The clock ticks one tock closer....
Scott McPherson
in influenza and infectious diseases
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The noted infectious disease rock star Dr. Yoshihiro Kawaoka of the University of Wisconsin-Madison is back in the news today, this time in a much better light. He and his team of researchers have confirmed that the H5N1 "Qinghai" substrain (Clade 2.2)has mutated into a form that is much easier for humans to catch.
The key is the ability of the virus to infect the upper respiratory tract. H5N1 normally has a tremendous affinity for the lower respiratory tract -- deep in the bottom of the lungs. This makes it extremely difficult for humans to catch the virus. But it also dooms most of the flu's human victims to death. The mutation noted by Kawaoka and his team adapts the virus to the comparatively colder regions of the human throat and nose.
As quoted in today's New York Times: http://www.nytimes.com/reuters/world/international-birdflu-mutations.html?_r=3&oref=slogin&oref=slogin&oref=slogin
NEW YORK (Reuters) - The H5N1 bird flu virus has mutated to infect people more easily, although it still has not transformed into a pandemic strain, researchers said on Thursday.
The changes are worrying, said Dr. Yoshihiro Kawaoka of the University of Wisconsin-Madison.
"We have identified a specific change that could make bird flu grow in the upper respiratory tract of humans," said Kawaoka, who led the study.
"The viruses that are circulating in Africa and Europe are the ones closest to becoming a human virus," Kawaoka said.
Recent samples of virus taken from birds in Africa and Europe all carry the mutation, Kawaoka and colleagues report in the Public Library of Science journal PLoS Pathogens.
The above image is from an early 2007 Powerpoint pandemic presentation I have given too many times to count. It is a graphical representation of Dr. Henry Niman's discoveries regarding changes in H5N1. All the mapped changes have been found in Qinghai H5N1. Dr. Henry Niman has a superb explanation for this. The link to his latest commentary is here:
http://www.recombinomics.com/News/10050702/H5N1_E627K_Temp.html
Dr. Niman was, as I recall, the first scientist to comment publicly on the presence of the mutation(s) in question. Dr. Niman observed this change in the virus last year. Here is a portion of today's commentary:
The detection of E627K in dead wild birds at Qinghai Lake in May, 2005 signaled a major change in the global spread of H5N1. At the time “Asian” H5N1 had not been reported in any country west of China. The massive die-off at Qinghai Lake signaled the movement of H5N1 in long range migratory birds and the strain of a major geographical expansion.
The data on the temperature dependence of E627K also explains why many surveillance programs fail to detect Qinghai H5N1 in live wild birds, including locations where H5N1 is readily detected in dead or dying wild birds. The body temperature of live wild birds keeps the levels of the virus low, below the detection levels of these assays. Dead and dying birds have a lower body temperature, allowing levels of the virus to rise.
Although the effect of E627K on viral replication has been know (sic) since 2001, this fact has been ignored in the surveillance programs that focus on live birds. Instead of measuring H5N1 antibody levels, which are more stable and reliable, these groups test thousands of birds and then use the false negatives to issue assurances and denials of the transport and transmission of H5N1 by wild birds.
Consequently, the alarming expansion of Qinghai H5N1 has largely happened below the radar of these (sic) surveillance, which remains a cause for concern, as have changes in the receptor binding domain in Qinghai isolates from fatal human cases, including V223I, S227N, and M230I.
Also from the Reuters story, posted by MSNBC.com:
All flu viruses evolve constantly and scientists have some ideas about what mutations are needed to change a virus from one that infects birds easily to one more comfortable in humans.
Birds usually have a body temperature of 106 degrees F, and humans are 98.6 degrees F usually. The human nose and throat, where flu viruses usually enter, is usually around 91.4 degrees F. (bold mine)
What this all means, in short:
1. As we have speculated for almost a year, Qinghai H5N1 has developed at least one, and probably several changes to its composition, the result of which is the ability of the virus to survive in the colder temperatures of the human throat and nose.
2. Surveillance programs are unable to detect the presence of Qinghai in live wildfowl, because we're not testing the birds correctly. This is why dead and dying birds (with lower temperatures) are filled with H5N1, but live birds (with higher temperatures) appear not to be affected -- at least, not until they begin dying of the virus.
