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π Health and biotech

The placenta: a legacy inherited from ancient viruses 

Tania Louis
Tania Louis
PhD in biology and Columnist at Polytechnique Insights
Key takeaways
  • In the human genome, there are about 500,000 of these retroviral genomes, which represent about 8% of its total length – much more than the length of our own genes which are only 1-2%.
  • These molecular companions are not new: the most recent one is about 150,000 years old, and they can be considered as viral fossils.
  • In 2000, during a survey of the proteins expressed by various human tissues, researchers identified a viral protein produced in a single organ: the placenta.
  • This viral envelope protein is specifically expressed in a tissue of the placenta called syncytiotrophoblast, which allows exchanges between the mother's blood and that of the foetus.
  • Observations of this type are multiplying, and it is becoming necessary to rethink our vision of viruses: they are not only vectors of disease, but also of genetic innovations.

Since their dis­cov­ery at the end of the 19th Cen­tu­ry, virus­es have been asso­ci­at­ed with the notion of dis­ease. And with good rea­son: it was in the search to under­stand the ori­gin of some of them that these new kinds of infec­tious agents were iden­ti­fied. How­ev­er, as explained in a pre­vi­ous col­umn, virus­es can become our allies in the fight against bac­te­r­i­al infec­tions. But this is only a recent twist: long before any human mind had the idea of using these micro­scop­ic enti­ties to our advan­tage, the vagaries of evo­lu­tion had already unit­ed us in a par­tic­u­lar­ly inti­mate way.

Viruses in our genome 

While only 1–2% of the human genome con­sists of pro­tein-cod­ing sequences, between half and two thirds are made up of dif­fer­ent types of mul­ti­ple-repeat­ed sequences, the func­tions of which are dif­fi­cult to deter­mine. And virus­es have a lot to do with this.

Those belong­ing to the retro­virus fam­i­ly, the best-known mem­ber of which is HIV, which caus­es AIDS, have a very spe­cial abil­i­ty: they can inte­grate their own genome into that of the cells they infect. This inser­tion some­times takes place in a germ cell that even­tu­al­ly pro­duces gametes (sper­ma­to­zoa or oocytes in humans, for exam­ple). In this case, the squat­ting viral genome is passed on to the next gen­er­a­tion and is found in all the cells of these new indi­vid­u­als, who will in turn pass it on to their off­spring. Thus, over time and through infec­tion, retro­virus genomes have become well-estab­lished in the DNA of oth­er species – includ­ing our own.

Schemat­ic of a retro­vi­ral par­ti­cle (Lentivirus type, such as HIV) with the genome with­in a nucle­o­cap­sid. The enve­lope pro­teins (gp120 and 41) are shown in yel­low. Over­all diam­e­ter: 80 to 100 nm. Source: Viral­Zone, SIB (Swiss Insti­tute of Bioinformatics).

In the human genome, there are about 500,000 of these retro­vi­ral genomes, which rep­re­sent about 8% of its total length… That’s much more than the length of our own genes (the 1–2% men­tioned above)! And these mol­e­c­u­lar com­pan­ions are not new: the most recent one is about 150,000 years old. So, they have had time to accu­mu­late many ran­dom muta­tions and most of these viral genes are no longer expressed today. They can be con­sid­ered as viral fos­sils, which are in fact among the objects of study of a dis­ci­pline called palaeovi­rol­o­gy1.

But as always in biol­o­gy, there are excep­tions. Some viral reg­u­la­to­ry sequences still mod­u­late the expres­sion of our own genes, and some viral genes are still expressed in our cells. Is this a rea­son to pan­ic? Not real­ly. On the con­trary. Because we owe our birth to them. Literally.

The viral origin of placenta 

In 2000, dur­ing a sur­vey of the pro­teins expressed by var­i­ous human tis­sues, researchers iden­ti­fied a viral pro­tein pro­duced in a sin­gle organ: the pla­cen­ta2. It is a retro­virus enve­lope pro­tein, usu­al­ly found on the sur­face of viral par­ti­cles, which has two par­tic­u­lar­i­ties. On the one hand, when exposed to host defences dur­ing infec­tions, enve­lope pro­teins are able to decrease the effi­cien­cy of the immune response. On the oth­er hand, it is these pro­teins that, like mol­e­c­u­lar keys look­ing for their locks, inter­act with recep­tors on the sur­face of cells and cause the virus enve­lope to fuse with the cell membrane.

