This is a continuation of the most excellent thread started by Monotreme with last posts here
Monotreme,
Apologies for such a late response. I had to set aside time to review the literature and your links etc.
You and I have had several debates about the nature of ‘selection’ in viral evolution, and my main objection with regards to H5N1 in b2h was the absence of a clear adaptive advantage for the virus to adopt á2,6 affinity in the avian host. However, your hypothesis regarding the presence of a mammalian host, possibly pig, is sound and in my very inexperienced opinion probably fulfills the criteria necessary for a selective ‘drive’ to occur.
What we are seeing in human cases over the past 3 years is a steadily rising trend both of percentage of cases who are part of a cluster, and the size of each new cluster over time. This phenomenon, assuming it is accurate, is likely to be caused by a series of progressive mutations (I’m not going to get into whether this is random or by recombination, as the effect is the same for the purpose of this discussion) over time.
It’s all very well to make a general statement that the virus appears to be adapting to humans, but the precise mechanism by which this is occurring has significant implications, as we shall see.
H5N1 at the moment preferentially binds to á2,3 receptors which are present in avian species. One of the barriers to becoming a pandemic virus is the ability to change this affinity to á2,6 receptors, the predominant type in the human upper respiratory tract, where replication and shedding would allow the virus to spread efficiently h2h.
How can this change occur? Theoretically the mutations required can occur in the human, avian, or an intermediate host. As discussed on this thread overcoming species barrier, changes arising from a series of mutations require each intermediate mutation to be passed on ie transmitted host2host, otherwise it would be lost. Mutations happening in human hosts, before there is efficient h2h, would be lost or ‘dead-ended’ with the last case, unless there is a significant pool of asymptomatic hosts, which current data does not suggest.
Mutations that happen in the donor species ie birds, can be retained because there already is efficient b2b. The problem here is that there is no adaptive advantage to the virus to be able to bind with á2,6 receptors, which was the topic of our previous debate. In the absence of adaptive advantage to the virus in avian species, such events would be more-or-less random, such that one would still observe some strains to be slightly more efficient in human hosts and causing clustering etc, but these would be randomly distributed over time and space, so that we would see varying cluster sizes instead of a steady and persistent trend. If we propose that the virus does not need intermediate steps but the transition to a pandemic strain can be achieved in one go, then we should see either isolated human cases (or minimal clustering), or an explosive outbreak signally the launching of a fully evolved pandemic strain.
So the phenomenon of progressively increasing clustering can only be explained adequately by the third mechanism, that the virus is accumulating mutations progressively in an intermediate mammalian host, the pig being one major candidate to be considered, and what we are seeing are the strains from these progressive mutations infecting humans every now and then, and demonstrating their progressive affinity change.
This 1998 paper using H1N1 Molecular Basis for the Generation in Pigs of Influenza A Viruses with Pandemic Potential shows how “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 ca2,6Gal.”
And proposes possible mechanisms driving the change:
“What types of selective pressure drive the shift in receptor specificity of avian-like swine influenza viruses from both NeuAca2,3Gal and NeuAca2,6Gal to NeuAca2,6Gal exclusively? One possibility is that the NeuAca2,6Gal linkage is more abundant than NeuAca2,3Gal on the epithelial cells of pig trachea, thus providing a replicative advantage for viruses that recognize the former receptor. Alternatively, glycoproteins containing NeuAca2,3Gal may exist at viral replication sites in pigs, serving as receptor analog inhibitors. Detection of the NeuAca2,3Gal linkage in mucin from human trachea supports this suggestion.”
If this model is correct, it would require a fair degree of endemicity of the virus in pigs. At the moment, we simply don’t have enough data to determine that.
But is the converse also true, that a high or rising prevalence in pigs imply that a pandemic by H5N1 is almost inevitable? In the absence of demonstrable efficient pig2pig transmission, and with our poor knowledge of the precise behavior of the virus in pigs, one cannot draw such a categorical conclusion. But I would think the chance not just of a pandemic but of a sudden explosive onset (as opposed to the current simmering progression) is increased dramatically if the virus is indeed circulating undetected in pigs already.
Even if we cannot get proper viral sequence data, the ability to simply quantify seroprevalence in pigs would go a long way to answering these questions.
Thanks annon 22.
Monotreme What do you make of Dr. Nidoms data?
Mono,
As an aside, why do you and I always agree on bad news?
annon 22. An excellent analysis. I could almost understand some of the specifics on mutations…
…in respect to the comments on a requirement for selective mutations in a species of mammal, we know that H1N1 in 1918 did not require an intermediary host and did all it needed to do to become a pandemic virus in birds.
Forgive me for intruding with my question, but hasn’t it been discussed here and elsewhere that the is a large degree of uncertainty as to the prevalence of human cell receptors of both the alpha 2,3 and alpha 2,6 isomers? Why couldn’t a viral variant arise within an index human that is more keyed to alpha 2,6 - from a predominantly alpha 2,3 in the inocculum, said variant then gaining the replicative advantage and the ability to move on to secondary and tertiary contacts? B2H2H…
Sarge,
What you are proposing is possible and is our nightmare scenario, that the virus makes one jump from predominant 2,3 preference to 2,6 preference. Fortunately, this is not our current observation.
Thanks Anon_22 - I was afraid I was beginning to comprehend this, and my fears are thus confirmed.
