Mystery of the Giant Virus’ ‘Stargate’ Solved

Scientists elucidate the conditions under which huge virus’ starfish-shaped seal attaches to a hapless host cell and opens up to inject its viral DNA

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Tupanvirus, a kind of giant virus.
Tupanvirus, a kind of giant virus.Credit: Jônatas Abrahão
Ruth Schuster
Ruth Schuster
Ruth Schuster
Ruth Schuster

The discovery of giant viruses so enormous that they were initially mistaken for bacteria shocked the microbiological community. Known for less than 20 years, much about these mega-viroids and their life cycle remains enigmatic. Now a team at the University of Michigan has discovered the mechanism by which certain giant viruses infect their hosts – usually other microorganisms – through a “stargate” on the virus’ surface.

The mechanism of the stargate, an exotic name for a starfish-shaped seal, and other new discoveries about giant viruses were published in Cell this week by Jason Schrad of the University of Texas Southwestern Medical Center, Kristin Parent of Michigan State University, and colleagues.

The stargate doesn’t exist in all giant viruses, Parent clarified to Haaretz, but it does appear in a lot of them. The mechanism seems to be unique to them, and hasn’t been found in other, “normal-sized” viruses to date. And now the team has figured out how it works.

The rise of the girus

Giant viruses, which some call “giruses,” were discovered in 2003  by a team that included the controversial scientist Didier Raoult,  who most recently made headlines for claiming that hydroxycholoroquine cures the coronavirus. The story began with a pneumonia outbreak in Bradford, England, in 1992, which led to the detection of amoebae in the town’s water tower. Yes, amoebas can cause pneumonia. Then the scientists noticed that the water tower’s amoebas themselves had an infection, by what they at first thought were bacteria.

Mimivirus, the first giant virus ever found, in 2003, inside an amoeba living in a water tower in Bradford.Credit: Ghigo, E., Kartenbeck, J., Lien, P.

The infecting agent inside the amoebas could be seen through a light microscope. At the time the thinking was that no virus was big enough to be seen through a simple microscope.

But bacteria they were not, subsequent research proved ten years after the pneumonia outbreak. The organisms infecting the amoebas were vast viruses with gigantic genomes that coded for hundreds of proteins, more than triple the maximal protein encoding capacity known in viruses until then. Around 70 percent of all other viruses code for 10 proteins at most – just the ones necessary for hijacking a host cell, which is subsequently subjugated to the production of viral progeny. The researchers wound up dubbing that giant virus “Acanthamoeba polyphaga mimivirus” because (in their eyes) it mimicked bacteria.

Subsequent study elucidated that aside from dimensions, mimivirus was a typical virus. It was icosahedral in shape (a 20-face polygon). Viruses typically have some sort of geometric form and many (though not all) giant viruses are icosahedral. But the mimivirus was ten times the size of “normal” viruses, at 400 nanometers in diameter and with a massive genome consisting of double-stranded DNA. Its humongous genome packs in the information for around 800 proteins, more than some bacteria and even some parasitic eukaryotes.

Although “giant virus” remains a relative rather than a clearly defined term, by now over a hundred species of them (arbitrarily defined as being more than 300 nanometers in diameter) have been reported in all sorts of ecosystems, including markedly inhospitable ones. To this day, scientists tend to misidentify newly discovered ones because they don’t fit our preconceptions of how small viruses are.

For comparison, the rhinovirus – the agent responsible for the common cold – is roughly 30 nanometers in diameter.

Make no mistake, these different giant viruses are not necessarily related to one another any more than octopi and mice are; they have different shapes and modes of replication, and very few genes are shared by the entire giant superfamily. Research into this is still young, but the commonly shared genes known so far include polymerases that control viral replication and genes that encode for the major capsid protein, Parent tells Haaretz.

Virus factories in amoeba co-infected with Zamilon virophage and the Mimiviridae, Credit: Morgan Gaia, Samia Benamar

Who do these giant viruses afflict? Mainly unicellular life forms such as amoebae and minute eukaryotic parasites. Whether or not they actually infect any vertebrates is still under study, but evidently the giant viruses reach people too, even if not by direct infection: antibodies to them were found in the blood of the pneumonia patients infected by the girus-bearing amoebas.

It’s alive!

It has also become abundantly clear that giruses are very hardy.

How hardy? A giant virus thawed from Siberian permafrost after 30,000 years was still infectious, Prof. Jean-Michel Claverie of the French National Research Center in Marseille reported in PNAS in 2014.  Asked how the virus could retain infectiousness after 30 millennia while the coronavirus becomes non-infectious after hours to days outside the host, Claverie explained to Haaretz that the giant viruses they investigated, which they called pithovirus, have relatively tough outer walls; but mainly it is because the cold, dry and hypoxic conditions in the permafrost helped preserve the little beasties.

And atop one face of that tough outer giant viral shell is the stargate: a unique mechanism for releasing the viral genome into the host cell.

It isn’t yet known whether the stargate contains the protein that physically docks onto a receptor on the host cell’s membrane, or whether it opens following docking by another protein, Parent tells Haaretz. The day is young on giral research.

What we can say is that the starfish-shaped seal sits atop one of the icosahedral faces and during infection, the stargate yawns open and releases the viral genome into the host cytoplasm. When not triggered by locking, the viral capsid remains closed off, protecting its precious DNA inside.

A breakthrough revealed in the new paper is the environmental conditions that successfully induced stargate-opening in the lab: low pH (highly acid), high temperature and high salt concentration.

“The low pH is reflective of the inside of the amoeba phagosome, which can be very acidic,” Parent says. “The other two conditions are artificial laboratory conditions that mimic biology. Likely a protein receptor in the host is needed to trigger opening. But we don’t know what that receptor is yet. So salt and high temperature ‘trick’ the virus into opening.

“We discovered that the starfish seal above the stargate portal slowly unzips while remaining attached to the capsid rather than simply releasing all at once,” Parent adds. “Our description of a new giant virus genome release strategy signifies another paradigm shift in our understanding of virology.”

She adds that the typical target for the giant virus, an ameba, exists in nature in moderate temperatures: between 25 and 30 degrees Celsius.

However, as demonstrated in Siberia – if the giant virus finds itself in an extreme environment, it doesn’t “die.” It remains dormant.

Outside a host, viruses are biologically inert, with zero metabolism. They don’t breathe or do anything else. Thus, a giant virus released by its host into an inclement environment – for instance, too cold – may continue to exist in that dormant state, protected by its rugged outer coating, until clement conditions resume.

In the case of the study of the 30,000-year-old pithovirus, once the permafrost thawed, it was ready to rock. Happily, that doesn’t seem to apply to the coronavirus: it isn’t a giant virus with a tough outer shell, it's a "normal" virus with a fatty, vulnerable outer casing.