Final Adaptation of H5N1 to Humans - Role of Mammalian Reservoirs
I have argued previously that H5N1 is evolving towards a pandemic strain. There was good discussion on that thread which revolved around the idea of selection. How could H5N1 being getting any closer to a human-adapted strain without being under positive selection? I argued that it was showing unmistakable signs of positive selection but could not, at that time, provide a good explanation for how H5N1 could be under positive selection for adaptation to humans while spending most of it’s time in birds. Each time the virus infected a human, it would have to start from scratch to adapt to humans. Hence, we should be no closer to a pandemic strain now than we were in 1997. Yet, larger and more frequent clusters and the recent finding of high viral loads in the nose and throat of members of the large Karo cluster clearly argue for adaptation to humans. Further, I believe that proper analysis of the clusters demonstrates that H5N1 spreads human-to-human more efficiently that it does bird-to-human. How can this be?
I believe the answer to this conundrum is a mammalian reservoir. There have been reports of H5N1 infections of numerous species of mammals. Further, there have been reports that H5N1 isolated from cats is more similar to H5N1 isolated from birds. This points strongly to the possibility of a mammalian reservoir. This is highly significant because if such reservoirs exist, H5N1 would be under positive selection to adapt to humans because humans share important biological characteristics with our fellow mammals that we do not share with birds. For example, the polymerase gene, which is important for replication of the virus, is temperature sensitive. The version which works well with birds, which have a higher body temperature than mammals, does not work as well in mammals. In order for polymerase gene to cause serious disease in humans, it must acquire changes that permit it to replicate at mammalian temperatures. There is recent evidence that it has done so. Circulation in a mammalian reservoir would provide positive selection for this trait to emerge.
Another important trait is hemagluttin binding. There are specific receptors in the upper respiratory tract of humans that are different than those found in birds. One of the steps for the evolution of a pandemic strain is spread of the virus via respiratory droplets. It is thought that acquisition of changes in the hemagluttin gene are necessary for this to occur. There is evidence that some of these changes have already been acquired. Pigs contain appropriate receptors in their trachea. H5N1 virus present in pigs is under positive selection to acquire these changes. There have been numerous reports of H5N1 infected pigs, although very little has been published recently.
Is a pandemic strain now inevitable? Mammalian reservoirs may make the answer to this question - yes. Pigs are often referred to as potential “mixing vessels” because they can host both bird and human flu viruses. This could permit reassortment. However, there is another potential role for these animals in the evolution of H5N1. Because they contain the human type sugars in their trachea, H5N1 hemagluttin is under selection to acquire the necessary changes to adapt to binding to these sugars. Ominously, other avian influenza viruses have been shown to undergo this change over a period of time in pigs.
Bottom-line, I think it’s possible that there is a mammalian reservoir for H5N1 and that this virus is under positive selection to adapt to humans in this species. If this correct, then it’s only a matter of time before a pandemic strain emerges. Perhaps not very much time given it’s recent behaviour.
References
Molecular Basis for the Generation in Pigs of Influenza A Viruses with Pandemic Potential
Indonesian pigs have avian flu virus
Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus
Hi Monotreme. As you know, I am more of a phentoypic expression later looking for a genetic explanation kind of guy.
I have never been a proponent of positive selective pushing adaption within a host. There is a chemical theory, that I am too far removed from to remember the name, that states the more molecules you have in a fixed volume, the greater probability of chemical interaction.
I kind of think of it as a door with a hole in it…on one side chickens, on the other humans. If random mutations are by definition random, then they could favour humans just as easily as birds…in a sense once the mutation potential (geographic spread, numbers domestic poultry) reaches a threshold…then a mutation will find the hole and cross species.
I think the reason we are seeing an unprecedented amount of diseases crossing species barriers is more to do to with animal and human populations producing the volume of random mutations that find the hole in the door. These mutations must be passing both ways at an equal rate.
Once the virus crosses the barrier then selecive adaption can occur, I would assume at a faster rate until a pandemic results.
Just one other thing to throw at you. Are you sure that there are not more simiarities between birds and humans than one might think?
Mammalian reservoirs would certainly be an advantage and could be the reason but most times, these things are multi-factoral.
I am looking forward to another interesting discussion.
Good to read such inteligent post.
Monotreme: You are an invaluable resource (and fluwikie friend) for this site. The articles were sequentially illuminating. : )
How is it that the “seeming” percentage of infected pigs has increased when you compare Viet Nam and Indonesia? Is it still just b2p going on in Indonesia as it seemed to be in Viet Nam? And that the percentage infected is more in Indonesia because there is just more H5N1 to be exposed to via bird sources? Or is it starting to be passed from pig to pig? But if H5N1 started being passed from p2p, wouldn’t virtually all of them be infected?
I’ve been worried for a long time that the enormous fowl culling totals might be serving to inadvertently select for the mutation conferring binding ability at the lower temperature, mammalian receptor site. Does this factor in at all or are the relative numbers miniscule? Wasn’t there a strain that was “ambidextrous” and had the ability to utilize either the alpha −2,3 or the alph-2,6 receptor or did I get that all garbled up?
Monotreme -
I am going to reiterate what I think you’re saying just to make sure I’m not misunderstanding you. Are you hypothesizing that H5N1 has established itself in some swine populations and that within those populations is selective pressure for more efficient H2H spread?
Interesting. (And I mean that in a genuine way, not in a sarcastic way).
Pigs are terribly efficient virus producers with some diseases (notably foot and mouth – they’re considered the “amplifier” species for this disease), so I guess its possible that they could be churning out vast quantities of H5N1 and shedding it asymptomatically. But – if it is pathogenic strains that they’re hosting – why are they asymptomatic? Swine flu is not uncommon and while the clinical signs aren’t pathognomonic, you can usually make a safe guess based on its rapid onset and resolution.
Also, wouldn’t we expect to have a seen a cluster as a result of swine but not bird exposure?
