a tiny bit faster than we were because what they had found was that there was a second

Virus in their system with the amoeba and the mimia virus which was able to parasitize the mimia virus in a co-infection event in the common Amal cell right and they had described this just a few months before we got our first genome sequences back and when I

Looked at these quantics I saw that there was something that looked very suspiciously like the virus they had described as a parasite of the Mimi virus which was called Sputnik in your viral CRV sequence exactly so we found a little extra genome in our genome sequence data that corresponded to a

So-called virro AG so it was not part of the CR gen no it was separate it was separate so when you got that uh you had already known about the Sputnik we had already known about the Sputnik for a few months the sequence had been published so it was relatively easy than

Uh to add one and one and we knew that we had an interfering virus in our system as well because I’m just thinking in terms of if you didn’t know anything about Sputnik and you get covie genome which and you get contigs that overlap and then you have this separate contig

What it would been much harder to come to the same conclusion would you have thought that was a separate virus or you maybe thought it was a piece of the genome that couldn’t be fit in well being in Curtis’s lab is a great experience also because you can bounce

The craziest ideas around and you’re not being scolded for that so Curtis always had the idea that maybe there’s a Fage that can infect the mitochondria inside the cell right so the idea of a second virus infecting the first one wasn’t completely off the table although this was not something we had discussed

As a viable hypothesis at the time but I think we would have eventually figured it out given another year or two so the the Sputnik Mimi virus system is that the the Sputnik interferes with the yield of Mimi virus exactly so you were thinking that this is what’s going on

With your uh crov attempts to grow right exactly and that turned out to be the case how did youal at the same time we also had electroic roscopy data from thin sections of infected cells where we can easily could also identify small virus particle in the same compartment

Where cro was replicating which is the cytoplasm of the H and how did you solve the problem of getting to grow cro without this this other virus by the way what did you call the uh the other virus the Sputnik like well um it turned out

To be similar to a type of transposable element that had been called Mavs or poons at the time so we called it the mic related virus or short M virus so you mentioned the word potin what does that mean so poon um I think that’s a

Topic we will maybe touch upon a bit later um but it basically is um consistent of the polymerase and the Integra so if you take the pole from the polymerase and the int from the Integra which are the two most conserved genes in those elements then you end up with

The name poon so these are pieces of DNA that move around cells by virtue of the polymerase and the Integra exactly and that those sequences were similar to Sputnik is that correct those were not similar to spot your virus but to the mar virus that we had yes okay so there

Was a piece of the mar virus genome that was similar to those Maverick poon elements and another piece that was similar to the spotnik that’s why you called it Maverick basically all right mavirus s name of it so M virus and now this is a reason why you can’t grow

Stocks so hence should deal with that so we did indeed use the last of our old stocks to produce sufficient amounts of cro to do our experiments um but eventually I figured out a way of getting rid of the virage of Mal virus from those lysates um but that didn’t

Happen until I moved to heidleberg so okay so let’s let’s move to heidleberg and then we’ll go back to this whole idea of interfering viruses or satellite do they do they require something from from the large virus they do right that’s why they reproduce in factories

In the cell in which the giant virus is reproduced maybe we should back up a little bit and talk about how these giant viruses replicate all right before that let’s say let’s get you to heidleberg okay so you you finished a post do in um a PhD in in Vancouver I

Did and then you want to come back home to Germany I guess right yes and so I found a place here in heidleberg um where I was welcome because I brought these unusual large viruses which turned out to be also fascinating for other techniques so here at the Institute

They’re using them to shoot them into high power laser um to test the novel method for reconstructing 3D structures of protein right so that was what year you came back to German that was uh I came back in 2010 and then 2011 I started here in hleg all right so that’s

Where you are that’s where we are now we’re sitting in your office and you’ve been continuing resarch on these large virus I should say protests as hosts right absolutely and last night I asked you at dinner what is a protest so tell me what it is so protest is a very old

Term actually that I think originally it was meant to refer to bacteria if you go all the way back nowadays it’s strictly speaking ukar that don’t fit into either animals plants or fungi okay and they sing do they have to be single cell or most of them are single cells there are

Some exceptions of multicellular or Colonial organisms um I think one of the best examples is kelp one of these algae that you find on the beach which look like macro algae but um technically speaking there are protests so protests include algy then could include algae most of them are microscopic then amoeba

Ciliates flatulates so cafeteria is a is a flatulate cafeteria is a flatulate two exactly and then you find these in both salt and freshwater environments absolutely yeah all right so now now we can go back to Giant virus you’re going to talk about how they they replicate

And that’ll explain to us how these uh satellites so the viral or viral fages so the French group called them a virage because they interfere with the reproduction of the helper right yes exactly so what’s is there one name that would Encompass all of them because I know that they have different

Properties um we know very little about the diversity especially about the phenotypic diversity of these virages so we only have a very few amount of cultured systems that we can study so the Sputnik Mimi virus system is one of them we established a second one with Mar virus andby right and there maybe

Two or three additional ones that came up in the meantime what are they what’s the name of those U the latest one uh is a Corella species which acts at the host and then we have a giant virus that is related to cro but um still probably a

