RICE (US) — Scientists have defined the structure, down to the atomic level, of a virus that causes juvenile diarrhea.
The findings could lead to the development of medications to block it before it becomes infectious.
Among four small RNA viruses that typically infect people and animals, astrovirus is the only one whose atomic structure was not yet known.
First visualized through electron microscopy in 1975, it became clear in subsequent studies that the virus plays a role in juvenile—and sometimes adult—outbreaks of diarrhea, as the second leading cause after rotavirus.
The spiky capsid shell of the astrovirus responsible for a form of juvenile diarrhea contains and protects single-strand RNA until it can be delivered to a cell. (Credit: Jinhui Dong)
Passed orally, most often through fecal matter, the illness is more inconvenient than dangerous, but if left untreated, can cause children to become dehydrated.
The research is published online in the journal Proceedings of the National Academy of Sciences.
The virus works its foul magic in humans’ lower intestines, but to get there it has to run a gauntlet through the digestive tract and avoid proteases, part of the human immune system whose job is to destroy it. (Though one, trypsin, actually plays a role in activating astrovirus, she says.)
When the astrovirus finds a target and viral RNA is let loose inside human cells, virus replication starts. If the host’s immune system does not do a good enough job in removing the viruses, the malady will run its uncomfortable course in a couple of days.
Astrovirus bears a strong resemblance to the virus that causes hepatitis E (HEV). Yizhi Tao, associate professor of biochemistry and cell biology at Rice University decided to investigate astrovirus after completing a similar study of HEV two years ago.
“I was thinking there’s some connection between those viruses,” she says. “Based on that assumption, we started to make constructs to see if we could produce, to start with, the surface spike on the viral capsid.”
The capsid is a hard shell 33 nanometers wide that contains and protects its RNA. It has 30 even tinier spikes projecting from the surface, and each of those spikes may have a receptor-binding site.
Once the atomic structure of the spike was known, finding the receptor site took detective work that involved comparing genomic sequences of eight variants of astrovirus to find which were the best conserved.
“Among those eight serotypes, we figured there must be a common receptor, and that should be conserved on the surface,” says postdoctoral researcher JinhuiDong, the paper’s lead author.
In looking for the common receptor, the team found a shallow pocket in the spike that became a prime suspect for receptor binding.
The researchers also discovered the astrovirus may have a sweet tooth. “The size of the pockets suggests that it would most likely bind to sugar molecules, like disaccharides or trisaccharides,” Tao says. “It may be that the virus binds to the sugar molecule and that helps it bind to the surface of a target cell.”
Astrovirus resembles another of the four types of RNA-based viruses, calicivirus, although more remotely than HEV. Researchers suspect astrovirus may be a hybrid, with parts derived from both HEV and calicivirus.
“Clearly, these three are related somehow. It’s an interesting point, but we can’t determine that relationship based on what we know right now.”
What researchers can do is begin to develop a vaccine or antiviral drug that will block astrovirus. “There’s already a phase II vaccine (in trials) for HEV, so that gives us hope,” Dong says.
“We will certainly work with other labs to identify compounds that can bind to this potential pocket,” Tao says. “We can do this computationally. We can screen 50,000 compounds, for example, to see which may bind to the protein with high affinity. Then we can start the optimization procedure.”
The Welch Foundation, the National Institutes of Health and the Kresge Science Initiative Endowment Fund supported the research.
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