Potential protection against pandemics

Mount Sinai researchers describe strategy to develop first broad-spectrum antiviral drug

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NEW YORK—In the movies and novels about some devastating disease wracking a nation, region or even the world—whether zombie-creating viruses or a superflu that kills more than 99 percent of the population or whatever else—the plot sometimes comes to rest eventually on one or a handful of people who are immune. And sometimes, in the course of the story, the reason for that immunity and thus a cure for the disease is found.
And, in a sense, that’s what Mount Sinai researchers are doing right now, as the school notes that “By studying the rare person—about one in a million—who can fight off viral infections more effectively than everyone else, investigators at the Icahn School of Medicine at Mount Sinai have developed a strategy to help the rest of us achieve this enhanced antiviral state.”
Their research, published in Nature Communications, provides a path toward creation of something we have never had before: a broad-spectrum antiviral drug.
The international research team demonstrated in human cell and animal studies that switching off a single gene bolsters immunity against seven viruses, including the extremely dangerous Nipah and Rift Valley fever viruses.
“We also have evidence suggesting the strategy protects against Zika infection, and we plan to test Ebola as soon as possible,” said the study’s lead investigator, Dr. Dusan Bogunovic, an assistant professor of microbiology and pediatrics at Icahn. “The idea is to develop a pill that people can use to protect against pandemics—or even to help an individual stop an emerging cold sore.”
The target in their work was the gene ISG15, whose activity is linked to type 1 interferon. Type 1 interferon, in turn, plays a key role in regulating the body’s immune response to viral infection. Scientists showed a couple decades ago that mice lacking the ISG15 gene are more susceptible to viral infections. In humans, though, that dynamic is reversed. As the Mount Sinai team has shown, along with collaborating international researchers at the Institut Pasteur in France, those very few people who don’t have the gene have an very robust response against viral infections.
“To our pleasant surprise, what doesn’t work in mice works beautifully in humans. If you, as a human, don’t have that gene, you may be more able to fight off viral infections than others,” said Bogunovic. “Additionally, if you do get infected, you control it better. You are basically like a vaccine in yourself. You don’t necessarily experience the same range and degree of symptoms, but you still develop antibodies and T cells and everything you need to be ready for the next infection.”
The researchers found that the normal role of ISG15 in humans is to help turn off the type 1 interferon response to a viral invader once it has been activated and is working.
“It fine-tunes the very end of shutting off that inflammation. So when you don’t have the gene, your body continues to trickle out type 1 interferon, thus continually priming the body against viral invaders,” Bogunovic explained. “So you are persistently ready to take on viruses.”
However, such long-term antiviral resiliency comes at a price for those lacking the ISG15 gene, he added, noting that many of those individuals develop occasional seizures and detectable auto-antibodies, although none have yet been known to develop autoimmune disorders as a result.
“We believe a drug that turns off ISG15 in humans for a brief amount of time would help many people facing an emerging viral infection—but of course, all this needs to be tested,” Bogunovic said. He added that his team is now screening millions of small molecules to create a pill that can provide such an antiviral boost.

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