Posted on 04/23/2008 1:16:55 PM PDT by blam
What horses can tell us now about the coming human flu pandemic
April 23, 2008
A computer-generated three-dimensional model of the molecular structure of the H7 influenza virus coat protein (hemagglutinin or HA, for short), the molecule responsible for enabling the influenza virus to recognize the host's cell and invade it.
Stored safely in a freezer at Cornell's James A. Baker Institute for Animal Health are samples of the virus thought to be most like the one public health experts expect someday to afflict record numbers of the world's population. The virus was collected in 1973 during an outbreak of equine influenza at a Florida racetrack. Dorothy Holmes, an infectious disease specialist in Cornell's College of Veterinary Medicine, had obtained samples of the virus with the intention of using it to create nasal spray vaccines for horses.
Now, 35 years later, Cornell scientists have the rare chance to study the behavior of the organism to figure out why this particular virus, an H7 serotype, outperforms all other serotypes in its lethal powers. The study is supported by a seven-year, $3 million award from the National Institutes of Health.
"Influenza H7 is unique in its capability to invade not only the lungs but other parts of the host's body, including the brain, and this is why it's so dangerous," explains Gary Whittaker, an associate professor of virology who leads the project.
All the action takes place where the virus enters the host's cells. To study what goes on there, Whittaker, a specialist in the entry mechanisms of viruses, has assembled a team of experts and computational resources from across campus. They include Daniel Ripoll, a senior research associate with the Computational Biology Service Unit at Cornell, who has created a computer-generated 3-D model of the molecular structure of the H7 influenza virus coat protein (hemagglutinin or HA, for short). This is the molecule responsible for enabling the influenza virus to recognize a cell and invade it.
"With this model we can look inside the structure of the virus and make a really good prediction of what's going on," Whittaker explains. "Without it we'd be shooting completely in the dark."
In preliminary studies, funded by Harry M. Zweig Memorial Fund for Equine Research, Whittaker found a surprising stretch of amino acids, the molecules that are the building blocks of a protein (tinted pink in illustration).
"That stretch fascinates me," Whittaker says. "No other influenza ever in any species has this sequence apart from equine H7 virus."
It's the exposure of this sequence that Whittaker believes controls the virus's ability to invade the tissues of many regions of the body rather than just the lungs, as do the currently circulating equine influenza (H3) and human influenza (H1 and H3).
Structural biologist and co-investigator Brian Crane, an associate professor of chemistry and chemical biology, is focusing on the static structure of HA. It is known that when viruses enter cells they undergo a change in their structure. Collaborator Lois Pollack, an associate professor of applied and engineering physics, is interested in the dynamics of this change -- how the protein undergoes a change in shape and structure when entering the cell. Susan Daniel, an assistant professor of chemical and biomolecular engineering and an expert in using solid-supported lipid bilayers as mimics of cell membranes, is looking at what happens next, when the virus enters the host's cell and contacts the plasma membrane of the cell (which is a lipid).
"With this highly talented group of people, we can go deeper and deeper into the mechanism of how the virus recognizes the cell and undergoes its conformational change, right through to when it fuses with the lipids," Whittaker explains.
There is another equally compelling reason to study the activity of surface proteins of the equine influenza virus.
"Mutations occurring at the entry site are very often what allow host switching; that is, the virus's ability to jump from one species to another -- say from birds to horses or from birds to people," Whittaker points out.
The H7 serotype -- the first documented equine influenza virus -- was isolated from an equine outbreak in Czechoslovakia in 1956 that spread around the world. Subsequently it was shown that the virus was a very highly pathogenic H7 virus in chickens and other birds that had moved into horses. Now H7 is prevalent in birds, a fact that gives public health officials great concern.
Whittaker thinks there's a significant probability that the characteristics of H7 (which has never been studied in any kind of molecular detail before) as it infected horses in the 1950s would be similar to the characteristics of virus behavior when the next virus pandemic occurs in horses and in humans.
"The horse," Whittaker says, "can give incredibly valuable information for our global understanding of influenza."
The investigators also plan to study the serotype of the virus that caused the 1918 flu pandemic and today's avian influenza serotypes to try to figure out what distinguishes those from flu viruses now circulating in the human population.
"We've shown that there's clearly an obvious difference between equine and avian viruses, but those between the human and avian viruses are more subtle, so we're going to have to do more work to find out what's going on there," Whittaker explains.
Source: Cornell University
Boo!
But, but, they used horses for testing.
Yes and no. The Spanish flu was H1N1. And while it was murderously lethal, it still only reproduced in the UR tract and sinuses.
However, the H7 equine *and* H5, of the now menacing Avian flu, have both been found reproducing in internal organs. This is very bad.