Finally – I just wanted to clarify your statement that “Because they contain the human type sugars in their trachea, H5N1 hemagluttin is under selection to acquire the necessary changes to adapt to binding to these sugars.” Swine have receptors that mimic both the receptors found in human tracheas and in bird GI tracts. Infection of swine tracheal cells with AIV is not going to put pressure on the virus to adapt to the human-type receptors – if the cell is also co-infected with a human influenza virus, then reassortment could potentially occur resulting in the virus being able to bind to human-type receptors, but that would be due to chance and wouldn’t be the result of selection pressure.
Here’s a good article off Effect Measure - http://tinyurl.com/mlonk , discussing how humans actually have some of the bird-type receptors in our trachea. Good food for thought.
My hypotheses on why we’re seeing larger and more frequent clusters? Totally don’t have one yet. So keep up with the brainstorming. It’s good.
As for the increase in size of the clusters, I’d be tempted to invoke Gould’s “left wall hypothesis” — it may simply be that what we are seeing are clusters of essentially random size, variation occurring in the only direction available.
As for the increase in frequency of clusters, I propose a thought experiment. We might try to predict what would happen if the virus were not mutating, but spreading at an increasing rate among avian populations. As more and more birds were infected, the likelihood of humans becoming infected would increase, and we’d see more frequent clusters.
In previous discussions, I’ve taken the position that positive selection for human receptors (etc) on virions infecting avian hosts is a logical contradiction, and I’m still sticking with that. The infection of a human patient begins with great misfortune for every single virion which thereby finds itself outside its natural range, and while the selective pressure to adapt to the new environment is strong, and the opportunity to exploit a vast new range is tremendous, it is a limited-time offer, good only until the host either dies or aquires immunity.
However.
I also still feel that the strong bias toward blood relatives in the distribution of cases within clusters suggests that the virus is “exploring” little pockets of genetic susceptibility in human populations. A lot depends on whether such clusters truly do represent H2H2H transmission. If so, then when the virus enters such a pocket, it gets an extension on the time limit; it now has until the last susceptible host in the cluster either dies or aquires immunity. If somewhere in the world there exist very large pockets of genetic susceptibility, these would provide the virus with the ideal reservoirs in which to adapt to humans.
If somewhere in the world there exist very large pockets of genetic susceptibility, these would provide the virus with the ideal reservoirs in which to adapt to humans.
Racter - you mean perhaps a village where all are cousins (susceptibility-wise)?
Interesting.
And if it’s pigs then would that mean reassortment and not drift, hence a milder but faster-to-start pandemic?
Yes. In small isolated populations this would hardly be surprising.
Not necessarily, but the possibility of a reassortment (or perhaps recombination) event is what virolgists are so worried about, regardless of what species acts as the “mixing vessel”.
Reassortment/recombination could certainly result in sudden eruption of a pandemic, but there doesn’t seem to be much basis for the assumption that it would be milder.
Hi everyone. This is a tough issue, hard to break it down into small bites…the usual way to solve a problem.
First of all, many of the questions could be answered if we had full disclosure of relevant information directed by the WHO…but that isn’t going to happen.
The question whether the clusters are due to genetic susceptibility or not could be answered quite easily by breaking down those involved…but that isn’t going to happen either.
So as before in the other threads we have to ‘witch’ the answers to these complex problems, and to do that we must use what little data we have avaliable to us.
Probably, the answers to all these questions is in the 1918 virus. We know that there is no immunity to pandemic strains, and we know that the death rate was pretty consistent across the world…there was no genetically immune race or subculture in 1918. In fact, pockets were highly susceptible (Canadian Native Communities) but we cannot know whether that was genetic or a more virulent strain of virus.
Last fall for the first time (hard to believe) it was found for the first time that H1N1 jumped directly from birds to humans without the previously thought intermediary step in pigs etc….
…so the question becomes…do we believe that evolution occurs in small orderly steps or can it occur in leaps…and is H1N1 (1918)a step or a leap…I believe it may demonstrate characteristics of a leap…certainly the jump in virulence and transmissibility between the first and second wave would be characterized as a leap.
Secondly, is evolution and adaption possible without presence in a tertiary species and how much faster will a virus evolve when it becomes entrenched in the tertiary species. I don’t know exactly why, but I kind of think that there are a lot less differences between species then we probably think…
…viral adaption probably occurs faster within a species but it must also work pretty well completely be random. SARS too me, looked like a leap rather than steady progression in adaption…
…now if we go to the multi-species discussion, is that in itself not an indication of how adaptable this virus is. There are definitely more similarities between man and other mammals then between birds and man…
…I guess in conclusion I see the potential for leaps in evolution and successful random mutations to this point and rapid evolution within our species from here on out…but it’s just intuition.
Specifically on the question of genetic predisposition or susceptibility producing the results we are seeing. In my field experience, it always seemed that if it appeared to be obvious, it never turned out to be true…
…the way to handle situations like this is to ignore the obvious and lay out all other possible explanations…if they are ruled out then you can really bring your focus back to try and prove the genetic link…without the inside information, I don’t think its genetic but explainable by 1) a specific viral mutation increasing transmissibility and 2) intermediate stage of transmissibility producing a short window of infectivity so that the only persons around you at this stage before going to the hospital, are family members.
This then demonstrates a significant leap in evolution and adaption.
They’ve isolated H1N1 from preserved birds, as well as the human samples. Do they show a step or a leap between the two?
anonymous. Good point. I keep coming back to Dr. Osterholms comment…that H1N1(1918) and H5N1(2006) are ‘kissing cousins’. Therefore, if there is an indication through historical records that H1N1 leaped then we could assume the potential was there for H5N1 as well.
One thing to remember was previous to 1997, high pathogenic influenza’s had never been identified crossing the species barrier…so one could say that the outbreak in 1997 was a great leap if you were an influenza virus.
Sorry, last line should have read…so one could say that the outbreak in 1997 was a great leap forward if you were an influenza virus.
Apologies to all for posting and running, but you’all have done fine without me :-)
I’ll start working my way down the thread.
Hi Tom DVM,
If I understand your post at 10:42, you’re endorsing the “casino” theory, which states that given enough chances an event, no matter how rare, will eventually happen. In the case the “payoff” is a pandemic strain of H5N1 that appears in chickens by chance.
