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Researchers Glimpse Polio Virus As It Enters Host Cell

Date:
January 24, 2000
Source:
Harvard Medical School
Summary:
A team of researchers at Harvard Medical School and other institutions has produced the first 3-D structures—the biological equivalent of snapshots—of the poliovirus in the moments after it attaches to and enters a host cell. The structures, which appear in the February Journal of Virology, follow on the heels of a molecular rendering by the same team of the virus as it attaches to the receptor of the host cell.

Images Could Shed Light on More Intractable Bugs

Boston, MA (January 20, 2000) —- A team of researchers at Harvard Medical School and other institutions has produced the first 3-D structures—the biological equivalent of snapshots—of the poliovirus in the moments after it attaches to and enters a host cell. The structures, which appear in the February Journal of Virology, follow on the heels of a molecular rendering by the same team of the virus as it attaches to the receptor of the host cell. The virus—receptor complex was published in the January 6 Proceedings of the National Academy of Sciences.

Though poliovirus has yielded to medical know-how—vaccination programs have eradicated it from the Western world and promise to eliminate it globally—it has proved to be a stubborn subject for scientists. Surprisingly little is known about how poliovirus enters the cells of the intestines, let alone how it makes its way to the nervous system where it can damage motor neurons and cause paralysis. Some have suspected that after attaching to the host cell, the virus undergoes a series of conformational changes, producing two intermediate forms. James Hogle and colleagues at Harvard Medical School and the National Institutes of Health have determined the structure of these two intermediate forms using a powerful combination of methods—cryoelectron microscopy and X-ray crystallography.

Hogle, who is professor of biological chemistry and molecular pharmacology, and his colleagues have interpreted the images, together with the receptor—virus structure, to tell a story of an extremely dynamic particle. From the moment it attaches to its host, the poliovirus appears to make tiny adjustments in its protein shell that allow it to grab onto its host receptor more tightly. Once bound, the virus creates temporary openings in its shell through which it throws out tiny protein threads which embed in the host cell membrane, not only anchoring the virus to the cell but possibly creating pores for the viral RNA to enter.

Hogle believes the story could be similar for a host of viruses that together cause a variety of effects including encephalitis, paralysis, diabetes and a range of heart ailments. These pathogens, including enteroviruses, echoviruses and Cocksackie viruses, are currently causing public health problems, most notably in American day care centers.

"They are significant pathogens in general, but they are emerging as especially important pathogens in day care centers where you have immunologically naοve beings with horrendous hygiene," he says. Though they use different receptors, the pathogen's primary process of infection is similar to that of poliovirus. "Understanding these viruses gives you a route to potentially making drugs to thwart them," says Hogle.

Ironically it was the onset of good hygiene, brought about by improved sanitation systems at the turn of the century, that turned polio from an endemic disease, with a few cases here and there, into a public health disaster. Deprived of constant exposure to poliovirus, people lost their immunity to the pathogen. Hundreds of thousands were infected during the 1930s and 1940s. "In a very real sense it was the AIDS of that era," Hogle says. Poliovirus's foothold in the West was first loosened with the development of the Salk and Sabin vaccines in the 1950s and early 1960s.

Meanwhile, poliovirus had become entrenched as a model system for understanding viruses. But the problem of how polio actually enters cells has been a tough nut to crack, mostly for technical reasons. Though intermediate forms were being detected biochemically in the 1980s, they were difficult to purify in large quantities.

A turning point came in 1991 when a researcher in Hogle's lab perfected a method for producing the first intermediate form, the 135S, by heating the virus. They even got the particle to crystallize, a prerequisite for determining its structure by X-ray crystallography, but the crystals did not diffract X-rays. With colleagues at the National Institutes of Health, the Hogle lab eventually produced good crystals and, through a combination of X-ray crystallography and cryoelectron microscopy, determined the structures of the 135S particle and, also, the second, or 80S, intermediate form.

"It's a very powerful combination for structures that are too large to look at by crystallographic techniques alone," Hogle says. "You can solve the structure of the components at high resolution crystallographically and take those models and fit them into the low resolution structure of electron microscopy." Of course, such fitting-together entails a certain amount of interpretation, Hogle says.

With that caveat, he says the most striking thing about the images is the evidence they give that the 135S particle shell undergoes a series of tectonic-like movements. Hogle believes these tiny tectonic shifts may open up gaps in the surface of the particle through which the 135S particle throws out coils of protein. These embed in the host cell membrane, tethering the 135S particle to the host. Once embedded, the protein coils may change their orientation to create pores through which the viral contents may be emptied. The 80S intermediate appears to be what is left. "It's the endproduct—what gets spit out after everything is done," Hogle says.

He and his colleagues would like to fill the gaps in the story. "We'd love to be able to see what the virus looks like with its protein coils embedded in the membrane," he says. They also would like to monitor the emptying of RNA from the virus into the host cell, though such a study would require biochemical techniques rather than structural approaches.

In addition to possibly leading to new antiviral therapies, Hogle believes there could be a more immediate payoff. "Ultimately the trickle down comes in that every time we understand something about how viruses enter cells, we understand something more about the way that cells work," says Hogle.

This study was funded in part by the National Institutes of Health and the National Science Foundation.


Story Source:

The above story is based on materials provided by Harvard Medical School. Note: Materials may be edited for content and length.


Cite This Page:

Harvard Medical School. "Researchers Glimpse Polio Virus As It Enters Host Cell." ScienceDaily. ScienceDaily, 24 January 2000. <www.sciencedaily.com/releases/2000/01/000124075528.htm>.
Harvard Medical School. (2000, January 24). Researchers Glimpse Polio Virus As It Enters Host Cell. ScienceDaily. Retrieved July 22, 2014 from www.sciencedaily.com/releases/2000/01/000124075528.htm
Harvard Medical School. "Researchers Glimpse Polio Virus As It Enters Host Cell." ScienceDaily. www.sciencedaily.com/releases/2000/01/000124075528.htm (accessed July 22, 2014).

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