The real world difference might be seen in mortality rates. As vicious as the Spanish flu was, it only killed about 18% of those who were infected. So far, H5N1 has mysteriously maintained an over 60% mortality.
With an effective Human to Human transmission, the world is facing mortality numbers not expected outside of a nuclear war. Concentrated mostly in Asia, 300m fatalities may be a good starting estimate.
lol! Beat me to it.
One Flu Over the Coo-Coo’s Nest
Horses originally evolved in the Americas, crossed the land bridge to Asia, and thrived. Somewhere along the line, every horse in the Americas died. I don’t think the cause was hunting to extinction. Lethal bugs could be a major factor in evolution and species extinction. The biggest threat to civilization is not terrorist nukes but bio gone wrong...either human-created in the lab or by natural means.
btt
Bioweapons have strict limitations. Influenza is the biggest bio threat around. Nothing else comes close. Every other bio agent falls by the wayside for several reasons:
1) Must be pulmonary, spread by cough and sneezing. And must cause coughing and sneezing. Must exist in quantity in the upper respiratory tract and sinuses.
2) Must mutate frequently to avoid both immunity and declining mortality.
3) Must have significant animal vectors.
4) Must have an incubation period between 4-21 days.
5) Must not incapacitate or show symptoms during much of incubation period.
No other virus or bacteria can match influenza. The closest is the common cold, though far from typically lethal. It does so because there are seven major different pathogens that can cause colds, and one of them has over 100 variations. They have to all gang up, just to match the infection capability of influenza.
Yikes! I’m still watching H5N1.
Now an H7?
*cue ‘Jaws’ theme*
H7 is not currently a threat to humans. But it has an amazing mechanism, so that if it did, it could really become a “Satan Bug”. H5 has something like it that makes it extra lethal, but it is far less complex than H7.
So if we can figure out H7, we will be well on the way to figuring out H5. It’s a lot safer to mess with H7, because there is little danger of it escaping and attacking humans.
In case you are interested, there are at least 16 known variants of “H” and 137 known variants of “N”. Simply put, the “H” factor is how viruses get into cells, and the “N” factor is how they get out again, so they can infect other cells.
The first three “H” types (H1, H2, H3) and H5, which is new, are found in humans. N1, N2, N3, and N7 are the known human “N” types, but only N1 and N2 have ever caused epidemics.
To make matters more complicated, Influenzas are also subdivided into types. Type A flus affect birds, humans and some mammals, especially pigs. It is the type of flu that mutates most frequently. Type B flus affect humans and, of all things, seals. It mutates more slowly. Then there are Type C flus, that only mutate rarely and generally are very mild.
When vaccines are prepared each year, it is based on the estimate of the two most likely A type flus, and the most likely B type flu. And yes, it is guessing. But importantly, even if they don’t guess the exact strain, the vaccine can sometimes lend partial protection. This means that it makes it harder to get infected, less severe, and that your immune system responds faster.
But within a flu type and strain, there is still a LOT of room left for variation. Influenza has an incredible number of what are called “flexible” genes, that are unstable and very prone to mutation.
To put this in perspective, Vietnam’s chief epidemiologist discovered a herd of swine, each of whom had about five distinct subtypes of the same strain of flu in them, fighting it out in “quarterfinals”, with one subtype emerging as the “best” flu in that pig. At the same time they were fighting with each other, they were also fighting against the pig’s immune system, the “super heavyweight fighter.”
Then their champion would fight with other pigs champion subtype, in “semifinals”, until the grand champion flu strain had defeated all challengers and become the winning strain, infecting all the pigs in the herd.
He noted that it was like a computer algorithm, and that countless other herds of mammals and flocks of birds were doing the same “computation”, to develop the best, all-around strain of influenza.
For this reason, when classifying strain subtypes of flus, they try to establish the lineage of the flu, what flu it is descended from. They also list where it was found, in what animal it was found, a number assigned to it as a unique classification, and sometimes whether it is low pathogenic (LPAI), or high pathogenic (HPAI), which means how deadly it is.
So the full name of a flu might be:
A/Burbank/Chicken/207/2004(H3N2)(LPAI). Type A, found in Burbank in a chicken, the 207th known subtype, in 2004, of the type H3N2, low pathogenic.
Thanks for the exposition, I appreciate it since I’ve followed and been concerned by H5N1 for some time.
Some of that info I knew, much of it was new to me, again, I thank you.
And something for the back to nature folks to consider as well.
Hopefully, understanding the ability of the virus to invade cells will lead to countermeasuers which will be effective for horse and human alike...and yes, even the folks who seem like the stern of the aforementioned critters.
Ping...
Wow! I've never even heard of that 'plague.' Thanks.
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