Viruses change structure at the temperature of the human body to better infect us.

09 Jan 2024 Isabelle Dumé

Infection: Illustration of a phage virus injecting its DNA into a cell. (Courtesy: Alex Evilevitch and Ting Liu)

A series of neutron scattering measurements has uncovered the structure of viral DNA in unprecedented detail, shedding new light on changes that make the DNA more fluid-like at temperatures close to that of the human body. According to the researchers at Lund University, Sweden, who performed the measurements, these structural changes help explain the rapidity with which viruses release DNA into host cells, so facilitating infection.

Unlike bacteria or fungi, viruses cannot survive without a host. Once they infect a cell, though, they produce new virus particles that then infect other cells. To protect the virus’ genetic information in the interim, the viral DNA is usually enclosed within a protein shell known as a capsid.

In the latest work, team leader Alex Evilevitch and colleagues focused on phage viruses – that is, those that attack bacteria. Using neutrons from the synchrotron research facility at the US National Institute of Standards and Technology (NIST) in Gaithersburg, Maryland, they imaged the structure of the virus DNA and its density inside the capsid as a function of temperature.

“The technique we employed is called small-angle neutron scattering (SANS), which is not typically used for microbiology research,” says Evilevitch. “By exposing the phage bacterial viruses to the neutron beam, we could reveal the structural details of virally packaged DNA with atomic resolution.”

Central role for delivery kinetics

The researchers undertook this work to follow up their earlier discovery that the structure of DNA material inside the capsid undergoes a sudden structural change when exposed to a temperature of 37 °C. This is the normal temperature of the human body, and it implies that structure plays a central role the way the virus delivers its genetic material into a cell – the first step in an infection. Notably, the DNA within viruses is packaged at a very high density, and it is hundreds of times longer than the diameter of the capsid. Even so, during infection, the DNA is rapidly ejected from the capsid through a single pore.

How this happens is a puzzle, Evilevitch says. “Because of the high packaging density of DNA in the capsid and the just-few-angstroms separation between the neighbouring negatively charged DNA surfaces, there is a strong electrostatic friction hindering DNA ejection,” he explains. “We therefore decided to investigate how temperature affects the structure of the viral genome, since it is known that at optimum body temperature (37°C) viruses can rapidly eject their fluid-like DNA.”

The researchers decided to use an atypical approach for neutron imaging because SANS allows for contrast matching, which makes protein capsids effectively invisible to the neutron beam. This enabled them to focus instead on the capsid’s contents, and therefore unearth the details of the DNA’s shape and density.

Two phases

“We demonstrated, for the first time, that DNA inside a virus capsid coexists in two phases – a hexagonally ordered high-density phase in the periphery of the capsid and a low-density less-ordered, fluid-like phase in the core of the capsid,” Evilevitch tells Physics World. “Increases in temperature trigger a transition in DNA where a portion of the ordered DNA in the periphery moves to the less ordered phase in the centre, which allows the DNA ejection from the virus into a cell to begin.”

According to Evilevitch, these findings show that temperature plays a significant role in the infection process and that neutron scattering is a useful tool for studying the structure of viral genomes inside viral capsids.READ MORE

Neutrons reveal secrets of self-assembly

The Lund team is now optimizing its approach with neutron light to investigate density changes in DNA packaged in type-1 human Herpes virus. “This knowledge will be important for understanding the DNA ejection mechanism, which in turn may control the course of infection,” Evilevitch says. “This can be either latent (dormant) or lytic (active, and where the virus rapidly replicates).”

So far, Evilevitch and colleagues have only observed DNA density changes in cell cultures in the laboratory. Analyses that take into account factors like the immune response and how they affect the course of infection will be needed in the future, they say.

Ultimately, the researchers believe the results from this study, which is detailed in PNAS, could help scientists better comprehend how DNA exits a virus and enters a host cell – something that might be important for developing techniques to, in effect, switch viruses on and off. In turn, this could help in the development of new antiviral agents.

Isabelle Dumé is a contributing editor to Physics World

FROM PHYSICSWORLD.COM    12/1//2024