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Giant viruses, enigmatic microscopic behemoths you should know about

Tania Louis
Tania Louis
PhD in biology and Columnist at Polytechnique Insights
Key takeaways
  • In 2003, researchers thought they were examining a bacterium under a microscope before realising that it was a very large virus, called "mimivirus".
  • Mimivirus is 0.7 µm, three times longer than the known length of viruses at the time, which is 0.2 µm.
  • Many cousins of mimivirus were quickly discovered, as well as pandoravirus, pithovirus and other molliviruses.
  • Metagenomics has made it possible to discover these giant viruses, of which there are thousands.
  • Many questions remain unanswered, especially concerning the genomes of the giant viruses, the content of which bears no resemblance to anything we have ever known.

In 1992, an epi­dem­ic of legionnaire’s dis­ease hit the Eng­lish city of Brad­ford and com­plete­ly changed virol­o­gy for­ev­er, even though this dis­ease is caused by bac­te­ria! Those of the Legionel­la genus, which live in warm water and usu­al­ly mul­ti­ply at the expense of amoe­bas (small organ­isms com­posed of a sin­gle cell, whose func­tion­ing is clos­er to that of our own cells than to that of bacteria).

A French discovery from England

One of the dis­tin­guish­ing fea­tures of Legion­naires’ dis­ease is that it is not trans­mit­ted direct­ly from human to human, but via aerosols from envi­ron­ments con­t­a­m­i­nat­ed by the bac­te­ria. To iden­ti­fy the ori­gin of the Brad­ford epi­dem­ic, micro­bi­ol­o­gist Tim­o­thy Row­both­am took a few sam­ples in search of the famous Legionel­la and the amoe­bae they parasitise.

Legionel­la bac­te­ria mul­ti­ply­ing in a human fibrob­last (cul­tured in vit­ro). Cred­it: CDC/Dr. Edwin P. Ewing, Jr. via Wiki­me­dia Commons.

Look­ing under a light micro­scope at a sam­ple recov­ered from the hos­pi­tal’s cool­ing tow­er, Row­both­am found that it did indeed con­tain amoe­bae, which in turn con­tained what looked like bac­te­ria… but whose shape did not match that of Legionel­la. He named this new microbe “Brad­ford coc­cus” and tried to char­ac­terise it with tools adapt­ed to the study of bac­te­ria for sev­er­al years. But to no avail.

The sam­ple was returned to a freez­er and then, in 1995, the young researcher Richard Bir­tles, leav­ing to do a post-doc­tor­ate in Mar­seille, took some of it with him1. At first, the French researchers did no bet­ter than the Eng­lish: it was impos­si­ble to char­ac­terise the genome of Brad­ford coc­cus… Until some­one had the idea of observ­ing this so-called bac­teri­um with an elec­tron micro­scope, which had suf­fi­cient mag­ni­fi­ca­tion pow­er to realise that it was in fact a virus, of aston­ish­ing size.

A few years lat­er, three research teams from Mar­seille shared their results in a paper enti­tled “A giant amoe­ba virus”2. Tim­o­thy Row­both­am had unknow­ing­ly iso­lat­ed a virus capa­ble of infect­ing amoe­bas and mea­sur­ing about 0.7 µm in diam­e­ter. In hon­our of its ini­tial con­fu­sion with a bac­teri­um, it was named mimivirus, lit­er­al­ly “microbe-mim­ic­k­ing”.

Giant viruses, a major discovery

The descrip­tion of this virus in 2003 was rev­o­lu­tion­ary! It took years to under­stand the true nature of mimivirus­es as nobody at the time thought that such large virus­es could exist. And with good rea­son. At the end of the 19th Cen­tu­ry, the abil­i­ty of virus­es to pass through the pores of fil­ters fine enough to retain bac­te­ria was one of the first char­ac­ter­is­tics that allowed them to be iden­ti­fied as a new type of infec­tious agent. In oth­er words, virus­es had always been defined as being small­er than bac­te­ria, which are on aver­age 1 µm in length, but were con­sid­ered to be up to about 0.2 µm in size. This is three times small­er than the size of mimiviruses.

Mimivirus par­ti­cle observed under the elec­tron micro­scope3.

How­ev­er, this micro­scop­ic colos­sus is not an excep­tion and the dis­cov­er­ies of giant virus­es have fol­lowed one after the oth­er since 2003, notably thanks to the work of the Genom­ic and Struc­tur­al Infor­ma­tion lab­o­ra­to­ry, now direct­ed by Chan­tal Abergel4. Many rel­a­tives of mimivirus­es are now known, grouped togeth­er in the Mimiviri­dae fam­i­ly. As well as pan­do­ravirus­es, pithovirus­es and oth­er mol­livirus­es: as is often the case in biol­o­gy, the more we look for giant virus­es, the more we find them!

