In the evolutionary arms race there’s a constant battle between infectious diseases and their hosts defences. Now new research from the University of Texas has identified one of influenza A’s countermeasures, and it may one day prove to be its Achilles heel.
Influenza A viruses are one of the causes of seasonal flu problems throughout the world. We have good weapons against them: vaccines. But flu is a tricky character; mutating constantly, swapping genes with other flu strains in different animal hosts. This means by the time flu season returns, you may not be facing the same strain and are now unprotected.
Vaccines take time to design and prepare. The seasonal flu vaccine you last had was based on a best guess made by health agencies across the world. This guess was informed by a world-wide surveillance system, monitoring seasonal flu and new outbreaks.
When a new flu strain, like swine flu, suddenly appears and jets off across the world in its human hosts, there isn’t time to develop a vaccine. Antivirals become the first line defence against fast-moving flu pandemics. Currently only two classes of flu antivirals exist, aimed against either viral neuraminidase (like the much debated Tamiflu), or a viral ion channel protein called M2.
But there are clear signs that flu is becoming resistant to both of these approaches. Something new is needed to protect us against the next flu pandemic when it comes.
So where could we find it?
One option is to look at the machinery the virus hijacks from its host in order to replicate, and find ways to disrupt this. This is exactly what a team of researchers from the University of Texas at Austin did. They noticed that following infection of a cell a viral protein, called NS1, was often bound to a host protein called DDX21.
NS1 is a protein that Influenza A viruses come pre-packaged with. It’s not structural, instead has a number of functions important to how they replicate, including stopping the host cells anti-viral efforts, such as production of interferon gamma.
That NS1 was binding DDX21 was curious. What was it doing that the virus needed to stop it? In order to work that out the researchers used RNA silencing to knock down the production of DDX21. When they did this there was 30-foldd increase in viral replication.
“That told us that DDX21 is a host restriction factor, that it inhibits replication,” said Robert Krug, a professor in the College of Natural Sciences at The University of Texas at Austin, speaking in a press release. “That was the key to understanding what was happening. It was an exciting moment.
Krug and his team went on to discover that DDX21 blocks viral replication by binding a protein called PB1. PB1 is a key viral protein needed for replication of its RNA genome. Without it, no replication happens. NS1, by binding DDX21, kept it out of PB1’s way, allowing viral replication to continue.
“If you could figure out how to stop NS1 from binding to DDX21, you could stop the virus cold,” said Krug in the team’s press release.
This makes NS1 an exciting potential target for future drugs. Not just because of NS1’s role as a countermeasure against our own defences, but also because it’s so important for a number of different roles in Influenza A replication.
Source: Chen, G., Liu, C.-H., Zhou, L., & Krug, R. M. (2014). Cellular DDX21 RNA Helicase Inhibits Influenza A Virus Replication but Is Counteracted by the Viral NS1 Protein. Cell Host & Microbe, 15(4), 484–493. DOI:10.1016/j.chom.2014.03.002
Swine flu, wikipedia, via the CDC