Inside the secret defense systems of giant viruses

The strangest life forms on Earth just got a lot stranger.

In 2003, Didier Raoult of Aix-Marseille University in France and his colleagues discovered a new kind of virus lurking inside single-celled protozoans. Like other viruses, it couldn’t grow on its own, lacking the biochemical machinery to build proteins and genes. Instead, it had to infect host cells and use their material to produce new viruses.

But this new virus was enormous, measuring hundreds of times bigger than any previously known virus. What’s more, it was far more complex. Typical viruses may have just a few genes. The new virus had over 900 — more than many species of bacteria.

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Since then, Raoult and his colleagues have found over 150 different kinds of giant viruses all over the world, in oceans, mountains, and the bodies of animals (including our own). One kind of giant virus contains over 2,500 genes.

Exactly what giant viruses do with all those genes has remained mostly a mystery. But on Monday, Raoult and his colleagues reported in Nature that some of those genes provide giant viruses with something never observed before in a virus: They have an immune system, one that works a lot like the CRISPR system in bacteria that scientists have co-opted as a powerful gene editing tool.

Jennifer Doudna, a University of California biologist and one of the leaders in co-opting CRISPR — short for clustered regularly interspaced short palindromic repeats — cautioned that the new study doesn’t lay out exactly how this viral immunity works. “But the potential for such a system to be harnessed for genetic control is intriguing,” she said.

Raoult and his colleagues first discovered that giant viruses get infected with viruses of their own back in 2008. These so-called virophages slip inside the giant viruses and hack their biochemistry, much as the giant viruses do to their own protozoan hosts.

One of these virophages, called Zamilon, infects a type of giant virus known as a mimivirus. But when Raoult and his colleagues unleashed Zamilon on closely related strains of mimiviruses, they were surprised to find that it couldn’t infect them. It appeared as if the giant viruses could defend themselves against their enemies.

Over billions of years, cellular life forms have evolved many different kinds of defenses against viruses. Vertebrates like ourselves, for example, make antibodies that guide immune cells to particular pathogens. Bacteria have other immune defenses, the most famous of which is CRISPR.

Scientists are currently using CRISPR to edit genes with exquisite precision. But they didn’t invent CRISPR on their own. Instead, they discovered it in bacteria, which use it to destroy viruses.

CRISPR works a bit like our antibodies, allowing bacteria to learn to quickly recognize invaders. When a virus infects bacteria, the bacteria capture bits of its genetic material and lodge it in their own DNA. Later, they can consult this library of captured DNA to recognize invading viruses. That recognition lets them guide enzymes to the viruses and destroy their DNA while sparing their own.

Raoult and his colleagues wondered if giant viruses were using a CRISPR-like defense system against Zamilon. To their surprise, they found that resistant giant viruses carried small pieces of the virophage’s DNA in their own genomes. When they searched the DNA that surrounded the Zamilon sequences, they found a gene that unwinds DNA, and another that slices it.

The scientists hypothesized that giant viruses used these two genes to chop up Zamilon DNA. To test that idea, they silenced each of the genes. Now, the giant viruses became vulnerable, and Zamilon was able to infect them.

Raoult and his colleagues have dubbed this stretch of giant virus DNA MIMIVIRE, short for “mimivirus virophage-resistance element.” They propose that it serves as an immune system, although they have yet to determine how the giant virus recognizes virophages and directs enzymes to attack it.

“What we know is that it’s critical,” said Raoult. “If you silence the genes, it doesn’t work anymore.”

Raoult said that like CRISPR, MIMIVIRE might be worth investigating as another potential gene editing tool: “It is different, so it may have different applications.”

Even if that search bears no fruit, Raoult thinks that MIMIVIRE is important for what it says about the evolution of giant viruses.

“It’s a witness of a very old life,” he said.

Scientists are currently locked in a debate over the evolutionary history of giant viruses. Some have suggested giant viruses recently evolved from cellular life into simplified parasites, for example.

Raoult and his colleagues argue instead that giant viruses are ancient. They branched off not long after the origin of life, before cellular life as we know it today even existed.

Over billions of years, giant viruses evolved into something unique: an organism that is like a virus in some ways, but like cellular life in others — including, it now appears, having its own immune system.

“It’s a different part of the world,” said Raoult.

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