Tom,
“we know that H1N1 in 1918 did not require an intermediary host and did all it needed to do to become a pandemic virus in birds.”
Actually, we don’t know that. All we know is Taubenberger saying that the 1918 virus is mostly avian in nature, ie most of the genome was from avian origin and not a result of reassortment and acquisition of mammalian genes, but still having acquired whatever mutations were necessary to cause a human pandemic. There are various theories but no definite conclusion (I think) as to whether the 1918 pandemic strain had passed through mammalian hosts before.
Just to clarify any potential confusion, in the study that I quoted, the observation was based on avian-type H1N1, introduced into European pigs in 1979, not the ‘classic H1N1’ that has been circulating in humans etc since 1918.
Yes, Thanks Anon_22! I could actually comprehend it also……I’m pretty amazed with myself actually!!!
Hi anon_22- well said! Thank you for the clear explaination. Talk about mind expansion!
This quote is from an article posted by Beehiver yesterday at 9:15 on Final Adaption 111 thread.
“What they found was: chicken colon cells - 87.07% were positive for the 2,3 linkage; and a surprising 95.01% were positive for the 2,6 linkage.”
“chicken lung cells - 94.91% were positive for the 2,3 linkage; and 72.67% were positive for the 2,6 linkage.”
“So to some degree, a large proportion of all chicken colon and lung cells displayed receptors for both 2,3 and 2,6 types of viral linkages. Different types of tissues displayed different proportions. It seems that when scientific articles say “such-and-such avian cells display a preference for 2,3 linkage”…well that would only be a preference…it does not rule out the presence of 2,6 linkages.”
It seems that the virus does not need mammals to have directed mutation to 2,6 linkages.
The next study will state that we were wrong (oops!sorry) about humans: that they also have a mixture of 2,3 and 2,6 linkages.
A22-
We should now naturally ask, Free the Girders and Rivets and Hoofs and Snoots, shouldn’t we?
I think that the handlers/information managers also know that the porcine seroprevalance will be as telling as the sequences we are requesting.
Dr. Nidom’s information is very helpful and courageous. Let’s hope that there are dozens of other independent minded researchers like Dr. Nidom who will share their data.
The Sarge – at 17:06
While we have some certainty on the mapping of the major concentrations of alpha2,3 and alpha2,6 isomers are at work in humans, birds and pigs, we also know that each type is found in amounts less than a concentration in other locations.
We don’t necessarily know the importance of those minute sprinklings.
We are concerned that having seasonal flu, H5N1, alpha2,3 and alpha2,6 in proximity will eventually conclude in a SEH2H HP H5N1. Mathematically, its highly possible, even in a random sense, but I think that we are far past random changes.
NS1,
There’s all sorts of data that would be useful. But since we cannot always get what we want, a kind of realistic targeted attitude is sometimes also useful ie learning how to draw important conclusions from slim data is a useful thing.
A22,
We’ll just keep doing the best we can, right?
As long as we are properly defining and weighting those conclusions on the basis of the sparsity, accuracy and confidence on the data, we’re ok.
Conclusions, though, are usually taken / mistaken as final conclusions.
Any theory is incorrect until proven by evidence, then it becomes fact. I’d like to see this thread stay on track, and as informative as it has been the past 24 hours. If there is evidence that proves or disproves anything, it is in fair play because we are undefined, uncharted, real-time evolution here, with a gift of the Internet to let these discussion help share that evidence.
I have gotten more from the contributions today about the importance of the subtle changes in binding and how easily they could create an explosion or a dead end than I would have gotten in 4 years of college. Thanks to all of you for breaking the complexities to an understandable level for the layman.
Possibly Very Important:
anonymous – at 19:08 on the “WHO Petition via Recombinomics” thread says he/she might be able to get his/her hands on the sequences. But that anonymous is arguing with Niman, questioning his motives (another Niman-bashing position). Yet this anonymous is just as nondisclosing about his/her situation as s/he asks of Niman. Is asking Niman to give up his patents, and then maybe trade that for the sequences! What?!
Thanks ricewiki. The new anonymous that has been here for a few days is not gs.
TRay75. Thank you Tom. You bring a lot to the table too.
Just thought I’d give the heads-up. The bashing by this anon has been going on all day. I just don’t understand. Moreover, if he/she really has potential access to the sequences, we should be directing our focus towards him/her instead of letting him/her attack niman for trying to make a living as a scientist.
anon_22, I agree with most of your post at at 16:35. It’s very well written, btw. I have enjoyed reading the very interesting discussion on this thread, but my position has not changed. Since my original post on 2 June 2006 is now buried under the strata of closed threads I reproduce it here in case anyone has not read it.
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 humans than H5N1 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
Monotreme: Good work. Would you be willing to wager how much more time before it gains what it needs to become a pandemic? I realize this would just be your opinion, but I think most of us respect the opinion of those that have obviously done some serious homework.
Tom DVM, I think Dr. Nidom’s statements are very interesting and probably very important, but they are difficult to interpret without seeing the same data he has seen, especially the sequence data. I think you and anon_22 have done a good job of separating what parts of his statements seem to be based on data he has seen what parts are pure speculation on his part. The apparent predilection of some strains of H5N1 for alpha 2,6 is very ominous, to say the least. I am stunned that the WHO has not made any comments on this statement. As regards his speculation about many humans already being infected with H5N1, I doubt it. If there were as many human cases as he seems to imply, it would mean the pandemic has already begun.
