This Viral DNA Infects Cells by Changing From a Solid to a Liquid

Illustration for article titled This Viral DNA Infects Cells by Changing From a Solid to a Liquid

Two new studies are showing that viral infections are possible owing to a remarkable biological phase transition. The research shows that viral DNA transforms from a glassy solid to a fluid-like state when the conditions for infection are just right. The new insight could result in new antiviral therapies.

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Above: A fluorescence image of viral DNA complexes in the cytoplasm of a cell. Cells use different mechanisms, including special proteins, to prevent infection. But as the new studies point out, these defensive measures often fail owing to special features of viral DNA. (Credit: A. Rottach / LMU)

The DNA that's tightly packed inside a virus's protein shell is denser than what's found in the nucleus of a human cell. Because of this tight packing, the genetic chain can barely budge. But as we know, infections most certainly do happen. Viruses somehow inject their DNA into the host cell at high speed. But how? How can the frozen and highly pressurized DNA suddenly become liquid enough for this to happen? Well, it's because the DNA does become liquid enough for this to happen.

Illustration for article titled This Viral DNA Infects Cells by Changing From a Solid to a Liquid

Two new studies, one in PNAS and the other in Nature Chemical Biology, have worked out the mechanics behind this process. Carnegie Mellon University's Alex Evilevitch has shown that certain viruses undergo a phase transition at the temperature of infection, allowing the DNA to morph from a stiff, rigid crystalline structure into a fluid-like mass that facilitates infection. (In the image at left, you can see how HSV-1 DNA undergoes a solid-to-fluid transition within the capsid. (credit: Evilevitch et al))

"The exciting part of this is that the physical properties of packaged DNA play a very important role in the spread of a viral infection, and those properties are universal," noted Evilevitch in a Carnegie Mellon statement. "This could lead to a therapy that isn't linked to the virus' gene sequence or protein structure, which would make developing resistance to the therapy highly unlikely."

Indeed, the new insight could provide a promising new target for antiviral therapies.

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Writing in Chemistry World, Michael Gross explains how viral DNA is capable of this trick:

For the bacteriophage lambda, which infects Escherichia coli bacteria in the human gut, the researchers studied the compressibility of the DNA using atomic force microscopy, and the energy released upon injection as a function of temperature. They found that the tightly-packed DNA melts and becomes sufficiently mobile for injection as the temperature approaches human body temperature, around 37°C.

'The evidence for a structural transition is very striking,' comments Smith, who led the earlier work on viral DNA packaging. 'The effect on ejection is not strict because lambda phage viruses do infect bacteria grown in a Petri dish at lower temperatures. Temperature also has complex effects on the metabolism of the host cells from which viruses draw their resources. However, the present studies reveal a clear and interesting effect of temperature on the physical properties of densely packed DNA.'

In a separate study on Herpes simplex virus type 1, which can reside in human cells for long periods and injects its DNA into the nucleus when it awakens, the Evilevitch group found that the ionic conditions in the cytoplasm of the host cell, as well as temperature, are key factors that determine when the DNA is liquefied in preparation for injection.

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Fascinatingly, DNA maintains its solid-like state when the conditions are not ideal for infection, thus stabilizing the virus particle and ensuring that its DNA isn't ejected at the wrong time. It's here where therapists are going to look when devising their antiviral therapies.

Read the studies at PNAS: "Solid-to-fluid–like DNA transition in viruses facilitates infection" and Nature Chemical Biology, "Solid-to-fluid DNA transition inside HSV-1 capsid close to the temperature of infection." Supplementary information via Carnegie Mellon University and Chemistry World.

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DISCUSSION

sanguine1
sanguine1

So, I think it's a very interesting result. One thing that I'm a little concerned about is that, by-in-large, most bacteriophage infections in the world are happening at something below that temperature. You posted an article just a few days ago that the oceans have some stratospheric number of bacteriophage infections taking place constantly and the ocean is mostly cooler than human body temperature. One might argue that chromosomes of viruses are perhaps tweaked to have the right base content to allow for similar phase transitions at lower temperatures, but I would be a little skeptical of that: in general, DNA duplex melting characteristics for longer sequences occur at temperatures of 40 degrees or higher. Intriguingly, 30 to 40 degrees is a temperature range where densely packed DNA readily undergoes phase transitions between various liquid crystalline phases, but again, below about 30, the phases are pretty well fixed unless the sequence is very very short... say a few bases or so. This effect may be specific to gut dwelling E. coli phages where the temperature is consistently high, but I'd be a little skeptical for the case of ocean dwelling phages where temperatures of infection are consistently lower than that.