I used to subscribe to that one myself, but don’t buy it anymore. It’s hard to prove, but I see signs of selection in the behaviour of the virus. One small piece of proof of this is the fact that H5N1 sequences isolated from cats in Indonesia have polymorphisms that are not found H5N1 viruses isolated from birds but which have been found in H5N1 viruses isolated from humans. This fact supports the idea of selection occuring in mammals independently of what is ocurring in birds. Of course, we only know about this because Andrew Jeremijenko told the press, and revere, about it.
My hunch is that if there were serious efforts at surveillance in pigs and other mammals, and the sequences of isolated H5N1 viruses were made public, there would be more support for my hypothesis. Absent that, I only have a few shreds of data and gut feeling to support my interpretation of what’s going on.
I haven’t put much thought into the genetic predisposition since I’m not a scientist but now I am wondering…from what I have heard from the 1918 virus, it seems that small villages were more prone to be wiped out. I was thinking it must have been because of racial susceptability, Eskimos, New Zealand natives, South Sea Islanders, but since that was prevelant in small villages, maybe the cousin factor does come into play. We used to live in a small town where the majority had double cousins everywhere. Something for you people to explore maybe.
Monotreme Actually, I am probably talking about a virus that gets part way up the evolution hill by chance and then goes the rest of the way with a bad combination of both…each pushing at the same time.
corn and Medical Maven, thanks.
I think pig-to-pig spread is definitely possible, but not necessarily via respiratory droplets. I’d being willing to bet quite a bit that H5N1 spreads fecal-oral in mammals, right now. Pigs being pigs, well, lots of spread via this route wouldn’t be too surprising. I also think there is a new strain of H5N1 which we first saw in Turkey that is causing the large clusters in humans. It may also be associated with more mammal-to-mammal spread.
Monotreme. That initial jump in 1997, was about as big a leap as occurs in disease in nature (if in fact no high pathogenic subtype had ever jumped)…
…Did this occur by chance? and if it did, does this indicate that H5N1(maybe like H1N1) has a specific genetic predisposition to very effectively mutate randomly…
…in other words, do viruses have genetic predispositons in the same way as birds, humans and other animals…
…this brings us to some of Clark’s points about viruses historically.
SaskyDVM – at 11:35
Are you hypothesizing that H5N1 has established itself in some swine populations and that within those populations is selective pressure for more efficient H2H spread?
Yes.
But – if it is pathogenic strains that they’re hosting – why are they asymptomatic?
Can’t answer that one. However, I do suspect that pig deaths might be hidden. And surveillance in Indonesia is not the best.
Swine have receptors that mimic both the receptors found in human tracheas and in bird GI tracts. Infection of swine tracheal cells with AIV is not going to put pressure on the virus to adapt to the human-type receptors – if the cell is also co-infected with a human influenza virus, then reassortment could potentially occur resulting in the virus being able to bind to human-type receptors, but that would be due to chance and wouldn’t be the result of selection pressure.
Have to disagree on this one. From the paper I cited above:
“Cell surface receptors for both human and avian influenza viruses were identified in the pig trachea, providing a milieu conducive to viral replication and genetic reassortment. Surprisingly, with continued replication, some avian-like swine viruses acquired the ability to recognize human virus receptors, raising the possibility of their direct transmission to human populations.”
and
“Surprisingly, the avian-like swine viruses showed a shift in receptor specificity over time. Viruses isolated from European pigs up to 1984 recognized both sialic acid-galactose linkages, whereas those isolated after 1985 recognized only NeuA cα2,6Gal (Table 1). A/Swine/Netherlands/12/85 recognized NeuAcα2,6Gal-containing erythrocytes appreciably less efficiently than those with native linkages, for unknown reasons. Nonetheless, the shift in receptor specificity suggests a mechanism that would allow avian viruses to replicate in humans efficiently.”
Reassortment is emphasized when pigs are discussed, but its clearly possible for avian flu viruses to adapt to pigs and acquire an affinity for α2,6Gal as well.
Tom DVM – at 21:46 ‘’That initial jump in 1997, was about as big a leap as occurs in disease in nature (if in fact no high pathogenic subtype had ever jumped)…
…Did this occur by chance? and if it did, does this indicate that H5N1(maybe like H1N1) has a specific genetic predisposition to very effectively mutate randomly… ‘’
Tom, I doubt the initial jump in 1997 was as big as it appears. I suspect there is alot of missing data that would show more gradual evolution if it was available.
I think the odd evolution of H5N1 is due to bad chicken vaccines in China which altered the selective pressures on a virus subtype that has been around for decades. This is what turned it into a killer, IMO.
Racter – at 14:11
As for the increase in size of the clusters, I’d be tempted to invoke Gould’s “left wall hypothesis” — it may simply be that what we are seeing are clusters of essentially random size, variation occurring in the only direction available.
There isn’t really enough data to exclude this hypothesis, but the sequence data regarding the changes in the polymerase gene in Turkey and Indonesia and the presence of high viral loads in the nose and throat of individuals from the Karo cluster suggests that changes in the virus are driving changes in cluster size.
In previous discussions, I’ve taken the position that positive selection for human receptors (etc) on virions infecting avian hosts is a logical contradiction, and I’m still sticking with that.
What, my first post on this thread didn’t convince you? ;-) Seriously, what is your objection to the idea H5N1 is evolving in a mammalian reseroir? Wouldn’t that address your concerns re: selection?
As regards genetic susceptibility, I have no doubt that this is a factor in H5N1 spread, morbidity and mortality as it is in other infectious diseases. All infectious disease depends on multiple factors including: viral genetics, viral mutation rate, host genetics, host ecology, host behaviour, host physiology, general health of the host, treatment of disease and more. Teasing out the contribution of each of these variables is quite difficult and has not yet been accomplished for any infectious disease that I am aware of. Like the issue of recombination, reassortment and mutation in viral evolution, it’s not a matter of choosing one mechanism from amongst the others, but rather, acknowledging that they all occur and trying to determine how much each contribute to the phenomemon we are observing - which will be very difficult if key data is witheld, hence my many rants on that subject.