Different family if you get down to it and that’s from a pond in China actually what is the organic Lake which a virage the organic Lake virage was uh one of the first metagenomic sequences of virages that have been published okay and so that means we don’t have it in

Culture I don’t have a host we don’t know what the host is we don’t know what the host is we have a good idea about the Genome of the giant virus that it associate with because that came from the same sample and was also sequenced by genomics but we don’t know anything

About the biology of this system unfortunately okay so you wanted to talk a little bit about how giant viruses reproduce yeah I think you touched upon this in quite a few episodes of twift in the past so these are in the past have been called nucleocytoplasmic large DNA

Viruses uh which is a bit of a term right so it has nucleus and cytoplasmic in there and I think originally they just wanted to call them cytoplasmic large DNA viruses because most of them replicate exclusively in a cytoplasm but then I think during review of that paper

Uh One reviewer noted that there also some of these large viruses that have a nuclear phase yeah and so they made them change the name to then became NBS a very commonly used abbreviation in our field nowadays they have been reclassified into a proper taxone uh

Which is the phum nucle side of viota so they still retain the name but it’s now slightly differently pronounced nucleo of viot that’s right you can do it the Italian way Italian way pronouncing it right and all of these have an extensive amount of genes that they bring with it into the

Host cell and often what they bring is a complete machinery for transcribing their own genes for making RNA from DNA absolutely right okay and usually viruses would either have RNA polymerize to do that if they have an RNA genome or if it’s a double strin DNA virus it

Might go into the nucleus and use the host cell Machinery but that’s not the case here so these viruses are so complex in their enatic Machinery that they basically bring their own version of this transcription system and they set this up in the cytoplasm in their own compartment which you call the viral

Factory mhm and within the viral Factory you find all these RNA polymerized subunits you find transcription factors uh you find capping enzymes you name it everything is there to make RNA from the genes and that is the most important property when you talk about the dependence of virages on their CH virus helpers

Because the virophages they also don’t use the host Machinery but their genomes are too small to bring their own transcription enzymes so what they do is they have specialized for whatever reason to exclusively rely on the transcription Machinery that’s brought in by the giant virus okay which is

Present only in the cytoplasm so that’s where they have have to be at the right time in the right cell mhm to get the genes transcribed okay and by the way these rnas that are made in these factories are they translated in the factory or do they go out into the

Cytool to be translated into protein so typically what we see in electr micrographs is that these um factories have uh very fine texture that excludes ribosomes okay so the common notion is that the MRNA is transported to to the periphery of this Factory where the proteins are made and then they’re

Shuttled back into the factory okay and these proteins would include DNA replication proteins for example yes and also structural proteins because the virus particles are assembled within this Factory right absolutely right yeah all right so the the virages or satellites mavirus and Sputnik those are the two main ones we’ve talked about so

Far these interfere with the production of the U the helper virus right right and how do they do that well that’s a good question because it’s not really known what the molecular basis for that interference is the most common assumption also based on our own experience with this system is that it’s

A competition effect that the virro AG is just more efficient in recruiting those transcription factors so I should also mention that um the reason why it can utilize the giant virus Machinery is that it carries the same sequences Upstream of its genes that the giant virus has when it switches into the late

Phase of its infection cycle and there a special type of protein is made a transcription factor that can recognize this promoter sequence which sits Upstream of the genes and exactly that promoter sequence is used for all of the genes in the vof genome so already by biomatic prediction we had a very good

Idea when the virro would become active during the infection cycle of the CH virus okay right so they basically recruit away all those essential transcription proteins leaving nothing behind for the giant virus to make it structural proteins which would be the main purpose of the late phase okay so

Is that what we need to know about the reproduction of these giant viruses in the satellites oh I think there is much more to talk about but uh for once we don’t know even half of the entic capabilities of these giant viruses many of their genes have no known homolog

If they have homes then we still cannot be sure about their function you talked about this great eive paper sometime in the past by Shantal Abel’s lab right um about the genomic fibroid Mimi virus which is made of a protein that was originally thought to be an oxido

Reductase a red ox protein right but it actually performs two different structural functions in the MIM virus so if you so you cannot be sure about this yeah the point is if you see a a protein and you say oh this is an oxido reductase it may not be it may it may

Not be it may have acquired a completely different function during the time it resided in the viral genome because originally it was presumably a cellular Gene right most likely mostely exactly so the um we don’t know the mechanism of interference but the the point is that these um these satellites interfere so

They’re a way of protecting the host really right that turns out to be a very interesting side effect and I think it has quite a significant implication for the Ecology of these organisms um but I also have to say that we shouldn’t generalize there are biases out there that live in perfect harmony

With their helpers with chus they don’t interfere with them they don’t interfere they replicate alongside with it one example is the the ton vro AG yeah uh which I think is Algerian or Tunisian for little companion right Sputnik is Russian for that um we named our Mar

Virus strain spel which is the Bavarian term for companion so you see there’s a there’s a theme to to naming these things right but that’s an example of of a wiof ag that doesn’t interfere with the replication of the giant virus okay and therefore it also has no effect on host cell