This viral enve­lope pro­tein is specif­i­cal­ly expressed in a tis­sue of the pla­cen­ta called syn­cy­tiotro­phoblast, which allows exchanges between the moth­er’s blood and that of the foe­tus. This tis­sue, which is essen­tial for the prop­er devel­op­ment of the preg­nan­cy, is formed by the fusion of sev­er­al cells and has immuno­sup­pres­sive activ­i­ty. This leads us to believe that the for­ma­tion of the essen­tial syn­cy­tiotro­phoblast is due to the action of a viral enve­lope protein…

Dia­gram of the inter­nal organ­i­sa­tion of the human pla­cen­ta. The blood ves­sels of the foe­tus arrive through the umbil­i­cal cord (bot­tom of the pic­ture) and come into con­tact with the mater­nal blood via tree-like struc­tures called chori­on­ic vil­li. The thin mem­brane that sep­a­rates the chori­on­ic vil­li from the area filled with mater­nal blood (trans­port­ed by the ves­sels shown at the top of the image) is a tis­sue formed by the fusion of sev­er­al cells: the syncytiotrophoblast.

The viral envelopes specif­i­cal­ly expressed in the pla­cen­ta and capa­ble of induc­ing the fusion of sev­er­al cells (to form tis­sues called syn­cy­tia) take their name from this last prop­er­ty and are now called syn­cytins. In the plur­al, because the dis­cov­er­ies have been made one after the oth­er since 2000.

And in other mammals…

Two human syn­cytins3 are now known, also present in oth­er Pri­mates4, and genes of the same type have been dis­cov­ered in many Mam­mals: Rodents5, Lep­ori­dae6, Car­ni­vores7, Rumi­nants8… And even Mar­su­pi­als9, which have lim­it­ed devel­op­ment in utero. And this list is nei­ther exhaus­tive nor detailed. In fact, syn­cytins have been found every time we have looked for them in a vivip­a­rous species (whose embryos devel­op inside the moth­er’s body, as opposed to oviparous species, which lay eggs). This under­lines the impor­tance of these viral genes in pla­cen­ta for­ma­tion! In mice, their indis­pens­able nature has even been direct­ly demon­strat­ed10.

The diver­si­ty of syn­cytins cur­rent­ly observed in mam­mals, which are descend­ed from the same com­mon ances­tor, is prob­a­bly explained by the pro­gres­sive acqui­si­tion of new endoge­nous retro­virus­es in each of the dif­fer­ent lin­eages. In a sort of evo­lu­tion­ary relay, the ances­tral syn­cytin would have giv­en way to a whole series of dif­fer­ent syn­cytins11. Sev­er­al stud­ies have already iden­ti­fied ancient syn­cytins in some organ­isms and the link between syn­cytin diver­si­ty and vari­a­tions in pla­cen­ta mor­phol­o­gy is an open research question.

This close link between vivipar­i­ty and domes­ti­ca­tion of a viral pro­tein could be due to one of the main dif­fi­cul­ties of non-egg repro­duc­tion: the moth­er’s organ­ism has to tol­er­ate that of the foe­tus dur­ing the whole ges­ta­tion peri­od. If there is no spe­cif­ic adap­ta­tion, its pres­ence should trig­ger rejec­tion, as in the case of a trans­plant. Var­i­ous mech­a­nisms now com­bine to allow this feto-mater­nal tol­er­ance but, at the time of the appear­ance of vivipar­i­ty, it is pos­si­ble that viral pro­teins of the syn­cytin type were indis­pens­able because of their immuno­sup­pres­sive capacities.

Mabuya lizard (species domini­cana), repro­duc­ing vivip­a­rous­ly and hav­ing a pla­cen­ta in which a viral syn­cytin is expressed. Pho­to by Mark Stevens, via Wiki­me­dia Commons.

In the absence of being able to go back in time to demon­strate this, we can look at the few vivip­a­rous ani­mals that do not belong to the mam­malian group12. French researchers study­ing syn­cytins have iden­ti­fied one of them… in a South Amer­i­can vivip­a­rous lizard13! The role of these viral pro­teins in vivip­a­rous repro­duc­tion is there­fore not lim­it­ed to Mam­mals, and it remains to be seen whether their pres­ence is real­ly sys­tem­at­ic in ani­mals with a placenta.