Monotreme-
Cumulative and accelerative factors, all! Extremely cogent thinking and clear messaging.
As you’ve stated, each must be addressed and acknowledged to get the full picture. We have never taken a full circumspect view with any pathogen group/ human host group interaction.
Its about time that we started.
Interesting comments. Is it true that virologists do not take a multivariate approach to their field? If this is true, why is it so?
Monotreme: In a world where everyone knows their cholestrol level; and a few (usually military people) know their blood type, I’m beginning to believe there may be a bigger playground for genetic susceptibility that directly effects immune systems. Blood types get passed off as not important and even dismissed, but I’m not convinced. Do blood types predict genetic resistantance? Who knows-it must not be PC because try finding pure scientific data on it of recent study especially in regards to viral disease. Some past studies suggest there is some resistance passed genetically and let me add blood types are passed genetically too. We have only recently seen the first BP pill targeted to African Americans and there was a swarm of controversy around its clinical trials. I don’t understand why it’s not openly discussed or dismissed as a possibility with some good clinical data behind either conclusion. Maybe it could offer a solution to who should get any vaccine first. Maybe the vets can state whether animals of certain blood types are more susceptible to viral illness? Seperate out the pig blood lines, the canine blood lines etc and examine for blood type with strongest viral response, if any. Do vets check that and if not why not? I wish someone could check in with some strong data on this topic. I can’t find the info on it.
Another thought to tease out is people taking drugs, especially multiple drugs, that are detoxed in the liver creating a predetermined lowered level immune response due to the amount of drugs in their system. (The liver is the epicenter of immune response). And with our lowered immune systems we fall in love with exotic pets—like ferrets, or civet cats, and even pot-bellied pigs for crying out loud. I don’t know the general state of health of Indonesians but I know they live close to pets and I’ve never once heard the vet suggest since parasites are found in a house pet, maybe the human owner got infected too and might need treatment? My point is—I know we do it—I do it-but maybe it is really true humans weren’t meant to live with pets in the home, under the home or close to the home. Bottom line is living with pets probably sabotaged both immune systems.
Forgive the off topic…
“what is your objection to the idea H5N1 is evolving in a mammalian reseroir?”
I don’t have any objection to that idea in principle, but we don’t have the same evidence for the virus spreading among mammalian populations that we do for it spreading among avian populations.
“Wouldn’t that address your concerns re: selection?”
It would help, but again we may be looking only under the streetlamp for the lost car keys if we assume that receptor binding specificities are the whole story, or that “adapted to humans” and “adapted to mammals” may be regarded as functionally equivalent.
Your last post I agree with entirely.
apparantly H5N1 can spread between humans and it does it almost the same way how normal influenza or the common cold does. Just not very efficiently. Or quite some humans are just not suspectable to infection for some unknown reason, probably genetical. However it is, there doesn’t seem to be a big hurdle to overcome this. No “species barrier”. Maybe some other barrier, maybe not. We didn’t observe this in experiments. Almost all of the cats or tigers were infected -less alone chickens. Intensive,close contact wasn’t necessary. Remember the trials in 1918, where they desparately were trying to infect human “volunteers” in experiments with panflu ? They failed.
On the other hand there doesn’t seem to be a mass dying of cats, an epidemic in cats in Asia.
H5N1 is acquiring human signatures in Vietnam/Thailand clade 1 and in Qinghai strain.
The acquisitions are via recombination and H5N1 clearly knows what it is doing.
Correct link for clade 1
(1) : Human / Swine H5N1 Signatures
Recombinomics Commentary August 20, 2004
(2) : European Swine Signatures in H5N1 Bird Flu at Qinghai Lake
Recombinomics Commentary July 20, 2005
but I assume, these are just your theories, not confirmed or even mentioned
elsewhere ?!
For some time the Papau New Guinea highlands have been on my mind concerning pandemic flu. The reason is that it is quite isolated, pigs are the dominant farm animal, and finally, there are many, many isolated family groups/communities. As part of this thread discussion concerning a genetic propensity towards infection/transmission of pan flu within family groups I wanted to post these links. If I am not mistaken, if/when pan flu gets into the highland area of Papau New Guinea (and it might already be there) then the conditions for large numbers of inter-related people in close contact with pigs and poultry, located in a very remote and medically backward area will be met. I have watched Indonesia for some time with increasing concern, but I just can’t shake this feeling that the highlands of Papau New Guinea is where pan flu will find what it needs to explode into the pandemic we all fear.
U.S. Dept of State website
Papua New Guinea
The indigenous population of Papua New Guinea is one of the most heterogeneous in the world. Papua New Guinea has several thousand separate communities, most with only a few hundred people. Divided by language, customs, and tradition, some of these communities have engaged in low-scale tribal conflict with their neighbors for millennia. The advent of modern weapons and modern migration into urban areas has greatly magnified the impact of this lawlessness. The isolation created by the mountainous terrain is so great that some groups, until recently, were unaware of the existence of neighboring groups only a few kilometers away. The diversity, reflected in a folk saying, “For each village, a different culture,” is perhaps best shown in the local languages. Spoken mainly on the island of New Guinea—composed of Papua New Guinea and the Indonesian province of West Papua—some 800 of these languages have been identified; of these, only 350–450 are related. The remainder seem to be totally unrelated either to each other or to the other major groupings. Most native languages are spoken by a few hundred to a few thousand, although Enga, used in part of the highlands, is spoken by some 130,000 people. (However, the Enga are subdivided into clans that regularly conflict with each other.) Many native languages are extremely complex grammatically.
http://www.state.gov/r/pa/ei/bgn/2797.htm
See the following link describing agriculture in Papau New Guinea. Pigs are the dominant farm animal and poultry second.
http://www.fao.org/AG/AGP/agpc/doc/Counprof/southpacific/png.htm
Please click on the “Introduction” in the second link posted up above for a good summary of percentage of types of animals raised by families in Papau New Guinea.
That’s exactly the sort of thing I’m talking about, Okieman — of course, it swings both ways: for all we know, the typical Papau New Guinea highlands denizen might have a particularly low genetic susceptibility to the virus.
