WTF EFVs?? More endogenous non-retroviruses

One of the scary things about filoviruses (eg Ebola, Marburg)... is that we dont know where they comes from. We know how polio is transmitted. We know how HIV-1 is transmitted. We know how influenza is transmitted. We know how rabies is transmitted.

Even if you dont have good vaccines or good therapies, if you know where a virus comes from or how it is transmitted, you can take steps to prevent illness.

But filoviruses....?

One hypothesis is that small mammals are the natural reservoir. A way to look for that would be to study the immunology of lots of small mammals-- Do they have intrinsic/innate defenses against these viruses, suggesting a co-evolution over time?

Um, some folks in Buffalo, NY did a bit better than that.

Filoviruses are ancient and integrated into mammalian genomes

We detected integrated filovirus-like elements in the genomes of bats, rodents, shrews, tenrecs and marsupials. Moreover, some filovirus-like elements were transcribed and the detected mammalian elements were homologous to a fragment of the filovirus genome whose expression is known to interfere with the assembly of Ebolavirus. The phylogenetic evidence strongly indicated that the direction of transfer was from virus to mammal. Eutherians other than bats, rodents, and insectivores (i.e., the candidate reservoir taxa for filoviruses) were significantly underrepresented in the taxa with detected integrated filovirus-like elements. The existence of orthologous filovirus-like elements shared among mammalian genera whose divergence dates have been estimated suggests that filoviruses are at least tens of millions of years old.

This should not happen. Filoviruses are not retroviral, and they do not replicate in the nucleus. So:

1) a filovirus has to be in a germ line cell, MISTAKE
2) the virus needs to get its genome into the nucleus, MISTAKE
3) the virus needs to co-opt the reverse transcriptase activity of an endogenous retroviral element, MISTAKE
4) the filovirus cDNA needs to be integrated into the host DNA, MISTAKE
5) the cell where all of these mistakes are made needs to be successfully fertilized, carried to term, grow up, and have offspring

Wow. I guess in an infinite universe, anything can happen, but daaaaamn!

How did they go about finding these improbable miracles?

First, they did a simple tBLASTn search. Take an amino acid sequence you know (in this case, the Marburg NP gene) and look for nucleotides that code for that series of amino acids in any of GeneBanks uploaded sequences. And any hit that has a good 'expect value' means the sequences are the same, and its probably not by chance.

They found sequences in a handful of small mammals and marsupials.

To double-check their digital findings, they designed PCR primers to look for filovirus integration sites in the tammar wallaby, the little brown bat, and the big brown bat. The sequences were what they should be, and where they should be.

They even found that these genes were transcribed into RNA in some tissues! This might be by chance, but also possibly by design-- these transcripts could act as RNA interference against real filovirus infections (which the authors hope will be investigated in the future), as some small mammals (mice and guinea pigs) are resistant to infection.

Now, the question many of you want an answer for-- if this endogenization event is so rare, do the endogenous filovirus sites follow common descent?

Well, not all of the animals compared have appropriately detailed chormosomal maps to make that distinction, except for mice and rats:

A clear indicator of antiquity is the syntenous genomic location of a rat and mouse filovirus-like NIRV (Fig. 7A, B). These are the same copies that have a sister group relationship (Fig. 2). It is unlikely that integration of filovirus NP genes at the same genomic position occurred independently in rats and mice. The rat-mouse orthology provides a minimum date of NIRV formation at 12 to 24 MY[31, 32].

NIRV = non-retroviral integrated RNA viruses, heh.

But yes, NIRVs support common descent, just like ERVs. YAY!

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It seems to me that integrated viral elements are essentially a special type of lateral gene transfer. When looked in in that regard it isn't as surprising that they are there somewhere in mammalian genomes, especially if they are (or once were) ubiquitous. Obviously the probability is low, but given the massive number of opportunities, almost bound to happen. Retroviruses just have an easier time of it since they have their own mechanism. But we are discovering more and more mechanisms all the time for how foreign DNA can become integrated.

"Little brown bat" "big brown bat", seriously? Who named these species? Boorrrring! Come on, if you're going to name a species, pick something a bit more creative. Put your name in it! Sheesh.

OTOH, those filovriuses, awesome!

By JustaTech (not verified) on 08 Jul 2010 #permalink

JustaTech

I think little brown bat's Latin name can literally translate as "tiny monk that flees from the light".

If I remember correctly.

Which I probably don't.

