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Cones, umbrellas, Chinese fathers, and H2H

Posted on Thursday, January 10, 2008 at 08:59AM by Registered CommenterScott McPherson in | CommentsPost a Comment | References1 Reference

mybrainhurts.jpgI have just finished reading the MIT study on the relationship between different-shaped receptors in human respiratory cells and H5N1, and all I can offer is the Monty Python rejoinder:

"My brain hurts!  My brain hurts......"

But here we go, anyway.  I will put this as simply as I can.  First, some background: We take as gospel the prevailing theory that all influenza A viruses originated within the intestinal tracts of wild birds, and are carried by migratory wildfowl.  It is theorized that influenza A started attacking humans back when the Chinese domesticated ducks a few thousand years ago.  You know, the old "Poultry, pigs and people" mantra.  We also know for certain that the cell receptor of wild bird intestines is of the type scientists call alpha 2-3.  The shape is somewhat elongated, like a cone. A cell receptor is a kind of landing strip for viruses.  The conventional description used in most media reports is a lock.  Whatever the metaphor, it involves joining the host cell with the invading cell. 

By the way, the same basic alpha 2-3 receptor is also found in the lungs of humans.  Most cases of H5N1 infection were attributed (very accurately, as it turns out) that the virus had a love-in with those alpha 2-3 receptors and the virus settled deep in the lungs of people, which also explains why the antiviral inhalant Relenza is basically worthless against the current strains of H5N1, except possibly as a precautionary measure.  The medicine cannot penetrate the crap in victims' lungs to get the antiviral medicine down there.  So swallowing Tamiflu is better than trying to inhale Relenza.

Somewhere along the way, influenza A viruses of the subtype H1, H2 and H3 grew away from this alpha 2-3 receptor and their hemagglutinin began to favor the alpha 2-6 receptors of human nasal passages and throats.  The theory was that as the virus mutated to infect people more easily, this had to do with a simple change that would make the 2-3 receptor less appealing and the 2-6 receptor more enticing, especially since it was so much easier to transmit via the nose and throat than the lungs. 

lee%20corso.jpgBut as Lee Corso would say, "Not so fast, my friend!"  An intrepid bunch of researchers at MIT have found something a little more sophisticated than all that.  You see, the conventional theory has failed a few times in previous years.  We all know that ferrets mimic the nasal and throat capabilities of humans, so ferrets are used routinely in experiments.  We also have read about tests where high-path flu has killed humans, but ferrets keep plugging along.  Indeed, the study references this in the first page, talking about the maddening experiments where some highly pathogenic influenza A viruses -- including derivatives of the 1918 pandemic strain -- would infect some ferrets, while other subtypes known to be deadly to humans would do nothing to the fuzzy little creatures.

ferret.jpgMay I also remind everyone that the CDC's own attempts to create a pandemic H5N1 virus failed to produce infection in ferrets.  Therefore, the CDC proclaimed, it was going to be much, much harder to produce a reassortant H5N1.  As a reminder, here is the link to the CDC report (which the new report also references):  http://www.pnas.org/cgi/content/abstract/0605134103v1 .

Now, MIT has given us an important road map to analyze the pandemic potential of any avian flu.  It is not as cut-and-dried to say the virus needs to adapt to alpha 2-6 receptors.  You see, H5N1 has apparently always had the ability to infect those upper tract tissues!  That, according to the MIT study, has more to do with the viral load than any other single factor.  MIT says that there are actually two different types of alpha 2-6 receptors in humans: those little cone-shaped doobers, plus some that are umbrella-shaped ( I think they look more like a mushroom cap, but what do I know?). 

The key to human-to-human sustained transmissibility is therefore NOT a simple matter of moving from alpha 2-3 to alpha 2-6.  It is the move from cone-shaped 2-6 to umbrella-shaped 2-6 receptors.  So if the virus can, indeed, infect humans via the nose and throat cone-shaped alpha 2-6 receptors, we can attribute that to an overwhelmingly devastating whiff of the virus.  A huge viral load. 

But if H5N1 is to really, really cause a mess, it has to change its affinity from cones to umbrellas/mushrooms.  And that, says MIT, is what people need to look for now:  A change in geometry, not simply an amino acid change.  So we need to think in three dimensions, not two. 

To paraphrase my buddy Shakespeare (why I return to Hamlet is unknown to me): Aye, there's the rub: The samples the scientists used were from 1997 and 2004, respectively.  They then data-mined the results against other H5N1 substrains.  Nowhere in the report does it indicate they matched this against data on Qinghai or Fujian strains of H5N1, nor Clade 2.1 Indonesian H5N1.  maybe they did and maybe they didn't.  That, apparently, is for the world's scientists to get busy with.

A good place to start looking for that new alpha 2-6 umbrella affinity would be China.  The WHO has admitted that human-to-human transmission was probably responsible for the hospitalization of a father, whose son died of confirmed H5N1 last month. 

Man in China got bird flu from contact with infected son: officials

BEIJING (AFP) — A man in China contracted bird flu because he was in close contact with his infected son, although the virus had not mutated into a form that is highly contagious among humans, authorities said Thursday.

A 52-year-old man, identified only by his surname Lu, was hospitalised with the potentially deadly H5N1 strain of the virus soon after his son died from it on December 2. Lu has since recovered.

Chinese health ministry spokesman Mao Qunan said Lu's infection was due to close contact with his son, but that the transmission was not technically "human-to-human".

"It has no biological features for human-to-human transmission," he told journalists.

Like many human cases of bird flu in China, authorities have not been able to identify the source as neither Lu nor his son had close contact with sick or dead poultry prior to infection, he said.

He refused to elaborate on the findings, which was reached by the ministry's expert group on bird flu.

Human-to-human transmission of bird flu remains rare, but experts fear such routes of infection could cause a global pandemic if the virus mutates with each person it infects and becomes more adaptable to humans.

The World Health Organisation (WHO) said Thursday that human-to-human transmission of bird flu in the case of Lu was possible but said it had not mutated into a highly contagious form.

"A human-to-human transmission through close contact between the son and the father cannot be ruled out in this family cluster," Hans Troedsson, the WHO representative in China, told AFP. (bold mine)

"However, the biological findings at this stage show that the virus has not mutated to a form that can be transmitted from human to human efficiently."

Bird flu has so far infected at least 27 people in China, 17 of whom have died.


Maybe, in light of this discovery, CDC should reassess the success or failure of its own experiments.  And authorities need to be very careful about making proclamations that the virus has not yet mutated, unless the samples meet this new "umbrella" test.  Now how easy or hard is it to conduct this test?  I leave that for others to answer.  My brain hurts too much for me to start looking again.


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    We were also repeatedly warned that if H5N1 reassorted with human flu, the combination would pack together the alleged severity of the bird virus and the infectiousness of the human one. Yet a 2006 Centers for Disease Control and Prevention study found the opposite: that a genetically engineered reassortment given to ...

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