If genetic predisposition does play a strong role in determining whether an individual becomes infected with the virus (in its current form) then the sort of details addressed in the piece you just quoted may be of prime importance. (Marriage customs and incest taboos among those peoples might also be worth looking into). A group of people closely related enough to share genetic susceptibility factors could pass the virus among themselves, and while that was happening, positive selective for human receptors (or whatever) would be strong. It may be that this is what has taken place in the clusters we have already seen, but that each time, the virus has “run out of runway” before achieving adaptation to a wider range of human hosts. But as a group gets larger, the chances of all of its members being very closely related is reduced accordingly — which, to follow the metaphor, could create “potholes” in the “runway”; hence, there may be a “goldilocks” host group size for the virus.
NS1, thanks.
JoeW Is it true that virologists do not take a multivariate approach to their field?
No. They are aware of the varaibles and have been for a long time, but it’s hard to tease them apart. The tools for understanding the genetic basis for disease resistance have only become available very recently. The necessary studies are expensive, now, but are expected to become much cheaper in the near future.
Leo7, there’s no doubt that genetics plays a role in disease susceptibility and that different ethnic groups are statistically more likely to get certain diseases. This applies to infectious diseases as well. For example, Africans are much more likely to get sickle cell disease which is the result of having 2 defective copies of a gene. However, sickle cell trait, which involves having 1 defective copy of the same gene confers resistance to malaria. In areas where there is a high incidence of malaria, it is beneficial, on a population basis, to have mutations that causes sickle cell trait. Although individuals who have sickle cell disease will die, more of their siblings with sickle cell trait will live than members of a family without sickle cell disease or sickle cell trait because the death toll from malaria is so high. This is just one example of the complex interaction between infectious diseases and human genetics.
You can find a nice explanation of this here.
Racter at 01:54
…we don’t have the same evidence for the virus spreading among mammalian populations that we do for it spreading among avian populations.
Your “looking where the light is best” analogy applies here. How much surveillance is going on in mammals? How many sequences from H5N1 isolated from mammals have been deposited? There is reason to believe that this information is being actively suppressed.
Adaption to pigs may not be sufficient for efficient human-to-human spread, but I think it takes H5N1 much closer to this.
Racter – at 11:58
A group of people closely related enough to share genetic susceptibility factors could pass the virus among themselves, and while that was happening, positive selective for human receptors (or whatever) would be strong. It may be that this is what has taken place in the clusters we have already seen, but that each time, the virus has “run out of runway” before achieving adaptation to a wider range of human hosts. But as a group gets larger, the chances of all of its members being very closely related is reduced accordingly — which, to follow the metaphor, could create “potholes” in the “runway”; hence, there may be a “goldilocks” host group size for the virus.
I have been thinking exactly the same thing. Co-infection with another infectious agent that causes immune suppression, like HIV, might also give a poorly adapted strain a foothold for human adaptation.
How many types of flu can ther be at one time? Is it possible that in the future, there will be 10 to 20 different types of flu every season? Are we going to be sick all the time with one flu or another?
Watch Dog, very good question. Not counting H5N1, there are currently at least three subtypes of influenza that circulate in humans every year: two subytpes of influenza A: H3N2 (most infections) and H1N1 and some strain(s) influenza B. To further complicate things, each subtype of the influenza can be subdivided into strains. Worse, a vaccine made against one strain may not work against another strain. This is why it is so important to have access to sequence information, even for the “everyday” flu. If you pick the wrong strain to make your vaccine against, it may not work.
One of my nightmares is the emergence of multiple strains of H5N1.
Watch Dog, here is a paper that feeds my nightmare.
Pandemic Influenza: Risk of Multiple Introductions and the Need to Prepare for Them
WatchDog-
There are always hundreds of strains of influenza and every other pathogen that is genetically promiscuous. We only see the few strains that are prevalent enough to infect a large number of people because these wild strains then are observed in the medical response community.
We have reason to believe that the cumulative weakness of the human host and the increasing capability and number of emerging pathogens could point to a higher level of illness in the coming decades. However, we are probably looking at multiple types of pathogens, not 10 or 20 influenza strains at one time.
Monotreme/Racter/JoeW/Watchdog-
We are certainly looking at a multi-factorial problem and, to date, as Monotreme has mentioned, we only have a four-pronged spotlight and have forgotten to illuminate the proximal and distal mammalian reservoirs (personal and community animals).
We have compelling evidence in general that a modern farming family will share zoonotic pathogens with their farm animals, even when the animals are kept separately from the family.
The following comment is NS1 impersonating a diversionary agent that is so prevalent on FluWiki these past few days. This work of fiction is intended to entertain and inform us on the techniques of diversion.
Please do not chase this rabbit or follow the red herring in your scope for any time or distance. This space is intentionally left intellectually blank. In the case of a real emergency (in the truest sense), you will be instructed to SIP under your desk or in the hallway while the protective siren calls your peers to comply.
<Start of diversion>
Has anyone thought of how we can manufacture integrase enzyme on a mass scale?
If I’m right and we can get the help of some key players, we may have a solution to this whole H5N1 matter.
I’m thinking that if we can go ahead and discover a human gene that confers protection from H5N1 (I think that we are almost there), then all we need to do is get that simple gene transfer into the other 6.5 billion people. I’m told that all of the components are currently in place and just need to be assembled and sequenced properly.
One gene should be pretty straightforward.
If our current lab techniques are more geared toward smaller experiments and productions, we just need to put our heads together and become more efficient.
I know that this is a good idea because I’ve talked to any number of informed individuals who agreed that we should go ahead and protect the world’s population.
Now there’s always the question of budget, of course. But remember, any facilities and production methods that we create can later be phased into various dual-use purposes.
We’ll need some arable land, but that’s no problem.
How simple is it to create a transgenesis of a plant (like a weed, dandelion, milk thistle, sunflower, et al) that is fast growing and acclimated to most growing zones. We could introduce the human gene into the selected plant and seed a small plot of land near each major city of the world.
