BioEd Online

Dengue and Zika viruses replicate inside people by hijacking some of the same proteins, according to a study published on 13 December in Cell.

This finding comes from a suite of techniques that exposes how viruses manipulate the cells they infect, which marks a shift in how researchers are thinking about drug development. The idea is to target human proteins exploited by viruses, rather than targeting the pathogens themselves. The medicines developed with such an approach might treat multiple illnesses, rather than a single disease. They could also and sidestep the drug resistance that results from rapid viral evolution.

In the new study, investigators demonstrate that dengue and Zika viruses replicate and spread by exploiting some of the same proteins in humans and mosquitoes — the insects that transmit both viruses to people. The study authors also identified a protein related to brain development that is hijacked by the Zika virus.

“This has the potential to change the paradigm of antiviral drug development,” says John Young, global head of infectious-diseases discovery at Roche, a pharmaceutical company in Basel, Switzerland.

Nevan Krogan, a geneticist at the University of California, San Francisco, led the project and is using this host-centered approach to also investigate how Ebola, HIV, chlamydia and four other infectious microbes hack human cells. He's also started to apply the approach to look at how human proteins are altered in non-communicable conditions — such as Alzheimer’s and cancer.

Go fish

Viruses are too tiny to fend off inflammatory attacks from their hosts and multiply on their own, so they manipulate the host’s proteins to do their bidding. Each virus exploits different weaknesses in the cells that they infiltrate. Yet Krogan wondered whether there might be some overlap in how viruses rewired the proteins in the cells they infect. “We want to find commonalities so that you can come up with one drug to hit multiple diseases,” he says.

To fish for hijacked proteins, Krogan and his colleagues used a molecular ‘hook’ attached to viral proteins that would stick to any other protein that the virus interacted with. The team then infused the modified viruses into human and mosquito cells. Next, they isolated the captured proteins and identified them using a technique that classifies compounds according to mass. The researchers then used machine learning and other computational methods to search for patterns in the data that indicated which proteins to explore further.

With this method, Krogan’s team identified 28 proteins in both people and mosquitoes that interact with both Zika and dengue viruses. One of these proteins, SEC61, normally shuttles other proteins around inside of cells.

Krogan suspected that the viruses might usurp SEC61 for their own transportation needs. To test this idea, the team treated cells infected with dengue or Zika with a chemical that inhibits SEC61, and found that both viruses couldn’t replicate.

That chemical is currently being tested as a cancer treatment, says Krogan. He suggests that it could one day be developed into a therapy for dengue and Zika — infections that result in fevers and, occasionally, death. Development of such a therapy could be hindered by the possible side effects of targeting proteins that are vital to cellular functions, because that could cause as much damage as the diseases themselves.

The team also discovered that a protein in humans and mosquitoes, ANKLE2, seemed integral to microcephaly — a brain abnormality seen in babies infected with Zika in utero. ANKLE2 is involved in brain development, and when the researchers injected excess ANKLE2 into fruit flies infected with Zika, their brains developed normally compared with infected flies that didn’t receive the injections. It’s still unclear exactly how Zika influences ANKLE2, and how that leads to microcephaly.

Finding common ground

“I am blown away by this paper,” says Nikos Vasilakis, a virologist at the University of Texas Medical Branch at Galveston. Researchers, including Vasilakis, had highlighted other proteins that might contribute to microcephaly. But Vasilakis says that this is the first time he’s read about an approach that reveals several, testable protein interactions.

Krogan hopes that this host-centered approach will help drug developers to find treatments for a range of maladies. In a study published alongside the dengue–Zika paper, Krogan’s team reveals human proteins that the Ebola virus manipulates. His group is also analysing the functions of 435 proteins that are potentially reprogrammed by HIV.

Furthermore, Krogan says that focusing on the host side of a condition, rather than on the pathogen, can help to bridge research gaps. For example, if the same network of proteins is altered in someone with dengue and cancer, then researchers could pool their knowledge to hunt for a treatment that targets those proteins. “Science is so siloed,” he says. “The data we are generating makes connections between proteins, and also between scientists.”