Survival but what we found in Mar virus which had already been described uh with with Sputnik and Mimi virus before but even to a greater degree in Mar virus in the cafeteria system was this protection of the host population through the presence of the barage mhm and it took

Us quite some years to figure out how that might come about um so basically what we’re dealing with here is not a typical defense system as you might find it in bacteria or also in multicellular organisms where you basically save the organism at the onset of infection you can cure the

Infection or you can even prevent the virus from getting started so how it works in uh in this system with cafeteria and its viruses is that the virage doeses not save the cell that is already infected with a giant virus but it would what it can do is during the co- infection it

Prevents the production of new giant virus particles but that cell will still die that cell will still die right but it is basically sacrific in order to save the rest of the population which hasn’t been infected by the giant virus yet so it’s the survival of the uninfected right which overall looks

Like the host population survives so is this a random process that a a virage and a giant virus will get into the same cell at the same time there’s no attachment to get them both in the same cell right for Sputnik and Mimi virus there’s probably physical attachment oh because MIM virus has

These external fibers on its capset which are very sticky and Sputnik is often observed um to be trapped in those fibers so they may enter as a composite okay very good the question how they escape from the fagos um is a different question for the V AG but but in the

Terms of mar virus and crob Mar virus can get on on get inside the cell on its own so it attaches probably to a receptor of the host cell it is endocytosed so it doesn’t need the giant virus to get inside the cell but it cannot replicate without the giant virus

So it probably enters many cells without replicating because there’s no giant virus in exactly right and the giant virus can get in on its own and if there’s no uh satellite that it just kills the cell and makes lots of virus okay but initially we wondered how this

Would be a viable system yeah because we saw a very strong inhibitory effect of M virus on crobby so basically every cell that gets co-infected with those two viruses will only produce the virro AG and not a single particle of crow that’s why you had so much trouble in the lab

Growing stocks it was very effective in reducing the amount of crow that came out absolutely so we wondered how this would be um viable on evolutionary time scales right and and we found the solution to that a few years later when we figured out that Mar virus has a second strategy up its

Sleeve because similar to some bacteria fages it can integrate into the host Geno and there it can remain silent for many generations it’s passed on passively by the dividing host cells until such a giant virus comes and infects the host cell apparently this infection event is then sensed by the

Otherwise silent genome that sits in the host nucleus and the vof genome is reactivated it makes particles and then the spread of the vof can yeah be resumed we we don’t know how the giant Virus Infection stimulates the production of this satellite right our best hypothesis at the moment is that it

Also has to do with the same transcription factors the late the late transcription factors exactly but it’s an interesting difference here in that situation because the chin virus replicates in the cytoplasm as far as we know it has no business in the nucleus but that’s exactly where these

Transcription factors need to go in order to activate MH the silent this the dormant biopage so how does that happen so yeah right right because the virage is in the nuclear DNA right absolutely yeah okay so some of these chin virus transcription factors need to migrate inside the nucleus do they have nuclear

Localization say oh maybe that’s not a thing in uh in produce they don’t well of course no that’s a thing yeah yeah that’s universally conserved um but as as far as we know there’s no NLS those um proteins so we think that either the no nuclear membrane is compromised at

Some point during infection so it might just be leakage and any protein can go in yeah or it is indeed transported at low levels why did you even look in the Genome of the host for this virage sequence there must have been some reason right or did you do it

Accidentally well we got a clue by looking at the Genome of mar virus so when we had the full genome sequence of course you’re trying to figure out what the genes do and one of the very recognizable genes that marus carried was a retrovirus type integrace which in

Itself was completely unusual because no DNA virus before had carried such a gene which is obviously as the name implies typical for retro viruses and retro elements right so now for the first time we had a DNA virus with a very strange combination of a typical DNA polymerase

Right and this retral Integra um so we got a clue that this retro integrat might help the virus genome to integrate into another piece of DNA okay that makes sense yeah yeah um but initially we didn’t know whether this was the natural situation so what we did is we

Took a host strain that didn’t have Mar virus in its genome before and we exposed it to a lot of mar virus which can get on inside the cell on its own as we talked about and then a week later we uh purified the DNA from those treated

Cells and sequenced it and as a control we sequenced the original strain MH and then we looked for differences and we found about a dozen integration events in the treated samples so they were scattered all over the genome there was no specific place where they integrated

But clearly marus was able to get into the hostel genome very efficiently so th that infection simply lets the mavar’s DNA get into the host cell it doesn’t replicate because there’s no helper exactly and so even though there’s no replication that DNA can get into the nuclear DNA via the integrace yes which

Is is it in the particle it is packaged CU otherwise it would be stuck right because if you need transcription in order to make the integrates first and you need a giant virus then the cell will not survive even if you manage to integrate all right so that’s very smart

So it brings the integr as a protein it’s it’s ready to go um we don’t know about the timing yet if it waits around in cytoplasm for some time to wait for a China virus and then it goes in or whether it immediately goes into the nucleus so these are still details that

We have to figure out right but it does integrate remarkably efficiently we had never expected that so it’s not a mandatory step I have to stress that it’s not like a retrovirus that needs to integrate as part of its replication cycle but it’s still I think is an