Janet, my bets are on my preps and on my community involvement.
Many seem to be picking this fall, but I think the pandemic could begin any time. There really is no way to know for sure when the virus will take the last step.
It seems like the flu in 1918 had a considerably long lead in time, where a less severe form of the form circulated for months and months and then went dormant only to come raging back as the full-blown pandemic.
This flu seems to be pocketing and affecting ever larger clusters and then doing a “hide and go seek” routine. Any similaries here to 1918 in that it crops up, goes dormant and, if so, would it be expected to just change “overnight” or to continue on this path with every increasing amount of hosts affected?
What are the professionals betting on this way - slow and steady progress to a pandemic or one in which we just wake up to the news that it is here.
Sorry, Monotreme, I know that you feel I am picking your brain. Unfortunately, that is exactly what I am doing!?!?
I have had some experience as a boy on a farm raising pigs. I observed a close relationship between birds in the area and pigs. I wonder if we might also have a back and forth infection of one by the other, that is contributing to the evolutionary behavior of H5N1?
Sorry the above was me.
anonymous.
I think you just hit the nail on the head!!
Pick a name and stick around!!
Hi Dude. I thought you were a computer expert, not a farm kid!!
Hi everyone, here is an article showing that the human airway epithelium (including the nasal passages), also contain both 2,3 and 2,6 types of receptors, depending on whether the cells are ciliated or non-ciliated. It is a free article, published in PNAS in 2004, the PubMed number is 15070767.
I’m also looking for research showing which types of receptors are present and/or predominant in the human colon, but haven’t been able to find anything definitive. Maybe someone else has input on that??
Here’s a snip from the abstract about the human ciliated & non-ciliated airway cells, and their receptors:
“Here, using cultures of differentiated human airway epithelial cells, we demonstrated that influenza viruses enter the airway epithelium through specific target cells and that there were striking differences in this respect between human and avian viruses. During the course of a single-cycle infection, human viruses preferentially infected nonciliated cells, whereas avian viruses as well as the egg-adapted human virus variant with an avian virus-like receptor specificity mainly infected ciliated cells. This pattern correlated with the predominant localization of receptors for human viruses (2–6-linked sialic acids) on nonciliated cells and of receptors for avian viruses (2–3-linked sialic acids) on ciliated cells. These findings suggest that although avian influenza viruses can infect human airway epithelium, their replication may be limited by a nonoptimal cellular tropism.”
And a brief statement from the full article: “Our data agree with the previous notion on the overall predominance of 2–6-linked sialic acids on the surface of human tracheal epithelium. However, we found that 2–6-linked receptors are mainly expressed on nonciliated cells and that ciliated cells, a substantial cellular subset of the respiratory epithelium, express 2–3-linked sialic acid receptors in sufficient density to allow entry and replication of avian viruses. Ciliated cells therefore most likely serve as primary target cells in those rare cases where avian viruses cause human disease, with sometimes even fatal outcome”.
Oops, missed one more important item from the full-text 2004 PNAS article (see above post), that I think you might want to see.
“Our data also add a dimension to the long-standing question concerning the necessity of an intermediate animal host for the generation of pandemic viruses (1–5, 14). Because late in infection ciliated cells from human airways are permissive to both avian and human influenza viruses, these cells themselves can provide a milieu for gene reassortment between the viruses, leading to a gene constellation optimal for replication and spread in humans. In this case, the receptor specificity of the viral HA may be the only barrier separating humans from a new pandemic virus. Alternatively, the avian virus can first change its receptor specificity during limited replication in human airways followed by reassortment with human virus in nonciliated cells.”
Earlier in the article, the researchers stated the results they found regarding spread of virus among mixed cell types:
“After infection (24 h), human virus produced continuous foci of infected cells, which included both nonciliated and ciliated cells, suggesting that the virus spreads from cell to cell and that it infects any encountered cell irrespective of its type. Thus, although ciliated cells are relatively refractory to infection with the human virus, this can be overcome by high local concentrations of the virus released from neighboring cells. Under the same conditions, the avian virus did not form continuous foci, with the viral antigen being found mainly in ciliated cells.”
Maybe this material helps shed some light on the nuances of receptors, and the spread of virus from one cell type to another. The more I read about this, the more the traditional dividing lines between “avian vs human”, “2,3 vs 2,6″ etc. become blurred.
Again, I apologize, I really should have given the title and link to the aforementioned article.
Human and avian influenza viruses target different cell types in cultures of human airway epithelium. http://www.pnas.org/cgi/content/full/101/13/4620
Again, as the pnas article notes that high concentrations of virus can overcome the normal refraction from the ciliated ciliated cells, we must see the potential correlation of the very high replication rate of H5N1 (read increased dosage) and their findings that high dosage can infect even cells that are typically uninfectable.
anon_22 – at 16:39
Mono, As an aside, why do you and I always agree on bad news?
I recall that we were among the very few who thought H5N1 was as lethal as it appeared to be, long before the deluge of seroprevalence data became public.
We also seem to be agreeing on the importance of a possible mammalian reservoir.