Some of these dis­cov­er­ies are real achieve­ments: pithovirus­es5 and mol­livirus­es6 were ini­tial­ly iso­lat­ed from per­mafrost that was about 30 000 years old. This has not pre­vent­ed them, in the expert hands of researchers, from still being able to infect amoe­bas. To show that this is not so unusu­al, the same team recent­ly pub­lished a preprint in which they revived no less than 13 dif­fer­ent amoe­ba virus­es in the same way7.

Family portrait

Although the first giant virus­es were iden­ti­fied by co-cul­tur­ing with hosts sus­cep­ti­ble to infec­tion (main­ly amoe­bae), over the past ten years a new tool has accel­er­at­ed the pace of dis­cov­ery: metage­nomics. This tech­nique, which com­bines mas­sive sequenc­ing and bioin­for­mat­ics analy­ses, has led to an explo­sion in the num­ber of known giant virus­es that now num­ber in the thou­sands8.

They are par­tic­u­lar­ly numer­ous in the ocean, but they are also found in soils and lakes. And it is clear that we are only just begin­ning to under­stand the quan­ti­ty, dis­tri­b­u­tion and diver­si­ty of these virus­es. If one were to sketch a fam­i­ly por­trait, all known giant virus­es have genomes com­posed of dou­ble-strand­ed DNA and most of them form viral fac­to­ries in the cells they infect, which are exact­ly what their name describes. Their size can reach up to 2 µm in length for tupan­virus­es, a mem­ber of the Mimiviri­dae9 and their genomes mea­sure up to 2.5 mil­lion base pairs for pan­do­ravirus­es10.

Left: Amoe­ba infect­ed with pan­do­ravirus and pro­duc­ing viral par­ti­cles (envi­ron­men­tal bac­te­ria are also vis­i­ble in the cul­ture medi­um around the amoe­ba). Scale bar: 10 µm. Right: Pan­do­ravirus par­ti­cles observed under the elec­tron micro­scope, sur­round­ed by amoe­ba pseudopo­dia11. Scale bar: 0.5 µm.

It is not clear which organ­isms are nat­u­ral­ly infect­ed with giant virus­es, espe­cial­ly when they are iden­ti­fied by metage­nomics. Dif­fer­ent approach­es, such as search­ing for genomes that are sys­tem­at­i­cal­ly asso­ci­at­ed with virus­es in sam­ples, sug­gest that giant virus­es can infect a large num­ber of eukary­ot­ic microor­gan­isms, not just amoe­bae12. The list is far from defin­i­tive at present, but the longer it goes on, the more like­ly it is that these virus­es will have sig­nif­i­cant impacts on ecosystems.

Many unresolved questions

Of all the things we have yet to dis­cov­er and under­stand about giant virus­es, it is their genomes that prob­a­bly raise the most ques­tions. Not only are they dis­pro­por­tion­ate­ly long (for virus­es), but their con­tent is aston­ish­ing. First­ly, because a large pro­por­tion of the genes (some­times more than 90%!13) often don’t resem­ble any­thing known to us. It is impos­si­ble to know where they come from or what they are used for. Sec­ond­ly, because some of the genes that we do under­stand have nev­er been observed in virus­es before.

Indeed, giant virus­es have genes involved in cel­lu­lar process­es, such as DNA repli­ca­tion or the expres­sion of genet­ic infor­ma­tion. They are far from being autonomous, but this still rais­es ques­tions about their degree of depen­dence, their ori­gin, and their evo­lu­tion­ary his­to­ry14. In 2008, the iden­ti­fi­ca­tion of virus­es capa­ble of infect­ing giant virus­es that were them­selves infect­ing an amoe­ba added anoth­er piece to this puz­zle15.

Unknown only twen­ty years ago, giant virus­es are reg­u­lar­ly the sub­ject of new dis­cov­er­ies and each one rais­es its own set of ques­tions. With many in the oceans and inter­act­ing with micro-organ­isms that play key roles in oxy­gen pro­duc­tion or atmos­pher­ic CO2 cap­ture, they may not be heard of out­side virol­o­gy jour­nals. But beyond their poten­tial impact, they are fas­ci­nat­ing in that they make us rethink how we define terms like ‘virus’ and ‘liv­ing’.

11From https://www.nature.com/articles/s41467-018–04698‑4

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