&Bullet; physics 14, 82

In order to infect a cell, the flu virus has to move, and a new theory suggests how to do that.

F. Ziebert / Heidelberg Univ.

Keep going. In this schematic cross-section, the cylindrical influenza A virus containing viral RNA is attached to a cell membrane. The connection takes place via connections between sialic acid groups protruding from the membrane (green) and HA spike proteins (blue). These connections are constantly forming, separating, and re-forming. Other viral proteins (NA, red) cut off the sialic acid groups (floating to the right), gradually reducing the available sites for HAs to connect. If the virus-cell interaction is weakened, the virus can rock more easily and enable new binding events through HA proteins on the left edge of the contact region, which can let the virus roll to the left.Keep going. In this schematic cross-section, the cylindrical influenza A virus containing viral RNA is attached to a cell membrane. The connection takes place via connections between sialic acid groups protruding from the membrane (green) and HA-Spikepr … show more

Before an influenza virus penetrates a cell in the airways, it expands into a thread-like structure that rolls over the cell surface like a pencil on a desk. Two theorists now propose a new mechanism for rolling [1] . They show that two proteins on the virus surface work together to drive movement through interactions with the cell membrane. Understanding this process could reveal ways to prevent infection. However, some experts will not convince without more detailed modeling.

It is not known why the flu virus is rolling. One possibility is that this movement represents a good compromise between the virus, looking for a point of attack, and holding on to the membrane via chemical bonds – similar to the crampon tips with which a climber remains anchored in the ice when crossing. The lung tissue targeted by the virus is lined with tiny appendages called cilia that move vigorously to sweep away debris and pathogens, so the virus needs a good grip to avoid being washed away.

The firm grip is provided by a “spike protein” called hemagglutinin (HA) that protrudes from the virus surface and binds to a chemical group called sialic acid on the surface of a cell membrane. The bond is temporary as each HA is constantly separating and reconnecting with a new sialic acid. Even so, since many of these bonds exist at some point, they would keep the virus in place. But there is a second spike protein called neuraminidase (NA) that cuts off sialic acid groups in the contact region, gradually reducing the number of binding sites available for HA. Experiments show that the virus cannot adhere without HA; without NA it cannot move [2] .

But how do HA and NA act together to create a concerted roll, rather than, for example, a disorganized sequence of bonding and splitting events? To explain this, physicists Falko Ziebert from the University of Heidelberg in Germany and Igor Kulić from the Charles Sadran Institute in Strasbourg, France, have now developed a model that applies ideas developed for other biological “engines” that Generate movements at the molecular level. They conclude that virus rolling works in ways that have not yet been identified in biological systems.

S. Vijayakrishnan et al., PLOS pathog. 9, e1003413 (2013)

Viral non-compliance. An electron micrograph shows some of the spherical, filamentous, and other shapes that the influenza A virus has assumed.

The theorists model the influenza A virus (IVA) as a long cylinder studded with a random mix of HA and NA spike proteins. First, the virus adheres to the membrane through several hundred HA-sialic acid compounds, and then the NAs gradually reduce the virus’s adhesive force by cutting off sialic acid groups. If the virus-cell connection is weakened, the virus can wiggle around its point of attachment, increasing the likelihood that some HAs will form new connections just beyond the edge of the contact region and pull the cylinder in rotation.

Using both model calculations and computer simulations, the two researchers found that this process can produce sustained rolling movements. Once the symmetry of the system is broken and the virus is pulled in a certain direction, the interaction of HA and NA creates a torque that keeps the virus going. Occasionally, through random fluctuations in the binding and cleavage events, the virus particles can reverse direction and take a new direction.

“The really surprising thing is that the rolling is almost independent of the system parameters,” says Kulić, as is the NA cleavage rate – it seems to be practically inevitable as long as the virus remains attached to the membrane. The researchers say their proposed mechanism is likely similar to what works in a recently published artificial system in which DNA-coated silica nanoparticles roll over a surface covered with RNA when a bond-cutting enzyme is present [3] .

“If this result is correct, it would open up important prospects for the construction of very simple enzyme-powered molecular machines,” says the biophysicist Dean Astumian of the University of Maine, a specialist in molecular and nanoscale motors. However, in the absence of a more detailed model, he is skeptical as to whether the mechanism explains how the virus can break symmetry and roll steadily in one direction. Kulić agrees that the virus was initially frozen, but says that this condition will not last.

Virologist Erik de Vries from Utrecht University in the Netherlands says that “any physical model or theory for analyzing and quantifying the rolling behavior of IVA is very valuable”. But he says more data on the response rates of HA and NA are needed to properly test the model.

Kulić points out that flu drugs like Tamiflu work by inhibiting NA and thus blocking rolling motion, thereby immobilizing the virus until it can be washed away. Some coronaviruses move on cell surfaces as well, and versions of the HA and NA proteins have been known to be involved, he says, but luckily, SARS-CoV-2 doesn’t move. “At the moment, SARS-CoV-2 is a one-trick pony that is not well adapted to the host,” he says. “Let’s hope it doesn’t find out the influenza rolling trick anytime soon.”

–Philip Ball

Philip Ball is a freelance science writer based in London. His latest book is How to make a person grow (University of Chicago Press, 2019).

References

  1. F. Ziebert and IM Kulić, “How the spike motor of influenza works”, Phys. Rev. Lett.126, 218101 (2021).
  2. E. de Vries et al., “Influenza A Virus Hemagglutinin Neuraminidase Receptor Balance: Maintaining Virus Motility”, Trends microbiol.28, 57 (2020).
  3. K. Yehl et al., “High-speed roll motors based on DNA, driven by RNase H”, Nat. Nanotechnology.11, 184 (2015).

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