Knowing your enemy is an important principle of competition, and scientists may just have become more familiar with one nasty stomach virus.
Closeup looks at several strains of norovirus reveal that the vomit- and diarrhea-inducing virus can come in a variety of sizes, researchers report online June 10 in the Proceedings of the National Academy of Sciences. Knobs studding the virus’s protein shell are twisted slightly in some strains, and the pathogen may need charged zinc atoms to maintain its shell, the team learned.
Those discoveries could aid in vaccine development or help researchers find better ways of disinfecting virus-contaminated surfaces. Scientists have known surprisingly little about the virus, though it is the leading cause of gastroenteritis and foodborne illness, sickening up to about 21 million people each year in the United States alone.
No drugs or vaccines against norovirus exist. And the virus is notoriously hard to grow in the lab, making it difficult to study. Only one strain has ever been crystallized to reveal its structure at the atomic level.
“We have no idea what cells it’s infecting, how it causes diarrhea, why the symptoms are so short,” says Craig Wilen, a virologist at Yale School of Medicine who was not involved in the study.
Researchers also don’t know: why the virus causes more cases of “stomach flu” in winter than other seasons; why only one strain seems to circulate at a time; why immunity to the virus lasts only about six months; nor why some people are more susceptible than others. “It’s a mystery,” Wilen says.
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Norovirus strains vary in size and the arrangement of their protein shells. For instance, the GII.2 Snow Mountain strain (C) is similar in size to the GI.1 Norwalk strain (A) and the GI.7 Houston strain (B), but has spikes that are twisted about 15 degrees counterclockwise relative to spikes on the other strains. Snow Mountain also formed smaller particles (D) with only 60 subunits, instead of the usual 180. The outbreak strain GII.4 Minerva (E) was composed of 240 subunits, and its surface knobs are rotated about 50 degrees clockwise relative to the other strains, researchers discovered. These differences might affect how the viruses interact with human cells.
Structural biologists Leemor Joshua-Tor and James Jung at Cold Spring Harbor Laboratory in New York led a study using cryo-electron microscopy to view the shells of several norovirus strains — including a type known as GII.4 that is responsible for about 70 percent of norovirus infections. That technique involves deep-freezing viral samples, which preserves how proteins and other molecules are arranged. (The researchers assembled just the outer protein shell for technical reasons and so that no one would be infected with a live norovirus during the experiments.)
Microscope pictures showed a surprising amount of diversity in the virus particle sizes, with some small, medium and large strains, and some even with differently sized particles within the same strain. Some virus shells even appeared too small to fit the RNA that carries the virus’s genetic instructions, meaning that those particles might be just hollow shells.
“Even ones that are the same size have quite a few differences,” says Joshua-Tor, who is also a Howard Hughes Medical Institute investigator. Spikes or knobs studding the virus shells are twisted differently in each strain, she says, though it’s not yet clear if those twists might influence how the virus infects cells.
Given that the team examined only the outer protein shells, Wilen says, it will be important to see whether complete noroviruses containing RNA and other proteins have the same structure as these shells do.
Knowing how the virus is structured might help scientists develop vaccines to target vulnerable spots in the shell, says Matthew Moore, a food microbiologist at the University of Massachusetts Amherst. He’s also intrigued by the finding that zinc ions appear to keep viral particles from falling apart, which could have more widespread implications. Adding zinc to future vaccines that include viral proteins might also help make the treatments more stable. And using chemicals that steal zinc from the viruses may aid in disinfecting surfaces, such as fabrics and stainless steel, that don’t hold up well to bleach treatment, he says.