I think our backgrounds and training are quite different, so the fact that we agree on the possibility of ominous scenarios is cause for concern ;-)
Janet – at 21:59
What are the professionals betting on this way - slow and steady progress to a pandemic or one in which we just wake up to the news that it is here
I’m *not* a flu professional, but I’ll try to answer your question anyways. I think we’ve already seen slow and steady progress towards a pandemic. I think the virus is in the final stages of adaptation to humans. How long this final phase will take is hard to know, without seeing the sequence data and doing appropriate animal experiments. Without this information, we are working in the dark. So, how much of a surprise the pandemic will be when it starts depends on human behaviour as much as viral evolution. If the data hoarding continues, the pandemic will start with no advance warning.
beehiver, that’s an important article that you quote above. As regards receptors in the human colon, I would focus on the intestine instead. H5N1 has already been shown to infect cat intestines:
In cats fed on virus-infected chicks only, virus-associated ganglioneuritis also occurred in the submucosal and myenteric plexi of the small intestine, suggesting direct infection from the intestinal lumen. All cats excreted virus not only via the respiratory tract but also via the digestive tract. This study in cats demonstrates that H5N1 virus infection causes systemic disease and spreads by potentially novel routes within and between mammalian hosts.
Tom DVM and beehiver have also mentioned that some birds could also allow for selection of alpha 2,6 and I agree.
This paper has appeared on other threads and I agree it is significant:
Quail carry sialic acid receptors compatible with binding of avian and human influenza viruses
In the present investigation, we examined whether quail, a widespread-farmed poultry, possess the proper characteristics for serving as an intermediate host for the zoonotic transmission of influenza viruses. Using a lectin-based staining based on specific agglutinins, we found that, in addition to the presence of sialic acid alpha2,3-galactose (SAalpha2,3-gal) linked receptors, there are abundant sialic acid alpha2,6-galactose (SAalpha2,6-gal) linked receptors in quail trachea and intestine. The presence of abundant SAalpha2,6-gal-linked receptors explains, at least in part, the circulation of avian influenza viruses with human-like receptor specificity in quail.
H5N1 has many opportunities to come under selection for binding to alpha 2,6 receptors. However, selection for the correct polymerase mutations probably requires a mammalian host as the core temperature differences between bird and mammals are significant.
Beehiver. You have presented the single most important grouping of resources of the last four months (as long as I’ve been on flu wiki). Thanks I can’t adequately say how important they have been.
Monotreme. H5N1 has all the tools it needs. It can do it completely within birds, it may take a little longer. It may do it in mammals, it will take less time…or it may do it in all species at the same time and then it will be even less time. Bats that cross over between both species will only speed things up further.
We have to face facts here…much of the debate is over and it’s pretty clear to me that we are not going to wait long for the end-result…and boy do I wish I was wrong!!
Thank you, beehiver. Sigh.
Can we all go stare into our root beers together, somewhere?
:-/
Go hug your loved ones…and see to finalizing massive preps. The root beer comes after that.
No, Dude.
The root beer comes before finalizing preps.
Says the procrastinator…
lol
Receptor specificities are not the whole story, experimental results seldom map perfectly to the real world, predictions still rely largely on guesswork, and the debate is most decidedly NOT over. Having said that, the prudent course continues to be to assume that a pandemic may start at any time, with little or no advance warning. Anyone who is planning to prep should have that project well under way, but allocating some time to hugging of loved ones and drinking of root beer is always a good idea.
Monotreme-
NimoTreme22 seems to only be one step from completion.
What is your probability that in the next 5 years, you, Anon22 and Niman will recombine into one organism?
Serious cause for concern. An organism bringing the best traits of the Twin Cities, London and Pittsburgh?
Isn’t it funny that we are all starting to sound so similar?
NS1,
Stop. You are giving me nightmares. Get away from me!
LOL
NS1, I’m not getting into a Transporter with Niman and anon_22. I’ve seen what happens when they malfunction ;-).
Tom DVM, I agree all of the “parts” of a pandemic strain may be available, now, they just haven’t been “assembled” into the final product, yet. Only questions remaining may be, when and where? And where probably won’t matter much.
so be happy, don’t worry…we create our own universe is not an option? sigh. I’m off to the store again.
I asked this on another thread the other day, but got no response (busy forum lately). I didn’t want to ask it here because it might be completely off-base. But anyway . . .
I’ve read that the human cases of h5n1 have tended to drop off in June-August. Is there a known reason for this?
I ask because it was mentioned above that swine (or some other mammal) may involved in the transmission. Is there some known reason why flu in swine would drop off in June-August, and if so, could this be a clue that swine are involved in the transmission? Or is there some other factor (breeding cycle, whatever) that would cause a mammalian reservoir to be less active, causing a June-August drop off?
I’m not a scientist (I study Classics). Might be off-base, but thought it was worth asking, if only because the question is stuck in my head.
Here are the charts showing cumulative confirmed cases by month since 2004. All this information is already on the wiki.
gardner, there is variability in the flu season in the Northern countries, but it’s at least somewhat predictable. There is actually more flu in tropical areas (a surprise to me when I first read it) but the patterns of transmission in these countries is much less studied. Clusters drive the big numbers, IMO, and these may be more related to human to human transmission. Or not. We really don’t have enought data to say.
