University study shows how cells locate viruses

A new study conducted by Yale researchers has revealed the way in which human cells detect the presence of certain viruses.

The study, published last week in the Proceedings of the National Academy of Sciences, shows the important role a toll-like receptor (TLR), called TLR7, has in recognizing single-stranded RNA viruses. The receptors are located in the cell membrane, and once the viruses are detected, the cell begins an immune response, even communicating to white blood cells — crucial components in the immune system.

“We, until now, didn’t understand how certain cells of the body recognize viral infection and secrete antiviral factors,” said Akiko Iwasaki, assistant professor of epidemiology and public health (EPH) and immunobiology at Yale School of Medicine. “Our study showed that recognition of single-stranded viruses by [toll-like] receptor 7 allowed cells to trigger signals that result in the secretion of [antiviral factors].”

The experiment was conducted using the influenza virus as well as the vesicular stomatitis virus, which causes fever. Single-stranded RNA viruses also include those that cause mumps and rabies, according to the Centers for Disease Control and Prevention website.

The authors of the study — including Iwasaki, immunobiology chairman Dr. Richard Flavell, EPH postdoctoral fellow Ayuko Sato and Dr. Jennifer Lund GRD ’07 — found that mice bred without the gene for toll-like receptor 7 (TLR7) failed to produce a response against two different single-stranded RNA viruses.

However, some genetic material is present in human cells in the form of single-stranded RNA. Researchers studied how the body can differentiate foreign single-stranded RNA from its own molecules.

The study found that activation of TLR7 requires an acidic environment, which is found inside endosomes, the bubbles created when the cell engulfs the virus by a folding of its cellular membrane. When the authors added a chemical to the cells that prevents acidification, TLR7 failed to activate, despite the presence of single-stranded viral RNA.

Ten TLRs have been identified to date, which have been shown to respond to different genetic materials. Viruses come in a variety of genetic forms, including single-stranded and double-stranded DNA and double-stranded RNA.

“We focused on single-stranded RNA since we had previously shown the involvement of other TLRs for other types of viruses,” Iwasaki said. “For instance, herpes simplex virus, which contains double-strand DNA genome, is recognized through TLR9.”

The study may provide insight into the development of antiviral medications and vaccines, using molecules known to trigger this immune response, Lund said.

“The recognition mechanism involves a receptor that we know there is a synthetic ligand for,” Lund said. “Basically, [this mechanism] could be involved in creating vaccines for different RNA viruses, by triggering the appropriate response.”

Lund said there is currently a dearth of antiviral treatments, and the few available antiviral drugs, like those available for treating the herpes simplex virus, can have unpleasant side effects.

Iwasaki said the findings may also be useful in treating patients with chronic infections.

“Chronic viral infection … may be a result of evasion of viruses from being detected by the toll-like receptors,” Iwasaki said. “We might be able to trigger an antiviral reaction in chronically infected patients.”

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