Essential survival strategy to uh endure these long times where a population not encounter a suitable giant virus now if you when you have a m virus and crov in the same cell does m virus ever integrate into the CRV genome not that we had seen so far no that’s weird right

It should it it could and it potentially should but um there is another example of a virage that does and that’s Sputnik so Sputnik has been shown to integrate into the mimivirus genome okay but I also have to mention that although Sputnik also carries an integrace it’s a

Complete compl different type it belongs to this large family of Tyrus and recombinases um for example the Lambda integr falls into that category and these are more sight specific okay so it’s possible that if you carry this tyris and recombinase type you’re more prone to integrate into a giant virus

Genome whereas if you have the retrov version you’re more prone to integrate into the house genome gen okay so the M virus CRV system suggests that M virus is actually protecting the host cells because it’s retained in the host cell genome and then when M virus comes in

With a and there’s a giant virus there will protect the population right so the question now is is this a laboratory specific thing or is this happening in the real world then can you get other examples of absolutely I mean that was the big question all along right um so

With these laboratory experiments it was basically a proof of principle right because marus already was delivered to us in the particle form we didn’t know about indous State um so now we could see that it integrates very efficiently into the host genome and the next question was as you said is this

Happening in nature right we thought it would be but we didn’t know there were no genomes available for cafeteria at the time so what do you do well you sequence your own genomes so we took a couple of strains from our collection cafeteria cafeteria uh we purified the

DNA and we sequenced it um now with new techniques so we had illumin sequencing um we had pack bio specific biosciences which is the first technique that produces very long sequences very long reads which makes it easier to assemble a complex genome so that really helped

Us along the way still it wasn’t easy um so these vages are not easy to find if you don’t know exactly what you’re looking for so that feeds into the bioinformatics discussion and computational Analysis of genomes which is uh a whole tricky business in itself but we we really had problems initially

So we we knew that the virro would be integrated into the host genome in those early experiments because we did PCR right and right and we could clearly associate that signal with Integrations but still in the early sequencing experiments that we did which were just done with Illumina sequencing we could

Not find any trace of the virage and that was very very peculiar and only later we figured out that it has to do with the protocol that they used at the time for prop ing the sequencing libraries for illum which included a PCR amplification step and that apparently

Had a strong bias against at Rich DNA right so you have the four different nucleotides and the genomes can have either more G’s and C’s or more a and T’s or it’s rather balanced in this case if you’re dealing with the viruses they have a very high percentage of at about

70% of the nucleotides are a and T’s the host Genome of cafeteria is exact the opposite it has 70% of G’s and C’s so with this sequencing method and this PCR amplification step apparently only the GC re regions were Amplified whereas all these vof AG genomes were poorly Amplified so that explains why

You can’t uh so that’s why we didn’t find them in the first place in cafeteria genome right in the cafeteria genome so we had to modify the protocol we just skipped the PCR and that worked fine but it also told us that maybe it’s not that easy easy to find it in other

Organisms for other people especially if you’re not looking for exactly those modes I mean the question then is if you look in all the protus genomes that we have do you find signatures of these you could look for the um the integrace right the that’s specific to M virus and

Other genomes or for the other for the um sputnic was a tyrosine rein Rec combinat right yes yes you can do that and nowadays we know that they’re all over the place but that is only a very recent development mhm so there was a paper in 2015 um that looked specifically for

Integrated virages in all the published um uko genomes that were available at the time and it actually only found one specific case where they were clear that yes we have integrated virages and that was also in a prote in a marine alga called Big natans which is a very strange uh type

Of organism it’s um the group is called chlorites and they have gone secondary endosymbiosis which is something you talked about Nel’s El in a recent too episode right um so they basically have the the plased along with its former host which they still retain um as a little pet basically this this

Nucleomorph which is the remnant of the nucleus of the original host for the uh plased um so these single cell algae apparently also have integrated baroes okay but for the rest of the published genomes there was no trace of any marage Integrations so at the time it really

Looked like this was an exceptional case but again you have to look at the way that these genomes were produced M the method that has been used mostly for sequencing them was Illumina and most people used the PCR amplification step so if other VES had a similarly high at

Content that would probably be neglected in those sequencing experiments okay the next problem comes if you’re trying to assemble those sequences even if you get them sequenced in the first place if they’re present in the Raw data you have to piece the pieces together to construct your genomes and that’s not an

Easy process right so how do you do that you look for overlap and these vof genomes they don’t just occur in one copy they are multiple copy elements and they occur in different positions of the genome right they may also differ in their positions if your population is not CLA so one

Cell might have them in a different position as another cell right then comes the fact that these are long elements they’re about 20 kilobases long mhm and still they are repetitive because they occur in multiple copies they also have special repetitive ends which makes it difficult so if now such

A computer algorithm encounters a wiof h genome it might be able to continue a little bit into it but then it might find several possibilities at the end to continue because they’re different integration sites and typically what an algorithm does in such a situation is it

Stops the assembly so you get the end of the cont right there even though it would continue in a natural situation um often what you also get is separate contexts for these vof agents also because they differ in their at content sometimes from the host as we talked about in

Cafeteria so they’re not together assembled with the host genome and then the next step that you do is you weed out all the stuff that you don’t want mhm in your final genome assembly right all the contamination that might be present in a sample right and often you

