The following extract is from the December 2006 Journal of General Virology
Recent H5N1 avian Influenza A virus increases rapidly in virulence to mice after a single passage in mice
Masaji Mase, Nobuhiko Tanimura, Tadao Imada, Masatoshi Okamatsu, Kenji Tsukamoto and Shigeo Yamaguchi
Department of Infectious Diseases, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-0856, Japan
To evaluate the potential pathogenicity to mammals of the recent H5N1 avian Influenza A virus, viruses recovered from dead mice infected with A/chicken/Yamaguchi/7/2004 isolated in Japan were examined. All recovered viruses from the brains of dead mice infected with this strain (without any prior adaptation to mice) had substituted the amino acid at position 627 of the PB2 protein from glutamic acid to lysine. Their mouse lethality had increased by approximately 5x104 times over that of the original virus. Histopathological analysis reinforced the finding that these variants caused more rapid and severe damage to mice than the original virus. This revealed that it might be useful to characterize the recovered virus to assess its potential pathogenicity to mammals.
While I was fully aware that an influenza virus artificially passed from one mouse to another (via injection of infected blood ) can GREATLY increase virulence, in fact, potentially producing a monster of unthinkable lethality, I never really worried about it too much because it was an artificial process, non-reproducible by nature.
This paper deals with the virus drawn out of the brain of an H5N1 infected mouse (an artificial process) grown in the lab, (an artificial process) and then the harvested H5N1 was used to infect other mice via their nasal passages (inoculated intranasally), a natural portal of virus introduction in the wild.
What the paper shows is that in this instance a strain of H5N1 with no known mammalian adaptations acquired the amino acid substitution from glutamic acid (Glu) to lysine (Lys) at position 627 of the PB2 gene when it reproduced in the original mouse. This substitution made the virus 50,000 times more lethal, which is what 5x10 raised to the fourth power is (unless my math has failed me.) on the FIRST PASSAGE.
Now granted, the Japanese H5N1 virus is of the V genotype and therefor it is a much less lethal than the Z genotype (Quinhai strain), so there is some cushion, BUT NOT 50,000 TIMES worth of cushion.
The V genotype is much less virulent in humans, causing a CFR of approximately 30%, whereas the Z type sits at roughly 69%.
In this experiment the systemic damage was significant throughout the bodies of the mice.
The truncus sympathicus ganglion (the sympathetic trunk) showed intermediate to severe lesions.
The sympathetic trunk (sympathetic chain, gangliated cord) is a bundle of nerve fibers that runs from the base of the skull to the coccyx. There are two sympathetic trunks in the body, a right one and a left one. (From Wikipedia)
Cerebrum, Brainstem and Thoracic spinal cord showed mild to intermediate lesions.
So, not only do we have to worry about pneumonia and ARDS we may have to worry about significant cerebral and neurological damage as well. And not just from the Z type but it seems also from the more mundane (relatively speaking of course) V type. My personal assumption....no matter what strain we face, this may be a trick hidden in its hat.
Don't know about all y'all but this little tidbit truly and deeply frightened me. Until I read this paper it seemed like some nebulous, theoretical threat, now the potential seems very real and not especially remote or theoretical.
The virus was found in the Brain Lungs Spleen Liver and Kidneys of the mice infected with the variant H5N1.
So, again, we are looking at the popularly viewed more benign version of H5N1, the V genotype, attacking the entire body. Not cytokine damage brought on by an over active immune system, but a direct onslaught, throughout major organs.
It's kinda hard to live without a liver or kidneys.
Again...IF someone is lucky enough to survive are they really gonna be lucky?
The paper closed with this line:
Urgent measures to deal with a possible pandemic, such as the development and application of effective vaccines and the stockpiling of anti-influenza drugs, are needed.
Seems I may not be the only one who had their world rocked.
The mouse is used for several reasons. They are small and cheap, and breed prolifically. They can be easily designed to specific testing needs, eat little and don't engender much public sympathy.
Mice were used in this experiment for all of the above I'm sure, but also because it has proven to be an immensely useful model for how influenza behaves in humans, at least with H1N1, H2N2 and H3N2, so it is assumed that it will provide a reasonable model for human infection of H5N1 as well. Probably a pretty safe assumption.
The lysine substitution allowed for far greater viral replication throughout the body, wielding damage from measurable to significant. This substitution already has a wide geographic distribution thanks to the Z genotype, (the Quinhai strain).
As far as is known, human H1N1, H2N2 and H3N2 have a lysine at 627 of PB2 (thanks to Dr Niman, this is fairly common Flubie knowledge.) To me this says that this frightful adaptation is pretty much a given if H5N1 becomes a human transmissible virus.
So, it all boils down to the possibility that instead of H5N1 having to acquire a myriad number of mutations, in just the right places, and in just the right host, in just the right location, at just the right time (reasonably thought to be rather astronomically high odds) to be just about as bad as it could be, it only takes this Lysine substitution. A substitution that appears to be common once the virus infects a mammal. Now, we just have to sit back to see if it acquires the transmission trick as well. Perhaps we will get lucky there and find out that that particular trick is as intricate a combination of amino acids, hosts, location and timing as I thought the nightmare virus was.