By Prometheus (not verified) on 08 Jul 2010 #permalink

First ERVs, then BDVs, and now NIRVs...

A-fucking-mazing...

By Kemanorel (not verified) on 08 Jul 2010 #permalink

My virology-fu is very weak, so please don't laugh at the white-belt, but I wonder. If an animal were co-infected with both a retrovirus and a filovirus, could the filovirus get packaged into a retroviral particle, along with RT? I seem to recall that retroviruses do things like that occasionally. Maybe that could help explain at least some of the steps needed to get germ-line integration of NIRVs?

In any case, fascinating stuff! Thanks for posting on it, erv.

@qetzal
I think if as the retroviral genome were replicated and it accidentally jumped templates onto a filovirus genome, it could pull part of the filovirus genome into a retroviral particle. It's happened with other viruses if I recall. That said, I don't think a filovirus genome can automatically be packaged into retroviral particles without a packaging signal (Psi) found within the retroviral genome.

Also, regarding "3) the virus needs to co-opt the reverse transcriptase activity of an endogenous retroviral element, MISTAKE," I think retrotransposons such as LINE-1 in mammals have retrotranscriptase activity, so integration doesn't necessarily have to go through an endogenous retrovirus.

ERV,

The endogenized filovirus does not have to integrate directly into a mature germ cell. It may be more likely that it inserts into the DNA of a germ line progenitor cell, this cell could then crank out numerous gametes with the insertion and increasing the chances of inheritance.

It also is not totally shocking that RNA viruses sometimes get inserted by LINE and related elements. During viral infection I would imagine that there would be tons of vRNA in the cell and it could rarely displace LINE RNA by mass action.

Sweet! I was reading the recent Science issue on Malaria and TB, and was wondering if anyone has bothered to do viral DNA searches within the genomes of diseases like these? Perhaps a search for ERVs in disease organisms could lead to finding a live modern virus that could be used for treatment. I would think such a strategy could work for many of the parasite diseases. After all, if there's a virus for a *virus*, come on, there's got to be one for malaria!

By Rich Hendricks (not verified) on 08 Jul 2010 #permalink

@Rich

Bacterial viruses are called bacteriophage and are very common. Most (all?) phage insert into the bacterial chromosome(s), typically at very defined locations and can either reside there with no harm to the host (lysogenic cycle) or respond to some trigger and replicate to the extent that the host dies (lytic cycle).

I don't know why phage therapy isn't studied more, every time I'm at a conference and someone talks about their work in the field it's like "omg best thing ever no resistance after a bazillion generations of exposure, specific for the very strain we're targeting, etc etc"

http://www.ncbi.nlm.nih.gov/pubmed/20528690
http://www.ncbi.nlm.nih.gov/pubmed/18653319

They found sequences in a handful of small mammals and marsupials

Sweet! That means my pet probably has these cool fragments of DNA from millions of years ago. She just got even more awesome than she already is!

By Kemanorel (not verified) on 09 Jul 2010 #permalink

@ kevinS & ERV

Couldn't an embryo pick up the virus in utero? Seems like it would have a better chance at hitting germ line progenitor cells when there are only a couple hundred to choose from.

Also, is there anyway that the filoviruses could have been retroviral in the past, but lost that ability?

By theshortearedowl (not verified) on 09 Jul 2010 #permalink

@JohnV (#10),

Lots of bacteriophage do not integrate into the bacterial chromosome. In fact, those are the ones that are more relevant for phage therapy, since they often have only a lytic cycle.

However, bacterial can certainly become resistant to phages. Phages usually enter bacteria the same way HIV enters human cells - by first binding to a specific cell surface protein. If that protein can mutate to be unrecognized by the phage, the host can become resistant. It's been shown countless times in the lab.

I can think of various reasons that might explain why phage therapy hasn't ever caught on, but I don't know the actual reasons.

I'm really dumb and now that you mention it I think I've had this same conversation here about some phage only having a lytic cycle and not both. And that those are much more useful because of that.

And yes depending on the receptor resistance can be pretty easy to develop, but when people are giving talks about their system of interest (I specifically recall a Staph phage talk) some receptors are in the "not gonna mutate" category. I wish I could remember the example, because it was neat, but it was some cell wall synthesis protein and over 100 generations of exposure they never got resistance. Of course once you get confident with something like that I'm sure the first time you try it clinically resistance springs :p

Wish I were from Africa, so I could say I had a big brown bat.

By unfunny but (not verified) on 30 Jul 2010 #permalink