References
Influenza-Associated Hospitalization in a Subtropical City
Influenza-related deaths and hospitalizations in Hong Kong: A subtropical area.
Monotreme @ 16:00
You are right about the “where”. In todays age of travel the “where” could also be in multiple places. As for the “when” (just my gut speaking) it’s to close for comfort. gina
gardner,
I don’t know the explanation but if you look at the demographics page here there does seem to be a slow down around that time in 2005. We’ll have to wait and see whether 2006 is the same.
Melanie,
you beat me to it :-)
Anon-22,
yeah, I was looking at that earlier. I guess I’m just desperate for an answer to the question “why?” (who isn’t) and we don’t have that answer yet, and might never have it. Must Be Patient. :)
From a dedicated lurker - thanks Anon 22, Mono, TomDVM, Beehiver, et al - I can (almost) understand what y’all are saying - and that’s saying a lot considering I have no strong science background. I so appreciate all of your contributions here and those of others too numerous to mention! :-)
You’re welcome, to all those who just thanked me/us.
I just hope that we (Mono and myself) are WRONG.
anon_22 – at 17:23
I just hope that we (Mono and myself) are WRONG.
Me too!
OMG! I don’t know what kept me from reading this thread and its predecesors.
Ok, now I know - simple fear!
Of course, while I feel all that fear, I also manage, somehow, to try and think a bit: how can we get this outside? I’ve been working on a presentation for local authorities to urge them to “community-prep” in simple steps - I want to make it as compelling as possible. Somehow I don’t think we have time for “individual-prep”. At least not in my “here”.
lugon, there have been several suggestions to put together a powerpoint presentation to convince our local PTB to prepare our communities. I put one together based for a talk I gave at my institution and it went over well. This was a while ago. If I gave a talk on panflu today, it would be much darker, I’m afraid.
If someone will create a space I will try to work on some slides. Perhaps put it up on the Wiki side. I think Dude is working on this.
can’t find where that would be - Dude, please?
yes, it’s being discussed on the ‘Thank you to wikie’ thread.
Forum.AThankYouToTheWikie?, yes. Found it, anon_22 - thanks!
Hi everyone. The following quote is from Dr. Jeremijenko on the H5N1 Receptor Binding Discrepancey thread.
“At least four of the survivors in Indonesia here have been a second case in a cluster and been children. The “cytokine storm” is a term used to describe why patients lungs fill with fluid. Is there a difference in the immune response of these second cases, because of younger age, genetics or viral change that that leads to their survival.”
The reason I bring it up is with respect to why the index case in the cluster may be a super-shedder and the later cases do not appear to be as infectious.
If the virus mutated, you would expect all later cases to be just as infective as the index case…
…so my question is…if a virus can increase in virulence through repeated passages in a new host, then is it possible that H5N1 is doing the reverse, decreasing in transmissibility with repeated passages?
Depending upon the environmental constraints, it should be equally likely to select for increasing or decreasing transmissibility, as far as I know.
I should say it should be equally likely to BE ABLE to select for either outcome. That is to say if the environment favors viral particle formation of the less transmissible variant (perhaps due to packaging requirements, etc.) then that is what will be produced in greater numbers. However, a lack of transmissibility is a dead-end for the virus.
Repeated passage through hosts can also result in attenuation ie reduce fitness of the virus. That is the basis upon which vaccines are sometimes made. Having said that, I don’t know enough to know what conditions are necessary for attenuation to happen.
Certainly a virus that is not yet fully adapted to humans eg retaining major avian characteristics will have a harder time surviving many passages through human hosts.
>>>The reason I bring it up is with respect to why the index case in the cluster may be a super-shedder and the later cases do not appear to be as infectious. If the virus mutated, you would expect all later cases to be just as infective as the index case…>>>
If the index case became infected by eating an infected animal, and the second generation is infected by aerosolization, maybe the oral infection into the gut is more devastating.
A twist on petperson’s remark:
Viruses have certain “tissue tropisms” that is to say, they are more likely to enter and replicate within some tissues rather than others, presumably due to their mechanism of entry and/or replication. Since this virus is “doing things no one would have believed possible” in other ways, it might be prudent to keep an eye on several possible lines of infectivity (aerosol and/or via ingestion). Nice little thought to ad to the mix…
Addendum: While signs of illness are mostly respiratory, for now; we know how things have a way of changing with H5N1. Any thoughts?
As each wild migratory bird becomes ill, those that survive will possess immunity, unless the virus is capable of drifting enough to elude the immune response of previously infected birds. I have not read much on this, yet it would seem to me, re-infection may play an important role in recombination. In my mind this is un or under discussed
Monotreme at 8:01, yes I should use the term “intestine” instead of “colon”. Thanks for the clarification.
Thank you also Tom DVM. I looked at another recent article today that gives very strong reinforcement about this matter of the receptors, and that the potential for pandemic is indeed much more involved than just receptors, it also involves the other influenza proteins. That actually may be good news to some degree. Considering that chickens and humans and swine all contain both types of receptors (2,3 and 2,6) in their airways, and that influenza viruses have been circulating for heaven knows how long - it appears that maybe it’s time to get beyond the box-like thinking about influenza illness simply in terms of avian or human receptors.