Might have viral contamination so you run an algorithm that identifies virus-like genes and throws out those conics something that looks obviously different than the rest of the genome and of course wi fages would fall into that category so they often ended up in the waist bins if they had been

Sequenced and assembled at that point so the genome sequences are not right because they’re missing integrated virales many of them certainly do nowadays the situation has gotten better because many people use long read sequencing especially nanopore technology that really has changed the picture tremendously and using that long

Read sequencing and also looking in the waist bins of other people’s projects um a post talk in um in insbook in Austria Christopher Bellas has uh published a paper this earlier this year where he looked specifically for these integrated Elements which include the virro ages but also many other elements which are

Remote relatives of vages and they’re again related to these poons or Maverick elements um collectively they’re referred to as pollon viruses so this this is MAV virus included right this includes Mar virus this includes Sputnik but it also includes other elements where we don’t really know what they’re

Doing okay they look like they are viable yeah viruses so they should be infectious they have all the structural proteins but we have no idea what their lifestyle is if they depend on another Chine virus if they’re independent and who which virus and which host yeah the

Host you can identify because you have sequence sequence we don’t know the the giant virus right right and what Chris very nicely showed is that basically every species of ukar has one or the other type of these integrating DNA virus so you say UK cariot do you mean

Protests or all ukari in this case all UK carots because M milon cell so even Mion cells have these poons H so do they have structural proteins associated with them they have structural proteins yes they have um these double jelly roll major capsure proteins so humans have

Have these I’m not sure about humans so I think humans may be a special case here so what are we talking about what kind of organisms oh we’re certainly talking about lower vertebrates you can find poons there um you find them in all kinds of animals um but the thing is

Nobody really has observe them in action right so they have been originally classified as transposons right which would exclude them from the viral world so to speak even though you know it’s sort of the same selfish mobile genetic element that we’re talking about so tell tell the listeners what a transposon is

So transposon in the simplest terms is a jumping Gene piece of DNA piece of DNA that can move its position independently of the genome where it’s integrated and typically they encode their own enzymes for that but they don’t package the genome in a particle like a virus would

Do so the fact that there are these viral like sequences in lower malean genomes does that suggest that there’s some giant virus that would infect those lower mammals as well that’s a difficult question to answer because these might be remnants um from the very past where we may have

Encountered some of these giant viruses yeah um they could be retained for different reasons often these endogenous viral sequences Can U be co-opted for new functions M that serve the host I mean you have great examples for that with the retral genes right sens for example um it’s just one prominent

Example of many more that are sure to follow right so we don’t know if they’re still associated with ch viruses okay but certainly for the prote many of them apparently are yeah the fact that they’re still in protees genome suggests that they they fulfill a function right they’re intact they have open reading

Frames and they or or is it not always the case um I think you have to be careful when you talk about they have a function because that implies they have a function for the host potentially right and I think that very much depends on your point of view even in the strong

Phenotypic case of mar virus which protects the host um it might just be the survival strategy of the vof age that It just fits into the selection scheme of evolution that is beneficial to save the host population in order to ensure your own persistence okay so saving the host is a reason function

That to be selected for right exactly right but it’s not the host driving these interactions I think I may be wrong but I think we should not fall into that trap of assuming that in the first place but also you said some of these uh viral fages don’t protect the

Host they just coexist right exactly so in that case why would they be maintained in a host genome that’s why I think it’s mainly driven by the viruses themselves as a mechanism for persistence and as long as it’s not detrimental for the host cell so for example in cafeteria we we’re curious

How many virages can we package into hosome and it turns out it can comprise more than 10% of the entire DNA and it’s still viable it’s amazing right well I I guess uh bacteria fases become lysogens in their hosts and that’s an example they persist and it not clear if it’s

Any benefit to the host but it’s a viral strategy as you say well it’s certainly beneficial in terms of horizontal Gene transfer right Rec combinations okay so why don’t the giant viruses sustain changes that make them not inhibited by the viral phases well with any parasite host relationship you

Will always find resistance right and the same is true vagant viruses and there is already one example that has been described which is a Mimi virus where there’s apparently um some kind of system they call it the the mimir system um which consists of a couple of genes

Mhm that that might confer resistance specifically against some of these vages namely SP I think we covered that on twiv actually you did yeah yes exactly you you listen while you bike ride right I do yes okay it’s quite entertaining do these uh virages recombine they certainly recombine especially if they’re closely related

And sitting in the same host genome um so we’re not quite sure yet what implications this has for uh the evolution of the host genomes themselves but it might very well be that this is also a possibility uh to refresh the gene content because for many of the

Protests we assume that they’re asexual so they’re just dividing but they don’t mate yeah um which is probably not true to begin with because we know very little about their Lifestyles many of them may have something like cryptic sex that we don’t know about but it’s also possible that these mobile genetic

Elements are a source for refreshing the genes that you have for recombining it with other chromosomes and potentially other microorganism that coming and the giant viruses themselves can also pick up genes and move them around right very much so absolutely I mean look at the genomes and each giant virus genome has