The link between syn­cytins and vivip­a­rous repro­duc­tion is par­tic­u­lar­ly well stud­ied, but it is not the only exam­ple of func­tion depen­dent on the domes­ti­ca­tion of a viral gene. Beyond the syn­cy­tiotro­phoblast, ini­tial results indi­cate that syn­cytins may play a role in the for­ma­tion of oth­er tis­sues that require the fusion of sev­er­al cells, name­ly cer­tain mus­cles14, cer­tain struc­tures respon­si­ble for the regres­sion of bone tis­sue and cer­tain giant cells involved in the reg­u­la­tion of inflam­ma­tion15.

Anoth­er retro­virus pro­tein is expressed in our brains, where it is notably involved in mem­o­ry1617. Par­a­sitoid wasps have domes­ti­cat­ed whole virus­es, which they inject into the arthro­pods they par­a­sitise at the same time as their eggs, to pro­mote their immune tol­er­ance18. Con­verse­ly, var­i­ous retro­virus genes pro­tect the organ­isms that car­ry them from infec­tion by oth­er virus­es19.

Obser­va­tions of this type are mul­ti­ply­ing, and it is becom­ing nec­es­sary to rethink our vision of virus­es. In con­stant inter­ac­tion with oth­er bio­log­i­cal enti­ties, they are not only vec­tors of dis­ease, but also of genet­ic inno­va­tions that have turned the evo­lu­tion of life upside down20.

1https://​www​.ncbi​.nlm​.nih​.gov/​p​m​c​/​a​r​t​i​c​l​e​s​/​P​M​C​3​2​2​8813/
2https://​pubmed​.ncbi​.nlm​.nih​.gov/​1​0​6​9​3809/
3https://​pubmed​.ncbi​.nlm​.nih​.gov/​1​4​5​5​7543/
4https://​www​.ncbi​.nlm​.nih​.gov/​p​m​c​/​a​r​t​i​c​l​e​s​/​P​M​C​3​6​1​0889/
5https://​pubmed​.ncbi​.nlm​.nih​.gov/​1​5​6​4​4441/
6https://​pubmed​.ncbi​.nlm​.nih​.gov/​1​9​9​4​3933/
7https://​pubmed​.ncbi​.nlm​.nih​.gov/​2​2​3​0​8384/
8https://​pubmed​.ncbi​.nlm​.nih​.gov/​2​3​4​0​1540/
9https://​www​.ncbi​.nlm​.nih​.gov/​p​m​c​/​a​r​t​i​c​l​e​s​/​P​M​C​4​3​2​1253/
10https://​www​.ncbi​.nlm​.nih​.gov/​p​m​c​/​a​r​t​i​c​l​e​s​/​P​M​C​3​2​1​9115/
11https://​www​.ncbi​.nlm​.nih​.gov/​p​m​c​/​a​r​t​i​c​l​e​s​/​P​M​C​3​7​5​8191/
12https://​www​.ncbi​.nlm​.nih​.gov/​p​m​c​/​a​r​t​i​c​l​e​s​/​P​M​C​5​0​3​3709/
13https://​www​.ncbi​.nlm​.nih​.gov/​p​m​c​/​a​r​t​i​c​l​e​s​/​P​M​C​5​7​5​4801/
14https://​www​.ncbi​.nlm​.nih​.gov/​p​m​c​/​a​r​t​i​c​l​e​s​/​P​M​C​5​0​1​0199/
15https://​www​.ncbi​.nlm​.nih​.gov/​p​m​c​/​a​r​t​i​c​l​e​s​/​P​M​C​6​6​3​7224/
16https://​www​.nature​.com/​a​r​t​i​c​l​e​s​/​n​r​n​.​2​0​1​8​.​9​.epdf
17https://​lejour​nal​.cnrs​.fr/​n​o​s​-​b​l​o​g​s​/​a​u​x​-​f​r​o​n​t​i​e​r​e​s​-​d​u​-​c​e​r​v​e​a​u​/​q​u​a​n​d​-​l​e​s​-​n​e​u​r​o​n​e​s​-​s​i​n​s​p​i​r​e​n​t​-​d​e​s​-​v​i​r​u​s​-​p​o​u​r​-​c​o​m​m​u​n​iquer
18https://​pubmed​.ncbi​.nlm​.nih​.gov/​2​8​7​2​8099/
19https://​pubmed​.ncbi​.nlm​.nih​.gov/​2​2​9​0​1901/
20https://​www​.sci​encedi​rect​.com/​s​c​i​e​n​c​e​/​a​r​t​i​c​l​e​/​a​b​s​/​p​i​i​/​S​1​8​7​9​6​2​5​7​1​8​3​00634