Series on Cytokinic Dysregulation
I’ve had something running through the back of my mind again that I posited early this year. Please feel free to take a look and add.
My thinking may appear to be counter-intuitive to some and at the moment I don’t have the opportunity to post a point by point reference.
Monotreme, TomDVM, ManyCats, Racter and our other esteemed guests interested in the genetic factors and microbiology are encouraged to engage, especially one Dr. A22 please.
Gather and Solve
Posted this comment earlier on Effect Measure: De Jong’s Vietnam Paper
I am convinced that these strains of H5N1 with the residue 92 polymorph on the NS1 gene segment are rapid replicants due to the Interferon pathway interference. The in vivo interference, likely a stultification of NF-kappaB, allows the early viral particles a headstart on the immune system, a temporary invisibility.
I surmise that the Cytokinic Dysregulation is closely mediated by the late start of the immune response due to this early stage failure to detect and respond. By the time the H5N1 infection is fully detected, numerous polymerase activities are already completed. The CD is a fail-safe, even a limited self-destruct, because the virus evaded the early sentinals.
I’ve additionally conjectured early this year that this particular glutamic acid polymorphism on the NS1 gene segment may also mediate higher mortality rates in pregnant women and the young due to the involvement again with NF-kappaB, which is also required in a number of phases of cell differentiation.
I can’t seem to get to the bottom of the actual mechanism / tropism as yet.
Perhaps the bulk of a particular cell’s NF-kappaB population is consistently engaged for cell differentiation in the pregnant and the young leaving the H5N1-infected cell short of resources when NF-kappaB is needed to unbind and translocate to spur the Interferon pathways?
Perhaps we are all short of NF-kappaB (or the two kinase units for unbinding) from the start . . . or some other important mediative factor?
The topic should be easily researchable . . . many viral strains outside of influenza employee an NS1 segment to evade the interferon response.
How exactly does it apply in H5N1 as we see it expressed today?
A22 or Pogge,
Can you correct my new window formatting by adding the trailing percent mnemonic?
NS1, don’t know if you have discussed this yet, but just in case you haven’t seen it, this is worth a read:
Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus
The influenza pandemic of 1918–19 was responsible for about 50 million deaths worldwide1. Modern histopathological analysis of autopsy samples from human influenza cases from 1918 revealed significant damage to the lungs with acute, focal bronchitis and alveolitis associated with massive pulmonary oedema, haemorrhage and rapid destruction of the respiratory epithelium2. The contribution of the host immune response leading to this severe pathology remains largely unknown. Here we show, in a comprehensive analysis of the global host response induced by the 1918 influenza virus, that mice infected with the reconstructed 1918 influenza virus displayed an increased and accelerated activation of host immune response genes associated with severe pulmonary pathology. We found that mice infected with a virus containing all eight genes from the pandemic virus showed marked activation of pro-inflammatory and cell-death pathways by 24 h after infection that remained unabated until death on day 5. This was in contrast with smaller host immune responses as measured at the genomic level, accompanied by less severe disease pathology and delays in death in mice infected with influenza viruses containing only subsets of 1918 genes. The results indicate a cooperative interaction between the 1918 influenza genes and show that study of the virulence of the 1918 influenza virus requires the use of the fully reconstructed virus. With recent concerns about the introduction of highly pathogenic avian influenza viruses into humans and their potential to cause a worldwide pandemic with disastrous health and economic consequences, a comprehensive understanding of the global host response to the 1918 virus is crucial. Moreover, understanding the contribution of host immune responses to virulent influenza virus infections is an important starting point for the identification of prognostic indicators and the development of novel antiviral therapies.
I have a few minutes here and thought I might throw out a few comments for consideration.
ducksoup. I saw a show on bacteriophages in Russia and how they were being used to treat untreatable osteomyelitis and drug resistant bacteria…the results were astounding.
Before antibiotics, researchers and doctors used vaccines, anti-toxins and bacteriophages…with the introduction of antibiotics anti-toxins and bacteriophages dropped out of sight except for one Russian researcher who predicted resistance to antibiotics and continued to develop them…My guess is that antitoxins and bacteriophages may be the equivalent to antibiotics in the future…because it seems they can custom design bacteriophages for different bugs and applications…and if they can cure osteomyelitis, they definitely get my attention. ……………………………………………………………
Racter. I think NS1′s article on viral junk is important and I can relate it to my personal experience. The reason I had that rabies reaction to the vaccine was not because of the antigen or I may have ended up paralyzed…it was instead due to in a sense the junk in the carrier of the vaccine. This junk does primarily attach to blood vessels and also gets trapped in lung, liver, kidney, and brain…and the immune system will punch holes in the blood vessels rather than leave the junk there.
When I had my reaction, several comments were made to the effect that it looked like I had been beaten all around my body with a two by four within an inch of my life…
…don’t underestimate the impact of this viral junk…and if it is higher in H5N1 than seasonal flu due to replications rates…then we might have a good part of the answer on the cytokine storm. …………………………………………………………….
