Posted by A couple of days ago Dr. Marion Koopmans, chief of virology in the infectious diseases laboratory of the National Institute of Public Health, The Netherlands, notified the infectious disease community through the website/email list ProMed that two of their swine flu isolates showed a particular genetic change in one of the virus’s eight genetic segments. Even though this virus has been described as relatively stable genetically, individual viruses, even within the same patient, often have small differences in the thousands of letters that make up their genetic code. Influenza A virus is a very sloppy reproducer, and while its only objective in life is to make a copy of itself it often does single task very badly. But it’s like the guy who was asked how he could sell his gasoline for a penny less than he paid for it, his answer was, “volume.” The flu virus makes so many copies of itself when it infects a host cell that it can afford to make a lot of mistakes. Usually those mistakes are disastrous for the copy and it doesn’t replicate any more. Very many of the little mistakes are just little mistakes and don’t affect the virus at all. And some of them turn out to be good for the virus and possibly bad for the host in that they allow the virus to replicate faster, infect more and different kinds of cells and increase its ability to transmit from one host organism to another (transmissibility). So research groups like Koopmans’s keep an eye on the genetic make-up of this pandemic virus as it continues to spread globally. Everyone expects it to change and we are getting what we are expecting. So what’s the big deal — if there is one — that caused Koopmans to send around an alert?
It would be nice if we could look at the genetic sequence of the virus and read off its biology. For the most part we can’t. We have only little clues here and there about what makes one flu virus able to infect a bird but not a human or vice versa or both. Or what makes the virus easily transmissible from one person to another or from a bird to a human or a human to a pig. Or what made the 1918 pandemic strain so virulent (able to cause a lot of serious disease) while the usual seasonal flu does so in only a minority of cases. Each time we think we’ve got “the answer” the flu virus crosses us up. Take the mutation in question, designated E627K in PB2. PB2 is a protein coded by one of the flu’s eight genetic segments. It is an abbreviation for polymerase basic protein 2 and is part of a three part package consisting of PB1, PB2 and PA proteins the virus uses to copy its genetic material and translate the genetic material into other proteins it needs (including themselves, i.e., PB1, PB2 and PA). These three proteins work together as a team and interact with another protein (NP) that acts as a structural scaffolding for the genetic material itself, the RNA (humans carry genetic information in DNA but flu viruses use RNA). The E627K mutation means that at position 627 along the amino acid chain that makes up the PB2 protein, one amino acid, glutamic acid. whose one letter abbreviation is E, had been changed to lysine (abbreviation, K). Bird influenza viruses usually have the E version at this position while humans usually have the K version. It had been thought that the switch from E to K is needed for full adaptation to humans and everyone was ore than a little surprised when the new pandemic strain turned out to have the E version and not the K version. So people have been expecting to see the K version pop up and they’ve been looking for it. Koopmans was the first to find it.
So what does this mean? So far we really don’t know. By the time the first mutation was detected it was too late to do comprehensive contact tracing. Only one other isolate showed the same mutation but it wouldn’t be surprising if there were others that were undetected (you can read more about the investigation in Koopmans ProMed notice or in an excellent piece by Helen Branswell of Canaddian Press). But that doesn’t answer the question of the significance of this event — if any. Both cases typical flu cases and recovered. When the isolate was inoculated into ferrets, Koopmans did not report it appeared to be any more virulent than the E version. One of the big fears was that the mutation would make things worse. The origin of this is a finding that the mutation makes it easier for the virus to replicate at lower temperatures. Birds have relatively high body temps (about 41 degrees C.) compared to humans (37 degrees C., and the temperature in our upper respiratory tracts is even lower, around 33 degrees C. The concern about this mutation arose around the bird flu virus, H5N1, which is extremely virulent. Since the deeper parts of the lung are warmer than the upper respiratory tract, the fear was that switching from E to K would allow the bird flu virus to replicate in the human upper tract more easily and make it much more transmissible. At the moment H5N1 causes a disastrous infection in a few people (why these people and not others equally or more exposed we don’t know), but it doesn’t transmit from person to person (only a few documented instances exist). An elegant experiment by Kawaoka we discussed here two years ago demonstrated that this single mutation was enough to switch the propensity of H5N1 to infect upper or lower respiratory tract host cells. He had found the two variants in the same Vietnamese patient infected with H5N1. The isolate from deep in the lung was the E variant (bird), the one in the upper tract was the K variant (human), but both were in PB2 that were part of the H5N1 bird flu virus. When Kawaoka switched the two amino acids experimentally, he also switched where the virus liked to infect (upper or lower).
So the way the story was reading in 2007 was that the E variant was more virulent (because it infected cells deep in the lungs) but the K variant might make the virus more transmissible. That’s something we really didn’t want to happen with H5N1, which so far is so virulent it is killing over half of the people we know to be infected. The K variant was thought to be necessary for full adaptation in humans. And maybe that’s right for H5N1. But it sure isn’t right for H1N1, which has managed to more than fully adapt (it’s crowding out the seasonal viruses) and is spreading like crazy even thought virtually all of it is the E variant at 627. Nor has it seemed to change the virulence of the virus, although we don’t have a lot of isolates to play with at this point.
I’ve often quoted a noted flu scientist who once said to me, “I knew much more about flu 20 years ago than I do now” (meaning that things we thought we knew then we now realize we didn’t really know). With this pandemic and the pace of new science and discoveries in the flu world, we’ll have to modify this to, “We knew much more about flu 6 months ago than we do now.” The simple truth is that as much as we know, we haven’t yet been able to put the pieces together into a solid story. Every time we think we’ve got a handle on what’s going on the flu virus thumbs its nose at us.
We’ll get it eventually. But right now when I read that this mutation is popping up or that we have now discovered the “secret” of why flu does this or that, I don’t jump up with fear or anticipation. It’s going to be a long, hard climb until we reach a place where we can really see the broader landscape and not just what’s a few inches in front of our face.
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