Local, mid-sized facilities reduce the need for transportation of the final product.
Co-locate the isolation and purification factory near the fields. Simple to build with designs that are widely available.
Place a clinic on the side of the factory next to the fields.
Harvest 80% of the plants for purification, introduce the integrated gene to a retrovirus, flood the body with integrase (safety and efficacy must be studied) and inject the retrovirus. Let nature do the rest.
Of course, some will die, but all in the service of humanity. From the remaining 20% of the GE crop, each human participant also will be allowed to take one transgenic plant home for future boosting, either as a foodstuff or for personal planting. Sort of like the “incredible, edible egg” concept. Our ad campaign could mimic that one to reduce costs.
The benefits of this approach are obvious.
Is there anyone out there who can help? If you have knowledge in any of these areas, please respond, even if its just as a lab assistant or a personal gardener.
Though, we know that many of the high status people may not assist us in such a straightforward and egalitarian quest, we reasonable few should move on this solution because the rest of the world beckons our assistance.
Let’s see if we can find some papers and combine our concerned hands in this work to building the solution together.
<End of Diversion>
Do you see how we’ve established a common enemy, created a division in the class structures of the contributors, used an emotional call, presented clever, sound-bite, intellectual sounding words, raised hope several ways and led the uninformed reader to believe that we should work together to pursue these ideas, any step of which could destroy the bulk of our population?
We are seeing more of these every day that are subtly shifting our thinking and limited resources away from viable solutions.
NS1: That was some great sci-fi. I will volunteer my “back 40″ for such a project.
MM-
Why not a nice, centerpiece green plant on the dining room table to supply the salad course and the pre-entree inoculant?
If we can make it taste like McDonalds we have a hit.
Hi there Allquietonthewesternfront – at 21:41 and all
In 1918 in New Zealand, the Moari were 7 times more likely to die than Europeans (pakeha). There are many possible explanations - but genetic suseptability could be one.
http://www.nzhistory.net.nz/culture/influenza-pandemic
Impact on Maori
The virus had an especially deadly impact on Maori, whose death rate, 4.2 percent, was about seven times that of Pakeha. Many people blamed substandard housing — Maori rural dwellings often had earthen floors and were damp and overcrowded — but the small size and isolation of Maori settlements also compounded the misery. The flu spread so fast that remote communities had little or no warning of its arrival. In the absence of outside help, there were often not enough locals left standing to care for the sick.
Whole settlements were decimated: at Mangatawhiri in Waikato, about 50 out of 200 local Maori died. Whina Cooper recalled similar suffering at Panguru, Hokianga:
Everyone was sick, no one to help, they were dying one after the other. My father was very, very sick then. He was the first to die. I couldn’t do anything for him. I remember we put him in a coffin, like a box. There were many others, you could see them on the roads, on the sledges, the ones that are able to drag them away, dragged them away to the cemetery. No time for tangis.
Thank you Monotreme for the artcile re:malaria. I did not know Hgb C offered protection against maleria. I too am concerned with 5 to 1 mingling with HIV. A stinky stew to be sure. What becomes clear is that until we learn to change human behavior we will continue to confront the pandemic/epidemic issues. Multiple strains of 5 to 1 is certainly a night terror as is the lack of research in using chemokines )(sp)to effect viral behavior. This entire thread reminds me of the movie Aeon Flux-a virus wiped out 99% of humanity and the vaccine that rescued the 1% created sterility.
I have been looking at the Papau New Guinea newspaper Post Courier on-line. Here is some of what I have found. The pertussis article is of some concern to me since it appears that pertussis and flu have some of the same symptoms and it also kills children. It is probably pertussis as they claim, but the article reveals the health care response in Papau New Guinea. It has to make one wonder about the “what ifs” concerning H5N1 if/when it reaches the remote areas of the country. Also read the article about HIV/AIDS in Papau New Guinea. If the concerns about H5N1 in HIV/AIDS patients are justified this is also a reason for concern. I wonder how it compares with Indonesia as far as percent infected. Finally, the last article describes the unregulated importation of gamecocks. I know this is somewhat off topic in this thread, but since I mentioned Papau New Guinea in my earlier post, I thought I would put it here.
Four die as epidemic sweeps across East Sepik Province
Four more children have died and more new cases have been reported as pertusis sweeps across East Sepik Province with the authorities taking their time in addressing it promptly. The latest figures bring the total death toll to 12 as the outbreak of the whooping cough spreads like wild fire from Yangoru to Kubalia, the Sepik Plains and into Maprik. The disease was detected late April, however, health operations to curtail it were called off for three weeks due to constraints in funding and accessibility into the hot spots. Dr Stenard Hiashiri, with the provincial pediatrician unit, had earlier declared a health emergency but now its has turned into an epidemic. “This is very serious. The children are dying,” Dr Hiashiri explained. He said they have approached the national and provincial disaster offices, however no response has been forthcoming. “The provincial government was even very slow in processing our claims, and now the treasury office is closed, we’re just working from faith,” the frustrated doctor said. Acting provincial administrator John Alman has approved the release of K10,000, however, they are yet to collect the cheque from them. “Hopefully this is the only epidemic for this year. If there’s another one, that’s a total disaster,” Dr Hiashiri said. Save the Children Fund (ESP branch) was generous enough to chip in K54,192. The money has been diverted by Dr Hiashiri and his team of medical officers to hire a chopper from Niugini Helicopters to comb areas hardest hit. The chopper will leave Yangoru station early tomorrow morning with the team. http://www.postcourier.com.pg/20060602/frhome.htm
Here is a portion of the CDC description of pertusis and its symptoms
The first stage, the catarrhal stage, is characterized by the insidious onset of coryza (runny nose), sneezing, low-grade fever, and a mild, occasional cough, similar to the common cold. The cough gradually becomes more severe, and after 1–2 weeks, the second, or paroxysmal stage, begins. It is during the paroxysmal stage that the diagnosis of pertussis is usually suspected. Characteristically, the patient has bursts, or paroxysms, of numerous, rapid coughs, apparently due to difficulty expelling thick mucus from the tracheobronchial tree. At the end of the paroxysm, a long inspiratory effort is usually accompanied by a characteristic high-pitched whoop. During such an attack, the patient may become cyanotic (turn blue). Children and young infants, especially, appear very ill and distressed. Vomiting and exhaustion commonly follow the episode. The patient usually appears normal between attacks. http://www.cdc.gov/niP/publications/pink/pert.pdf
In this article it mentions that one in fifteen people in Papau New Guinea have HIV/AIDS. http://www.postcourier.com.pg/20060529/mohome.htm
This article addresses cockfighting in Papau New Guinea
Cockfights, a weak link to bird flu A POPULAR Asian sport could become the weak link in the Government’s strive to keep out bird flu from Papua New Guinea. Cockfighting, a centuries-old South-east Asian blood sport using chickens, is slowly being introduced in isolated parts of the country by Asian-owned logging companies. This is despite recent concerns internationally that fighting cocks could be a risk factor for the spread of the H5N1 strain of avian influenza. http://www.postcourier.com.pg/20060530/tuhome.htm
Here is a map of Papua New Guinea. Maprik is in the upper left portion of the map. Notice its proximity to the Indonesia border.