I will try to report on this newest article asap, when I can write with a clearer head. I also want to look at some of the articles Monotreme has posted. There’s a lot of material “out there” to try and make sense from, but I think it can point us in some realistic direction. We sure can’t expect to get direction from much of anywhere else, and I am deeply grateful for the fluwiki and this group.
So much of this circles back to the same issue(s): we need the protein sequences, and not just part of them…along with much better clinical and epidemiological reporting. Dr. Jeremijenko’s post earlier today from the Receptor Binding Discrepancy thread was a real eye-opener what’s happening in Indonesia. I guess we tend to take a lot for granted.
If I may add a thought on “environmental” factors that came to mind on the index verses the secondary cases. If H5N1 were not yet fully adapted to the human core temperature for optimal replication, could we maybe be seeing the index cases start with a higher initial core temperature (due to minor illness or ovulation, etc.) and thus be more susceptible, then the secondary cases not be as “hot” at onset and therefore less favorable in the early (apparent “supershedder”) period?
I noted on the charts some minor variations with seasons as well, which fostered a thought that ambient air temperature may hold core body temperatures higher (you can’t cool off very well in extreme heat, so core temps could be higher). Have we gotten a correlation to outbreaks and weather condition s in the clusters that anyone is aware of?
Again, I’m from a mechanical sciences background, not biological, so my thinking is more influenced by that aspect - and the fact I grew up in the hot, humid southeastern US and remember summer nights where you’d never seem to cool off.
I have to admit the information I saw on this forum today gives me little hope for dodging a bullet on this one. It seems only a matter of time now for adaptation to finalize the strain to sustained H2H2H2H ad infinitum.
In more northern areas of the country, during the cooler months, dry cold weather tends to irritate bronchioles and nasal passages. This often leads to spikes in flu infection rates.
Cooperative sense-making. What would the outline look like?
With regard to abundant sialic acid alpha2,6-galactose (SAalpha2,6-gal) linked receptors in quail trachea and intestine, do Asian breeders of poultry mix chicken and quail in the same enclosures, or raise them in close proximity to chicken, as they do in France? What would the consequences of this be?
Naplespark – at 00:11
The mucous layer becomes much more permeable when dry allowing more detritus and pathogens to enter unchecked.
FrenchieGirl,
“With regard to abundant sialic acid alpha2,6-galactose (SAalpha2,6-gal) linked receptors in quail trachea and intestine, do Asian breeders of poultry mix chicken and quail in the same enclosures, or raise them in close proximity to chicken, as they do in France? What would the consequences of this be?”
They mix everything with everything. Birds, pigs, humans, dogs, etc.
Frenchiegirl — I doubt they mix quail in the same enclosure as chickens. If you were to put chickens and quail in the same enclosure, the chickens would likely kill the quail or the quail would kill themselves trying to get away. Chickens are rather vicious and cannabilistic.
Quail, at least domestic button quail I’m familiar with, can’t be free ranged. They go wild. Also, every predator out there considers them prey including things (like domestic housecats!) that won’t touch a chicken.
(Close proximity to chickens is probably a good bet, though, on quail.)
Cygnet,
The cages are stacked on top of each other.
Hi everyone. It is good to read the level of dissociative thinking on some of the variables.
All of the points raised are pertinent to a discussion centered around transmisibility to answer the big question about the pandemic…When?
I believe we have already answered the other two questions…If and How Big?
TRay. I think we had a discussion on Monotremes last thread (H-H more efficient than B-H) about core temperatures as a genetic predisposition to infection…but I don’t think they apply in this case.
We have an index case that must be highly infectious followed by a string of cases that aren’t but in all those cases the patient dies.
The core temperature could explain the initial infection but all are, in effect, contaminated with the same relative numbers of viri later leading to their deaths…Therefore concentration of pathogens cannot explain the lack of infectivity of the later cases.
It is possible however, that the virus can only maintain its found transmisibility for one passage through its new target host (probably a temporary situation in an adolescent pathogen?)
Anon-22 — from the standpoint of economics, stacking the cages probably makes sense to people in rural areas. Birds on the bottom get to eat what food is spilled by the birds on the top.
(Chickens are NOT fussy eaters. They’ll eat things you wouldn’t normally think of as edible, and I don’t believe it’s possible to give a chicken food poisoning.)
Leva
Exactly. Plus they are just short of room and ignorant as well.
NS1,
“The mucous layer becomes much more permeable when dry allowing more detritus and pathogens to enter unchecked.”
Actually it does not become more permiable, it becomes more solid and the motion decreases allowing more time for a pathogen to penetrate cell membranes (given less clearence time). Permiability, really is more relavant to cell membranes in the airway, and this remains constant even in a dry environment. More so the effect is an issue of chemical interaction within the muscus layer itself. And really my point had more to do with the composition of the “dry air” and how it tends to freely allow pathogens to move more deeply into an airway. This has been found more often to be the reason for geographical changes in flu incidence seasonally. The litterature strongly has supported this for decades, and while I already know the simple answer, the more complex one of “does this virus follow the same pattern” is open for discussion. That was more the gist of my question.
Naplespark-
We have so little population data that tracking a pattern at this time is unreliable. We’ll likely have those types of studies and answers about this subtype post-pandemic. I expect that replication rate will far outweigh any other mediator. At the same time, I will be certain to maintain a moderate humidity in our personal environments.