Basically a different set of unique genes that you don’t find anywhere else and the most logical assumption is that they have been picked up from a previous host right they’re very efficient at taking up genes um but they’re also very good at losing them if they don’t need

Them anymore so it seems to me we have a couple of model systems for viral f giant virus interaction we probably should have some more to be able to make some more generalizations right is are people working on this people are working on it but I have to say not enough

So a lot of the data that we have about giant viruses comes from the Cana system with Mimi virus which has turned out to be a fantastic tool to look deep into what’s happening with the host cells um it also turned out to be a fantastic

Host to pull out different typ types of giant viruses it’s not just Mimi virus of course you talked about different ones in the past there is these Marse viruses which is own family the Pandora viruses their PIFA viruses mly virus um do they have uh viral phages associated

With them um so far the virages are restricted to members of the order imit rales um which includes all the Mimi viruses and their relatives including cro including these alal okay Mimi like viruses okay but for Pandora viruses um P viruses Mar viruses they haven’t found

Any virages so far okay yeah back to your question so this is the system that most people work on when they work on giant viruses um so we tried to establish an alternative system over the years and I think we contributed some data from the cafeteria system but still

I mean virages and giant viruses don’t just infect amoeba and these flatulates they’re probably infect every clay of prote every type of UK carot that you can imagine do they infect humans uh why you have the pox viruses right but what about bigger viruses than pox right I

Mean there’s many papers out there that suggest that humans get infected with Mimi viruses right what do you think many there there some right there’s some well according if you talk to Eugene I I once asked you jeene at a at the giant virus meeting I had lunch with them I

Said do they infect humans of course they do he’s very emphatic well but I’m not sure I’m not convinced yet that they actually replicate in uh in our cells what certainly the case is that we live together with giant viruses and we have them on us and in us because we might

Also be host for the hosts of these Mimi viruses that’s a very nice example I think you mentioned it at some point where there was an amoeba isolated from a patient with keratitis the amoeba was infected with the Mimi virus the Mimi virus had its own virus of AG right

Right so it’s this microcosm that we carry on us that we know nothing about and apparently it doesn’t affect us in either way wasn’t there a prominent paper published saying that Mimi virus infections were associated with people with mental illness H that was not Mimi virus giant

Virus of some kind that was one of these alal viruses that was a chloro virus virus yeah right I think Jim vanet was on that paper exactly very controversial very controversial um yeah so I would be careful with my predictions in Direction okay but it’s certainly possible that

They have effects on us that we don’t know about but as far as we know right now we don’t have to be afraid of CH viruses causing the next pandemic and I hope it stays that way to be honest but you you you and others are interested in finding more virus host combinations

That can be studied in terms ofes right and it’s not easy to do you showed me yesterday in your lab the systems you use and it’s it’s hard right yes of course but you can increase your chances um if you know how to prepare the environmental

Samples you have to go somewhere and you have to go somewhere exactly this map shows some of the Lakes yeah so we have a map of the European Alps behind me and uh this is going to be our new playground so I recently um got the good

News that one of my grants was approved which will allow us to look specifically at High Mountain Lakes in the Alps and characterize the viral contents and of course we also going to look at other microorganisms including bacteria and protests and that turns out to be a very exciting environment because we’ve done

Some pilot studies in in the lake um in the in Austria also high altitude and that turned out to be a very good environment to first of all um collect your samples it’s not cluttered with stuff that you not interested in so there’s very low biomass um because

These are oligotrophic lakes which means they have low nutrient levels right so whatever hosts you find there are probably well adapted to the extreme conditions that you find in these Lakes so lots of radiation in the Summer Long freezing periods in the winter so not everybody can tolerate this right right

So we find very discrete virus host systems there and uh already with just a few samples that we took we found giant viruses that had morphologies like we hadn’t seen them before mhm um we had done a similar study where we just looked for shapes of virus particles in

Environmental samples and that was a soil sample where we teamed up with Jeff Blanchard from the University of Massachusetts right and they had looked or had accidentally found giant virus genomes looking at these Soul samples for metag genomics before so we knew they should be present M so what we did

Is we shipped a sample over to heidleberg and purified the size fraction that contains these giant viruses um and then we took them under the electron microscope and we found an amazing array of shapes that obviously corresponded to Giant virus particles but they had tail structures like no

Other virus that has been described before they had fibers they had appendages tentacle like structures modified portals so there’s a whole lot of structural diversity out there that we have absolutely no idea about so is that what this image is here behind these are some of the drawings of the uh

The different types of viruses that we found exactly from soil right these are all from soil and there’s a pre-print out there on bio archive that you can look up um where we talk about this in more details so this one with the fibers is Mimi virus like this looks like a

Mimi virus but it has a second layer of presumably proteins that cover the capset and then you have the external fiber layer exactly and this one is interesting it has long hairs at one end are those they’re all they’re all fibers to like sort of like the MIM vir they’re

Just asymmetric right yeah so one of the surprises to be found in Sample is the diversity of fiber structures we know fibers for Mimi virus and a few others but um we always thought that this is restricted to a few types of virus now what we see is that basically every

Virus particle had some kind of um fiber coverage in some sorts they can be long they can be short they can have globular heads they can have triangular heads they can be curly fibers straight fibers so you name it so there’s an entire diversity of also glycosilation patterns