Wow. Did not mean to do that. Sorry mods. I thought I was posting a link, not a wall mural.
well, now you’ve done it. you’ve broken the site.
kidding, of course. Lovely map, even if a bit large. One of the interesting side parts of looking into the BF stuff is how much I’m learning about SE Asia, which I knew woefully little about before.
I have enjoyed the great analysis here and agree with so many of the ideas:
the virus is “exploring” little pockets of genetic susceptibility in human populations.
One more idea regarding P2P and P2H. This virus presumably is ambidextrious; crossing between pig and birds now, with no barrier between the two. It is well adapted to both, which has happened before. That’s not news, pigs get fed chicken manure, pigs get viruses from chickens. In pigs it could pick up mammal advantages and ricochet back through birds. Since pigs don’t fly, the trans-species virus can fly to other farms and infect poultry, pigs/mammals or ‘certain’ people. It is not surprising that only one dead cat has been sequenced in Indonesia, rather it’s surprising ANY dead animal was reported and sequenced. Yes, we really should have much more investigation going on (about different animals), in order to understand how this incredible feat is happening.
The point of semantics warping our views has been made before in threads. Watch out with the words -‘positive/adaptive/selection pressure’. It leads to a belief that there has to be a reason for mutations. It looks like reasonable progression only in hindsight I put a higher priority on “design by accident”. We put a value of advantage on it only because it is still around. This is worth hammering about because of the danger-factor difference in the two beliefs- selection and accident. All scientist know the mutations are random, but too much power is given to there being a reason for a change to occur. Some say “there’s no reason for it to change to a human adapted virus, that would be extremely rare,” etc.
There never is a reason for a virus to cross species, it just does it. 90% of the viruses being created in a cell are wrong mutations. If one of these mistakes land in the right mistaken spot, it just keeps going. It has no purpose and doesn’t know where it’s going, but in its shotgun method, it gets there. That’s what’s so dangerous to consider: it’s a plain and simple fluke. We aren’t protected by “it’s not suppose to do that.” People like Fauci are misleading the media and public, by saying there is no need for great concern. How can he sweep aside history, and the process that has led to so many human deaths over the centuries as “no need for concern”?
And these “calmsayers” say it can just disappear or mutate down to harmlessness. A few humans have been killed before by a virus that flared up and was stamped out. But that was a single location event. This virus is all over and can not be culled out. Another big point, is that in our 60 years of knowing about bird virus types, we have not seen any of them disappear or go extinct. They could change, but this one would have to change simultaneously around the world. As long as it is successfully procreating, it’s not likely to be displaced by a weaker version. When a virus has stumbled upon a winning game, such as polio, small pox, AIDS, it can keep going for decades without mutating down. I do believe that the human mutated version could be different (but not neccessarily hugely different) and that human influenzas do normalize eventually, after being a pandemic.
I see H5N1 being so broadcasted and having such a toehold in humans as Very Bad News. Remember that the virus is more prevalent Oct.- March. I see optimism as an emotional preference rather than a sensible one.
To answer my own question up above, Indonesia has a ratio of 1 in 1000 people with HIV/AIDS compared to Papau New Guineas 1 in 15 ratio.
Here is the info:
Global Health Reporting website
241,973,872: population of Indonesia (July 2005 est.)
170,000: Estimated number of people living with HIV/AIDS by the end of 2005
0.1%: Estimated percentage of adults (ages 15–49) living with HIV/AIDS by the end of 2005
ps- Again everyone, sorry for the side-scroll.
Hi guys- the the CCR5-Delta32 mutation could explain why some families/populations were more suseptable to 1918 flu.
http://www.nature.com/news/2005/050…0307-15_pf.html NATURE 11 March 2005; | doi:10.1038/news050307–15
Did Black Death boost HIV immunity in Europe? Michael Hopkin Experts argue over whether smallpox or plague should take the credit.
Deaths from plague in the Middle Ages may have left more people with a gene that guards against HIV.
Devastating epidemics that swept Europe during the Middle Ages seem to have had an unexpected benefit - leaving 10% of today’s Europeans resistant to HIV infection.
But epidemics of which disease? Researchers claimed this week that plague helped boost our immunity to HIV, but rival teams are arguing that the credit should go to smallpox.
What is clear is that something has boosted the prevalence of a mutation that helps protect against the virus. The mutation, which affects a protein called CCR5 on the surface of white blood cells, prevents HIV from entering these cells and damaging the immune system.
Around 10% of today’s Europeans carry the mutation, a significantly higher proportion than in other populations. Why is it so common in Europe? One possibility is that it favours carriers by protecting them from disease. But geneticists know that the mutation, called CCR5-Delta32, appeared some 2,500 years ago - long before HIV reared its head.
“You need something that has been around for generation upon generation,” explains Christopher Duncan of the University of Liverpool, UK, who led the latest analysis. Plague fits the bill, he and his colleagues conclude from a mathematical modelling study published in the Journal of Medical Genetics1.