Your expertise is evident; thank you for clarifying your question. My comment on the mucous layer stands, biomechanically. I selected the discrete term, permeabiity, without properly regarding our discussing of respiration. My error. Mathematically, measuring the surface area and the amount of detritus crossing the boundary, you are likely correct.
My comment refers to the extremis of moisture loss and potential tiny fissures that develop opening the door to insertion. The reduction in moisture creates a drying effect, slowing the movement as you mentioned and allowing fissures to develop, interspersed in the mucous layer, much like mud flats on a hot day, just not as dramatic.
Tiny fissures are welcoming arches to a virus particle.
since H3N2 is constantly changing, is there the potencial for H3N2 to become more deadly and become the next pandemic?
“since H3N2 is constantly changing, is there the potencial for H3N2 to become more deadly and become the next pandemic?”
No, a pandemic depends on almost complete immune naivety of the population. Whatever mutation existing strains take on, there is a substantial degree of herd immunity.
Oh Mods! Spam alert here!
Or perhaps i should put that in the Author box.
Sarge
We do see it when you do that, Sarge. It’s one advantage to having it wide open like this.
Thanks.
Glad to be of service.
There I was trying to work my way through the back and forth on H5N1 adapting through other species, and to go along with Tom DVM I almost understood it, then you scare the hell out of me with a vision of Anon_22, Monotreme, NS1 in that pod with the Fly! Not to mention Niman. Boggles the mind to imagine that kind of recombination!! Or reassortment!
My question here is that in John Barry’s book, if my memory is correct, he led readers to think that the “Spanish Flu” probably started in Kansas. During that time, were there a large number of pigs raised there in Kansas? With the limited number of samples available, Taubenberger and associates were able to reconstruct H1N1. Do any of these or todays virus samples show any mix of avian and swine virus? Or is that something that can be seen after the mixing? Probably this is something that has been discussed or dismissed before, but do not recall it.
As I recall Barry’s book, he referred to both poultry and pork being rasied at Ft. Riley. I don’t have my copy here at work though, so don’t know if he inferred that the final link came through the chickens or the pigs.
“With the limited number of samples available, Taubenberger and associates were able to reconstruct H1N1. Do any of these or todays virus samples show any mix of avian and swine virus? “
The 1918 virus did not. Subsequent to that H1N1 did evolve in both swines and humans, branching out from their original avian source.
anon_22 – at 16:21
Q “since H3N2 is constantly changing, is there the potencial for H3N2 to become more deadly and become the next pandemic?”
“No, a pandemic depends on almost complete immune naivety of the population. Whatever mutation existing strains take on, there is a substantial degree of herd immunity.”
Then why can’t I just kiss a sick bird with Low Path H5N1 like that which has already in other places, maybe get a bit of “pink eye”, and start building at least some immunity to the nasty Asian variety?
I know, I know. Way too simple.
Birdman,
:-)
Birdman, I’d like to hypothesize that we’re already on our way there.
beehiver at 23:55
“I looked at another recent article today that gives very strong reinforcement about this matter of the receptors, and that the potential for pandemic is indeed much more involved than just receptors, it also involves the other influenza proteins.”
I agree. I think there’s disproportionate attention paid towards receptors. However, my discussion at the beginning of this page applies equally to other changes in the same way. I was only using receptor binding as an example.
The other interesting thing to consider is whether there are sets of mutations that tend to happen together, for some reason, co-mutations, so to speak. Examples are mentioned in Ghedin and Taubenberger Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution which is also discussed on this thread I can’t say we know enough to know how important this is but certainly conceptually an important question to ask would be whether certain mutations tend to increase the chance of certain other mutations needed for the virus to acquire human transmissibility.
This is simplistic but sort of how I view things…
…think of it like a bicycle lock with 5 spinners spinning at once. In 1997 they were spinning for 5 minutes per day…in 2003 they were spinning a couple of hours a day and now they are spinning constantly for say 14 hours per day and the rate of time the wheels are spinning is increasing constantly and linearly over fixed periods of time.
We know there are many combinations that will potentially open the pandemic lock.
I guess the point is that it is only a matter of time until H5N1 finds the combination and therefore whether or not we know the combinations really do not matter because we can track its evolution phenotypically.
Asymptomatic infections in many mammals and more and more evidence that it is playing in pigs asymptomatically in very very troubling information and shortens evolutionary time considerably…I do not like the trend-line
Tom,
Your metaphor is so graphic that I’m sure I will have nightmares about with spinning wheels in them. :-)
“Asymptomatic infections in many mammals and more and more evidence that it is playing in pigs asymptomatically in very very troubling information and shortens evolutionary time considerably…I do not like the trend-line”
Well, most of it is speculation at this point. As I said, I just hope we are wrong. But I have an unfortunate habit of being right about nasty things so it’s a little hard to talk myself into optimism. Oh well…
annon 22. I may be reading the tea leaves wrong but remember at the start of the year Dr’s Nabarro, Webster and Osterholm were making some stark predictions in response and to counter the WHO’s ridiculous statements of the time. This was the point that Dr. Webster was chastized for going to far (I thought he was only being honest…refreshing!!).
Then in March, all of a sudden, a lot of backtracking went on and some on flu wiki were predicting that this was due to the fact that everyone had realized that the skeptics (Dr. Butcher et al) were correct.