Blessedly, this change in the receptor binding domain is not the only precondition for H5N1 to "go pandemic." As stated by Drs. Robert Webster and Elena Govorkova stated in the New England Journal of Medicine last November,
Moreover, receptor specificity is only one of the requirements for human infection; the virus must also find compatible enzyme systems in the infected human cells if the viral polymerase complex is to function. Currently, these conditions are apparently met in only a few persons. But the virus is always changing, and mutations that make it more compatible with human transmission may occur at any time. http://content.nejm.org/cgi/content/full/355/21/2174
Today's news reminds us that influenza smoulders. It moves and evolves/mutates at its own speed, on its own timetable. Today's news also officially moves us one tick closer to pandemic.
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Reader Comments (6)
So, if H5N1 learns how to survive cooler, upper respiratory environment (ability to adhere) then, does this necessarily mean that it will maintain its virulence (ability to cause disease)? I mean, it could acquire one ability and lose another, making it less virulent. Yes? Do the researchers take this into account. Do we/they clearly understand what other parts in the viral coat cause other parts of virulence (e.g., colonization, toxin production, hiding from immune system). Is this critter mapped out enough to even know? Despite my weak suggestion that changes can also make a pathogen less virulent, I suspect that the overall conditions for creating a pandemic pathogen exist, nonetheless. Until this critter stops mixing with other strains (and other viruses), how can we expect it to lose virulence?
Wow,
Great questions! Let me try to summarize the answer, the best I can.
I think everything is in play with this virus. We all certainly pray that if it acquires the ability to go H2H, that it loses its virulence. Maybe that is some sort of genetic counterweight. However, the WHO's report of 9/2006, published 11/2006, said (toward the back) that if the virus does not reassort, but keeps its current characteristics, it could potentially maintain its extreme lethality while going pandemic.
I am currently in prep to write a blog called "Searching for the Tipping Point," and maybe I can work toward an answer there. I am also going to send your question to Dr. Webby at St. Jude for an authorative response.
A ton of money is being thrown at mapping the H5N1 virus, gene by gene. I would say the mapping is pretty good; the biggest problem is that not enough nations are forthcoming with the full genetic sequences to enable everyone to work the problem. At Genbank and Los Alamos, there is a treasure-trove of genetic mapping that is simply not being made public. If there are good reasons for this, I have not heard them. Likewise, China and Indonesia are sitting on human, swine and avian samples and will not release them for others to analyze. Even the US and Canada are sitting on avian samples of H5 and H7 influenzas. Canada claims the H5N1 that killed the bird in Newfoundland was low path, but never released the sequences. I don't mean to infer conspiracies, but I am inferring ther are organizations that will benefit from having first dibs at the sequences.
Most predictions are made by trend and not endpoint.
We may not know the endpoint...but the trendline is consistent...unfortunately.
This virus is steadily progressing down the road to pandemic potential with high mortality...a 'freak' biological asteroid.
...and if you think about it...that is why there have been so many worried regulators since Karo and Q. Lake.
Tp put it another way. We are out on a limb upon which H5N1 has been feasting happily away for ten years...it's relative numbers increasing by the day, week, month and year.
The endpoint would be wether we could conclude, based on the historical data...with 100% confidence... that H5N1 will eat enough of the branch such than human civilization falls off.
...and the answer would be no. There are potentials that could create a situation where H5N1 'loses interest' and goes away...maybe forever.
However...the chewing is getting louder and louder...and the period H5N1 has been with us and expanding in relative numbers (template) and geographically expands...
...we can observe a historical timeline indicating that the limb and we with it will fall...
...the last question is when.
However, it should be kept in mind that biological systems, as we are presently observing with global warming...speed up as they go along...
...In way of explanation, it was recently reported that experts had measured that the ice cap in the Artic would be gone by the end of the century. Based on the results in the last few years including record rates of ice cap loss this year, that the ice cap may be lost by 2020.
I would expect the same with H5N1. It has the template both in numbers and geographically...and it has the precise tool...astronamical mutation rates...to reach its endpoint...which I believe is a human pandemic.
...and let no scientist tell you that they have ever seen a virus, let along an influenza virus, with these precise abilities...
...H5N1 is in reality a freak of nature.
Well said Tom DVM. Ashen-faced influenza researchers are apparently not enough to move public opinion toward prepredness. Even a growing body of knowledge regarding this "mutating fool of a virus" is not enough to get people off their duffs.
But we must continue to fight to get the word out, and we must avoid "pandemic fatigue", as Mike Osterholm would say.
Scott
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