On those fibers and underlying chemistry that is completely unexplored at this point so one of your goals is to get a v a giant virus host system established in the laboratory that might also have a viral phage that interferes and you can study that might be it doesn’t have to

Be the case so in this case with the Alpine Lake projects we will be interested in chin viruses that have these special unusual modifications on their campet and we want to try to figure out first of all what do these things do are they important for infection um are they some kind of

Environmental adaptation to the conditions you find in the lakes for example are they conferring resistance to UV are they helping the virus to stay afloat um all of these questions are possible and then we try to figure out where these proteins came from that make up these special structures how did the

Viruses acquire them mhm did they steal them from the host they get them from other viruses are these modified genes that they use for a different purpose in uh in laboring virus so these are all questions that we’re trying to explore so having talked for about an

Hour uh on this topic giant viruses and their hosts and and viruses that interfere why should a non-scientist be interested in learning about these things I think if you just have a little bit of curiosity about the world that you live in um this is certainly some interesting piece of trivia right these

Giant viruses were initially thought to be exceptional freaks of nature read some of the comments on the first Publications on Mimi virus so it was thought that this was an exceptional finding you got incredibly lucky to find those but what we know now is luck doesn’t have much to do with it it’s

Just that nobody cared to look before and if we just open our eyes to what’s right in front of us I mean look at the soil sample with all the bial diversity that’s basically on your doorstep right you’re you’re treading on viruses of that kind all the time and you have no

Idea what their function is how they’re influencing the ecology um we know of course that viruses are important drivers of evolution sure so with these experiments we can study ukar um which are not as complex as multicellular animals for example and we can do experiments in the lab also experimental

Evolution experiments right so we trying to speed up the evolutionary process by putting them under certain conditions bottleneck conditions and then we can see how the viruses react how the hosts react how resistance plays out so we can figure out how Evolution works by looking at these examples directly from

Nature so I think it will teach us a whole lot about the world that we live in and who knows many of these exotic projects have turned out to be real useful in biotechnology just take the crisper cast system right um that was not a targeted search that led to an

Application it was an observation of some repetitive sequences in bacterial genomes which led to this whole Revolution and and medicine and biotech that we have nowadays so I think if we just open our eyes and are aware of what’s around us uh we can make tremendous progress um in different

Fields right so a big proponent of fundamental research as you can see yeah I think you just need to be curious yes and ask questions about what you see and then good things happen absolutely mostly that’s how good things happen rather than by saying we’re going to

Discover a new Gene editing Protocol no no those targeted approaches tend to fail a lot I agree I agree but unfortunately the funding sources think that they’re important and so you know in the US we we target diabetes and cancer and heart disease and so forth

But really okay that’s fine but you need to have some curiosity driven because that’s what gives us crisper cast that may impact all those diseases one day right yeah that’s why I’m also so grateful to the European Union that um they approved this grant that’s great

For anyone out there who loves hiking in electr microscopy a weird combination I know but if there’s anybody I will be looking for people to join my team in the future oh I’m sure there are a lot of people that like being outside that uh would love to participate so this is

On the wall there I don’t think we’ll be able to see it but we have four photographs of the ringberg Symposium on giant virus biology which is in Dean z Germany I went to the first first one and the fourth one and now we’re going to have the fifth one this week starting

Tomorrow right that’s right why why do you do this it’s a lot of work I’ve seen you go crazy here why do you organize this meeting oh it’s not as much work as you might think but we still a fairly small community um so typically around 50 to 60 people who attend these

Meetings but um I started these in 2013 because it became apparent that the community had grown to a certain step where we needed our own meeting to exchange is so previously we went to for example this aquatic virus Workshop right but that was not exclusively about these CH viruses of course there are

Lots of bacteria fages um alal viruses and a lot of diversity which is great in itself but the meeting became too big basically um to interact with just the core Community um so in 2013 I ask around if people would be interested in joining such a meeting and so the

Response wasn’t overwhelming yes so we got together at this um nice venue in the south of Bavaria um a castle owned by the maxlang society um it’s not big but it was big enough certainly for um our International small group and these meetings kept going on they were popular so I

Held them every two years unfortunately I had to cancel the one in 21 due to the pandemic yeah but now we’re back at it and we’re very happy to have them um I tried to bring in people that not only strictly work on giant viruses in the lab but have different expertises that

Sort of feed into the biology of what giant viruses do so that also includes for example structural biologists who work on specific enzymes that could come from a giant virus or it could be chemists who work on the glycosilation patterns on the surface of these giant virus capsules it could also be

Bioinformaticians who have never seen a virus live in in front of them right um so different expertises coming together but all caring about these giant viruses and what they do and I think that has already led to some new collaborations along the way you just said live virus

So are viruses alive te the old question it depends on your definition of life right um I was very interested in that question for many years um then I thought it’s it’s bit too philosophical to be tackled by a scientist like me um but what really changed my view on this

Question was uh the introduction of the virus cell concept M um I think they were mostly Patrick forter who um put this forward but also people like claudo Banda was one of the prominent people to push this forward and what the virus cell concept makes us see is that there’s a