Duncan’s team points out that when the Black Death first struck, killing some 40% of Europeans between 1347 and 1350, only 1 person in 20,000 had the CCR5-Delta32 mutation. As the centuries wore on, repeated outbreaks, culminating in the Great Plague of London in the 1660s, have occurred in tandem with rises in the mutation’s frequency.
Other experts are not convinced, however. A similar study2 published in 2003 suggests that it was smallpox that boosted the mutation’s frequency. “Smallpox would still be my favoured hypothesis,” comments Neil Ferguson, an infectious disease expert at Imperial College in London, who was not involved in the study.
Duncan counters that smallpox has only been a serious threat in Europe since the 1600s, which may not have been enough time to have such a big genetic effect. But Ferguson argues that the influence of smallpox over the centuries may have been underestimated, because it largely affected children.
“Smallpox seems the most parsimonious explanation,” he adds. He points out that one major problem with Duncan’s plague theory is that it requires a rethink of how plague was caused. If those with a virus-blocking mutation were more likely to survive, it follows that plague would have been caused by a virus. But the conventional view is that the plague epidemics of the Middle Ages were caused by a bacterium, Yersinia pestis.
Duncan admits that his theory is difficult to prove. But he argues that the outbreaks are easier to explain if one assumes that plague was passed directly from person to person as a virus, rather than the ‘bubonic plague’ that was caused by bacteria carried by rats and their fleas. “Rats are absolutely in the clear for Europe,” he argues.
If that’s true, then Duncan can explain not only the mutation’s average levels in Europe, but also the fact that people in Finland and Russia have the highest level, around 16%, whereas a mere 4% of Sardinians possess it.
He points out that outbreaks of feverish viral disease continued in Scandinavia and Russia for far longer than in the rest of the continent, reinforcing the mutation’s status as a valuable asset. “It was mouldering on until about 1800 in northern Europe.”
1. Duncan S. R., Scott S. & Duncan C. J. J. Med. Genet. 42, 205 - 208 (2005). | ChemPort | 2. Galvani A. P. & Slatkin M. Proc. Natl Acad. Sci. USA 100, 15276 - 15279 (2005).
Hi guys- the the CCR5-Delta32 mutation could explain why some families/populations were more suseptable to 1918 flu.
http://www.nature.com/news/2005/050…0307-15_pf.html
NATURE 11 March 2005; | doi:10.1038/news050307–15
Did Black Death boost HIV immunity in Europe? Michael Hopkin Experts argue over whether smallpox or plague should take the credit.
Deaths from plague in the Middle Ages may have left more people with a gene that guards against HIV.
Devastating epidemics that swept Europe during the Middle Ages seem to have had an unexpected benefit - leaving 10% of today’s Europeans resistant to HIV infection.
But epidemics of which disease? Researchers claimed this week that plague helped boost our immunity to HIV, but rival teams are arguing that the credit should go to smallpox.
What is clear is that something has boosted the prevalence of a mutation that helps protect against the virus. The mutation, which affects a protein called CCR5 on the surface of white blood cells, prevents HIV from entering these cells and damaging the immune system.
Around 10% of today’s Europeans carry the mutation, a significantly higher proportion than in other populations. Why is it so common in Europe? One possibility is that it favours carriers by protecting them from disease. But geneticists know that the mutation, called CCR5-Delta32, appeared some 2,500 years ago - long before HIV reared its head.
“You need something that has been around for generation upon generation,” explains Christopher Duncan of the University of Liverpool, UK, who led the latest analysis. Plague fits the bill, he and his colleagues conclude from a mathematical modelling study published in the Journal of Medical Genetics1.
Duncan’s team points out that when the Black Death first struck, killing some 40% of Europeans between 1347 and 1350, only 1 person in 20,000 had the CCR5-Delta32 mutation. As the centuries wore on, repeated outbreaks, culminating in the Great Plague of London in the 1660s, have occurred in tandem with rises in the mutation’s frequency.
Other experts are not convinced, however. A similar study2 published in 2003 suggests that it was smallpox that boosted the mutation’s frequency. “Smallpox would still be my favoured hypothesis,” comments Neil Ferguson, an infectious disease expert at Imperial College in London, who was not involved in the study.
Duncan counters that smallpox has only been a serious threat in Europe since the 1600s, which may not have been enough time to have such a big genetic effect. But Ferguson argues that the influence of smallpox over the centuries may have been underestimated, because it largely affected children.
“Smallpox seems the most parsimonious explanation,” he adds. He points out that one major problem with Duncan’s plague theory is that it requires a rethink of how plague was caused. If those with a virus-blocking mutation were more likely to survive, it follows that plague would have been caused by a virus. But the conventional view is that the plague epidemics of the Middle Ages were caused by a bacterium, Yersinia pestis.
Duncan admits that his theory is difficult to prove. But he argues that the outbreaks are easier to explain if one assumes that plague was passed directly from person to person as a virus, rather than the ‘bubonic plague’ that was caused by bacteria carried by rats and their fleas. “Rats are absolutely in the clear for Europe,” he argues.
If that’s true, then Duncan can explain not only the mutation’s average levels in Europe, but also the fact that people in Finland and Russia have the highest level, around 16%, whereas a mere 4% of Sardinians possess it.
He points out that outbreaks of feverish viral disease continued in Scandinavia and Russia for far longer than in the rest of the continent, reinforcing the mutation’s status as a valuable asset. “It was mouldering on until about 1800 in northern Europe.”
1. Duncan S. R., Scott S. & Duncan C. J. J. Med. Genet. 42, 205 - 208 (2005). | ChemPort | 2. Galvani A. P. & Slatkin M. Proc. Natl Acad. Sci. USA 100, 15276 - 15279 (2005).
the thread is too long to read everything.
Apparantly monotreme has an interest to paint the future dark.
Even if H5N1 is adapting and has a reservoir in pigs, a H5N1-pandemic
is not certain. It could be theoretically impossible to design a pandemic strain
in the genetic neighborhood of current H5N1 because there is none.
To get the mods attention to fix side-scroll.
done
close thread for length. Continue here
