The turn of the worm: Viral infection

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  • Published: Sep 1, 2014
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: The turn of the worm: Viral infection

Worm turning

Rice University researchers have determined the crystal structure of the Orsay virus known to infect at least one type of nematode. The structure of the viral shell known as a capsid, seen in a computer model, will help scientists understand how such viruses infect their targets. (Credit: Tao Laboratory/Rice University)

The first structure of a virus known to naturally infect nematode worms has been revealed by researchers using X-ray diffraction. Given the nematodes rank in molecular biology as a useful model for processes in humans, the structure could offer many new clues as to how viral infection occurs in humans too, thus presenting novel targets for the pharmaceutical therapies.

Rice University researchers are the first to obtain a crystal structure for a virus known to infect the most abundant animal on Earth, the nematode worm, Caenorhabditis elegans. The worms are something of a darling of biology laboratories the world over. They are relatively easy to handle, simple and transparent organisms for studying a wide range of biological processes that have parallels in human biology. Now, structural biologist Yizhi Jane Tao and geneticist Weiwei Zhong working alongside colleagues at Baylor College of Medicine and Washington University, have analysed the Orsay virus that infects one particular type of nematode. The structure will help provide insights into how the virus infects its nematode host. There are also implications for finding ways to engineer related viruses to attack parasitic and other pathogenic worms. In addition, there might be new knowledge to gain from how viruses infect other species, including ourselves especially given that we share thousands of genes with this seemingly humble creature.

Zhong, who studies gene networks in C. elegans in order to trace signal pathways common to all animals explains that in 2011 she and her colleagues were hoping to find a virus that infected nematodes with a view to learning more about viral infection. Unfortunately, at the time there were no known viral pathogens of this organism. This has meant that despite its prominence in biology, the nematode-virus connection had not been made. That year, however, Marie-Anne Félix, of L'Institut Jacques-Monod in Paris, France, Eric Miska of Cambridge University, UK and David Wang of Washington University in St Louis, Missouri, USA, identified the first virus in an apple orchard in France, in the class Nodaviridae, which was found to infect nematodes; they have by now identified two such viruses.

Viral blocking

Having requested a sample from Wang and colleagues, Tao’s laboratory began by synthesizing the Orsay capsid protein and then coaxing the proteins to self-assemble into an inactive but structural identical form to that seen in the complete virus. A comparison of these structures with those of the virus observed under the electron microscope confirmed their success in self assembling the capsid. “We got the crystals in May after three months of molecular cloning, expression and purification of the proteins,” explains lead author on the paper Yusong Guo, who is a graduate student co-mentored by Tao and Zhong. “Then we spent about a year and a half to actually solve the structure as fast and accurately as possible, knowing that other groups were competing with us.”

Their efforts led to a detailed structural model of the viral capsid, the hard, spiky shell that protects the infectious contents as the virus searches for and then attaches to a host cell in the nematode. Tao’s lab X-ray crystallography lab has identified the binding sites that allow the virus to attach to its target. Scientists can then search for ways to modify the sites through genetic engineering or design drugs to block viruses.

Orsay calling

Guo’s structure showed the protein capsid of the Orsay virus comprises 180 copies of the requisite protein, each protein contributing to one of 60 spikes that cover the surface of the shell. Tao explains that the capsid structure reveals many surprising similarities with a group of viruses that infect fish, the aforementioned nodaviruses. The researchers also observed similarities in the part of the protein that forms the spikes with the human hepatitis E virus and calicivirus. Such close similarities in protein structures are often indicative of common ancestry in evolution.

Importantly, the team also demonstrated that it could destabilize the virus by modifying one end, the N-terminal arm, of the capsid protein. Zhong said the virus doesn’t kill its host, but causes intestinal distress. “That’s actually a sign that these two species (the worm and the virus) have been co-evolving for a long time, because if a virus kills its host, they’re not going to coexist for long,” she explains. “The worm and the virus thus make a good model system to study host-virus interactions.” Such interactions are an important topic in the area of human virology where spread from stable animal-virus ecosystems occurs sporadically as is the case with severe acute respiratory syndrom (SARS), H1N1 swine flu, bird flu, Ebola, Hantavirus and many other viruses. Many of these diseases are lethal and so self limiting, but understanding what makes a co-evolutionary host-virus system stable could provide new clues into the emergence of pandemic diseases and how we might defend against them.

The team explains that the capsid spike structures are important. The spikes are thought to interact with receptors on the surface of the host cell, Tao explains: "Now that we know this domain, we can specifically change it so that maybe, instead of targeting this worm, it will target a different species of worm.” Moreover, given that of the 20000 genes in C. elegans 8000 are also identified in people, there is now the possibility of an intellectual quest to identify which of those genes shared by both nematode and human are involved in defending the organism from viral infection.

Related Links

Proc Natl Acad Sci (USA), 2014, online: "Crystal structure of a nematode-infecting virus"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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