In the past month or so, I have noticed another 180 degree turn back into the more negative tone especially after the recent events in Karo etc.
I cannot help but believe that they know a lot more than they are letting on particularly since they have changed streams three times in 5 months…and it seems there is a strange silence of the skeptics and an even more strange unanimous and constant message now from all others.
If things in the next twelve months change as much as they have changed in the previous twelve months…who knows where we will be next year at this time…and as I said, I do not see one optimistic thing in the trend-line even though I would like to be proven wrong.
The only optimistic thing I can see is if statins work, as we are discussing on the When Vaccines and Antivirals Are Not Available thread. But it needs a lot of work, and fast.
Hope you are right about the statins. Will they have to monitor for liver damage if statins are used? …How often?
Wow, this thread was resurrected by Spam! Sometimes even bad people do good things by mistake.
There is considerable interest in the role of the polymerase gene complex in adaptation of avian viruses to mammals. Some of the necessary changes were made back 2004 - polymorphisms were observed in H5N1 and only one other virus - the one from the 1918 pandemic. Given how well H5N1 replicates in humans currently, I would say not much more needs to be done there. The NS genomic segment is involved in lethality, and H5N1 is already pretty lethal, so, not much more to do there. I really think H5N1 is pretty set to go except for efficient transmission. We’ve already got H2H2H. A couple more H2H’s and time’s up.
If it’s being transmitted in pigs right now, I suspect full adaptation to humans is inevitable.
I’ve been noticing also that the spam guy seems to be pretty good at choosing threads…
…I’m not sure we shouldn’t let him continue and maybe congratulate him as well…
…He Spam guy…why not choose a name and do it legitimately…why not get out of the anoymoooses herd?
The spammers routinely choose random old threads. Don’t assume spam guy is reading them, these are bots at work.
Monotreme – at 22:03
“If it’s being transmitted in pigs right now, I suspect full adaptation to humans is inevitable. “
How much longer (the H5N1 baby in the back seat asks)?
Soon, real soon (the driver mom said).
Seriously, what’s your best guess?
Monotreme. How do you view the importance of the receptors in Chickens vs humans (2,3–2,6) in transmissibility…is there another way around the mountain for the virus that could leave receptors as they are and increase transmissibility?
Tom DVM – at 21:58 “Hope you are right about the statins. Will they have to monitor for liver damage if statins are used? …How often?”
I don’t know about that one. Gotta find out..
ANON-YYZ
Seriously, what’s your best guess?
2 months ago.
Seriously, the virus has taken longer to go pandemic than I thought it would. At times, this has tempted me to think that maybe it never will, then things suddenly get much worse, like Karo. The virus is getting more dangerous but it’s hard to know how dangerous WITHOUT THE FRICKIN’ KARO SEQUENCES! ARE YOU LISTENING INDONESIA AND THE WHO?
Sorry, had to get that out of my system. Like everyone else, I think this flu season will be extremely dangerous. I will start getting nervous in November and won’t relax until next March.
Tom DVM – at 22:21
How do you view the importance of the receptors in Chickens vs humans (2,3–2,6) in transmissibility…is there another way around the mountain for the virus that could leave receptors as they are and increase transmissibility?
Well conventional wisdom is that 2,6 is required, and who am I to question conventional wisdom? It’s possible that there might be some other way to increase transmissibility, but based on the data we have so far I’d guess that the final changes before a pandemic strain emmerges will be in the HA gene.
Monotreme. I’ll bet you when it goes pandemic…all of the sequences will be released within a week.
I was almost going to ask you for some of what you are on…but now I guess I won’t have to…the ‘worms of weybridge’ Monotreme is back…Ya Hoooooooo. /;0)
Tom DVM,
Do you ever sleep?
Melanie, I don’t think you sleep either—or maybe with one eye open? ;-)
I’m going to take a risk and offer my opinion, for what it’s worth, about whether and when this virus will go pandemic.
I think the biggest near-term risk is a new reassortant from south China. This is still ongoing, with signs of increasing virulence towards mammals.
The Indonesian cluster has actually quieted down my fears somewhat. Millions of people have been exposed to H5N1 by now. In comparison to the extent of exposure, the number of human cases is still relatively small.
So we watch the clusters. And the fact that they are increasing in size is worrying.
But the fact that the Karo cluster was limited only to people related by blood, despite probably extensive exposure of other family members and neighbours, is very significant. It tells me that the observed ability of the virus to go h2h2h in that instance may be more dependent on host responses than innate characteristics of the virus.
Next we need to figure out how patients in the previous clusters are related to each other. I am no statistician but I would imagine being able to get rid of this confounding factor of blood-relationship will give us a far better picture of the ability of the existent H5N1 strains to go h2h.
Another place that poses some risk is Africa, in the context of HIV/AIDS. Up to this point, we have been able to observe how the virus behaves in healthy individuals. We have no idea how it would behave in someone with compromised immune system, specifically deficiencies in cell-mediated immunity, particularly if it is passed repeatedly through many human hosts with such suboptimal cell-mediated responses.
anon_22 – at 10:09
“I think the biggest near-term risk is a new reassortant from south China. This is still ongoing, with signs of increasing virulence towards mammals. “
More details, links? I must have missed some news from China.
close, new thread here