May 2015

Where's the evolution?

When Evo in the News last reported on H5N1, we discussed horizontal transfer — i.e., the possibility of a human flu virus passing the gene versions necessary for human-to-human transmission to the avian flu. While horizontal transfer is still a threat, new research focuses on the incremental adaptations that the avian flu virus evolved as natural selection acted on it within human hosts. In particular, the new research focuses on avian flu strains from Egypt, which are unusually good at making the leap to mammals from birds. What evolutionary changes are responsible for this ability?

Human flu viruses have adaptations that allow them to invade human cells in our upper respiratory system; however, bird flu works in a different way. It mainly invades cells in birds’ intestines. Which cells a flu virus can bind to and attack is determined at least partly by a protein called hemagglutinin — HA for short — that is positioned on the outside of the virus. HA recognizes and binds to the victim cell, ultimately prompting the host cell to envelope the virus. HA also helps the virus release its genetic material (in this case RNA) once it is inside the host cell, allowing more copies of the virus to be produced.

The new study focused on HA proteins and catalogued the mutations that differentiated the Egyptian viruses that had invaded humans from other H5N1 viruses. The researchers then inserted copies of those mutations into more typical H5N1 viruses and investigated the effect those had on the virus and its HA proteins. They discovered that the mutated HA proteins made the viruses better able to bind to cells lining the human airway and also altered when the virus released its RNA inside the host cell. This allowed the mutant bird flu viruses to replicate more efficiently inside human cells — though not (yet!) as efficiently as human flu viruses do.

Natural selection seems to have acted on the Egyptian viruses’ HA proteins, favoring genetic variants in humans that are copied more quickly. This is exactly how we would expect natural selection to occur in this situation. In Egypt, humans come into close contact with infected poultry, and so the viruses frequently wind up in the human airway. When they do, any virus particle carrying a mutation that allows it to invade and replicate in a human cell would be favored. As the infection continues in that host, any random mutations that happen to make that process even more efficient would be favored.

So what’s stopping these Egyptian avian flu viruses from being passed from human to human? The viruses have some of the adaptations that would be necessary for this to occur, but not all of them. They can infect and replicate quickly inside human cells, but other research suggests that they’d have to be better at growing in the upper respiratory tract and stable enough to remain infectious when outside the host’s body. And it appears that some of the mutations favored in the Egyptian strain, while increasing replication within the host, actually make the virus less stable and so potentially less able to move from human to human.

Nevertheless, the Egyptian viruses have high pandemic potential, since they are already unusually good at infecting humans. This research gives us a much clearer picture of what adaptations are involved when a virus switches hosts — and points the way towards some practical steps that can be taken to prevent a pandemic, such as close monitoring of viral strains that are primed for human infection.