Distinction between a virus and a virus particle uh because that’s typically something that’s very easily confused virus infected cell and a virus particle right so the the viral cell is the virus infected cell viral cell that’s vir cell exactly and that could very well be seen as the living phase of

A virus sure because that’s where all the entic activity comes to play right if you just look in the particle there’s not much going on I’m not saying there’s nothing going on but very little and generally these are just vehicles to deliver the viral genome from one host

Cell to the next right so they need to be a little fortresses against all these adverse environmental conditions but what people typically then say is well this is the typical state of the virus this particle form but no it’s more like a Spore it’s a persistent form that’s

Just made as a helper to get you from one host to the next so what the virus then really does and where it also evolves some people say it’s evolved by the host cell right but still where it replicates its genome where all the genes are transcribed where the

Enzimatic activity plays out is in the host cell and it completely turns the metabolism of that infected host cell upside down and that’s been conserved confirmed on many different levels so if you do transcriptomics if you do metabolomics an infected cell has a very different profile than an uninfected

Cell which basically means that for me it’s legitimate to say that viruses are alive during that intercellular phase right when they are a viral cell and that also feeds nicely into this analogy with the viral fages and the giant viruses because you could very well say that virages are parasites of the viral

Cell viral cell not the virus not the virus particle so that’s very important to stress so they don’t interact outside the host cell yes by penetrating the capset of the giant virus and replicating them that’s not how it happens right it all happens inside the infected cell now it’s important because

Many people say to me oh did you know there’s these viruses that reproduce inside other viruses yeah if you see virus as the conceptual ter firm then I might agree but if you’re referring to the particle then that’s clearly not the case I think when most people say virus

They’re referring to particle by the way let’s grab those two particles here just so we can so this is a virus particle yeah this is just a paper model and this is another paper model but this is about um so if you’re listening and not seeing

The video sorry about that but uh this is about the size relationship between crob the giant virus and the vir h m virus yeah so I mean you could rep of course imagine that it goes inside it might fit inside but it will also displace a lot of the important content

That’s already packaged in the giant virus particle so I would imagine that if a giant virus carries such a virage it would no longer be infectious it might still get inside the host Cel but it would not be able to fulfill its infectious AR and there certainly

Wouldn’t be any Evolution to select for carrying the virage inside the giant firus because it’s detrimental to the giant virus unless of course you have higher multiplicity of infection you get um infection by multiple Chine viruses some of them might carry the virage others won’t so they can they can

Complement right complement it exactly that might happen theas is there anything we didn’t cover I know there’s a lot more in this this whole field of giant viruses and produce but is there anything that we should have covered that we didn’t so I think we’re going to hear a

Lot more about these endogenous DNA viruses in ukic genomes um that really just got started and there’s so much diversity among these poon viruses um that needs to be looked at in more detail there’s going to be a lot of reclassification so I avoided getting into T taxonomy at this point because

It’s prone to change even within the next couple of months right but what we found out in the last years is that endogenous DNA viruses are very very abundant among UK carots MH and it’s quite comparable to situation in bacteria and ARA where you have um a lot

Of these um inserting Pro ages right right right um and also invertebrates where you have a lot of the endogenous retroviruses so it seems there are different types of viruses which tend to endogenize in certain groups of hosts and that just confirms to me how important viruses overall are for

Cellular Evolution right uh I have a paper here large scale invasion of unicellular eukariotic genomes by integrating the ni viruses is April 2023 that’s that’s the paper I mentioned before by Christopher Bellas yes and you’re on that paper as well and this is um pnas uh so this is the establishing

Study that says there are a lot of these integrated viruses in I think this is the most uh recent and most comprehensive one but they have certainly been reports in the direction before yes all right that’s great we’ll put a link to that before before we leave

Matias uh I usually don’t do picks when I interview people but I know you want to have one so I would very much suggest a pick yes and uh that is a webinar series that is going to be uh hosted this winter by the international Society for viruses of microbes or isvm for

Short so membership is free you can sign up and um we are organizing this webinar series with Talks by early career scientists working on exciting projects that involve viruses infecting microorganisms and it’s called iarm fre so if you Google Fage directory I then you will find the page and you will find

I w m i vom IV ivom uh for viruses of microbes and the first seminar is starting um very soon mid December and we’re going to have more in uh January February and March so sign up for it it’s going to be nice content very exciting research by early careers and

Uh we hope to see you there so viruses of microbes next year is in Australia yes the big meeting is in Australia next year the plan is for for me to go and do some podcasts that will be very exciting so and you will go so I’ll see you there

Again all right uh that is uh a special episode of twiv at the max plank Institute for medical research you can find the show notes at micro.sd if you enjoy our work please support us we need to have your financial support to continue these programs you can go to

Micro.sd for medical research here in heidleberg has been Maas Fischer thank you so much Matias it’s been a pleasure thank you I was looking forward to talking to you for many years so happy to be able to do it I’m Vincent ranello you can find me at Society for virology and the American

Society for microbiology for their support of twiv Ronald Janes for the music and Jolene for the timestamps you’ve been listening to this week in virology thanks for joining us we’ll be back next week another Twi is Viral