Earlier Spok said: “Longterm use of corticosteroids isvery different than a two to four day blast of prednisolone” He said it better than I could and I would like to expand on this…
…not because I am enamoured with prednisolone but because I know it is the only option…unless things change significantly within a very short time-frame.
Racter. I don’t like long term steroids and I especially don’t like longterm prednisolone but for a lot of people, longterm steroids are the difference between life and death from immune mediated diseases. This is an discussion for another day…
…but prednisolone (see extra l in the name) is not prednisone. Hopefully, these two names can be searched because if the are searched one would see that they are really totally different drugs with totally different pharmacological actions and biochemistries etc. They are similar in name but there is little similarity in function.
prednisone is an immune suppressor…prednisolone is an anti-shock drug primarily and that is where the real potential benefit is for the cytokine storm…
…this drug allows me to take a harmless dosage of one of the most commonly used intensive care drugs in the world…put it in pill form and put it in your hands to use at home if required and the oral dosage form is equally effective…and it is very cheap with no patents to increase the price etc. etc. etc.
My sister in law got stung with a bee and they sent her home with 50mg per day for four days with no monitoring at all…and she is a person with mutiple health problems.
My brother in law had a significant auto immune disease that threatened his life…he was on 100 mg of prednisolone a day for one year…after a year they had to pull him off it when a minor abrasion almost killed him…
…I am not talking about this type of dosage rate but this drug if used with reasonable caution is completely harmless (and therefore my sister in law being given 50 mg per day without monitoring).
I agree with you on long term prednisone but please don’t compare these drugs they are really unrelated.
For those who are curious, my understanding is that the extra l in the name means that prednisolone does not have to be liver activated and hence the use for shock where liver may not be functioning properly.
One of prednisolones biggest benefits is re sealing holes in blood vessels and moving fluid out of the lungs for better oxygen exchange which is probably the cause of death for most H5N1 patients.
I am all for another solution like an antitoxin etc. but there isn’t an alternative and neither will be prednisolone or antibiotics if they don’t bump production capabilities now.
thanks.
Tom:
“This junk does primarily attach to blood vessels”
Do you know anything about the low-level mechanism by which this occurs?
“I agree with you on long term prednisone but please don’t compare these drugs they are really unrelated.”
Since prednisone is converted by the liver into prednisolone, it’s hard to see them as completely unrelated, eh?
Yellow zone — versus “green zone” or “red zone”.
Just a quick drive-by.
Racter. My studies of pharmacology are from far in the past…so while the jury is out on the pharmacological similarites or lack thereof, my impression from watching how the body reacts to the two drugs indicates to me that they are related but distantly…the specific beneficial effect of prednisolone does not occur with prednisone no matter how you used it…and the same goes for another steroid dexamethazone.
In many ways, this specific discussion is ‘mute’ as well because if hey don’t realize the potential of prednisolone…and lack of any effective alternative…they won’t scale up production anyway…and if and when they do have a realization…it won’t matter.
The mechanism by which the ‘junk’ attaches to blood vessels I think is entirely functional…and when the immune system identifies it and decides to remove it…it will be ruthless in the attempt…I know because I lay on a couch for more than a week undiagnosed before I got some help…with prednisone treatments. /:0)
Monotreme – at 22:59
Thank you for visiting. We need you interpreting some of these ideas. I haven’t been able to read the article yet.
In the study you’ve cited, did the authors describe the activation time / periodicity of each particular pathway and the concentration of markers at those times? I’m very interested in what they found.
If you can comment on that matter here, I’d be very appreciative.
Racter,
Is yellow an improvement or a degradation? NS1
I haven’t been able to read any of this or previous threads in detail, and frankly I know too little about the minutiae of cytokine reactions to make comments. Suffice it to say that I take the big picture view and think it is a good idea to include immune modulators in treatment protocols, specifically statins. I’m rather more reluctant on the issue of steroids simply because the risks are higher and there aren’t as direct links to the cytokine mechanisms as those shown by statins.
A22,
Statins are potent dyregulators as well including imbalancing their primary target, cholesterol, a substance required for proper functioning throughout many systems of the human body.
I hope that the evidence becomes clearer before any wave sweeps the world; otherwise, medical experimentation on a grand scale will be occurring in a pressurised chamber.
Tom,
We already have the US FDA approving a combination of six bacteriophages ostensibly to treat package meat and poultry for Listeria prevention?
I’ll be watching for recombination in the next two years. I believe that we are working at the wrong end of the food production cycle and that introducing these phages is just another bad idea by a market group with a long list of deadly decisions.
Again, we are hoping to win a war fought on a battlefield terrain that we can’t begin to see or measure.
anon_22 – at 19:08
Would / could statins be started after virus takes hold (like Tamiflu) ???
NS1. Bacteriophages in practice and in concept are a good thing especially in light of the limitations of antibiotics and the fact that no new antibiotics have been developed for decades (not enough profit for the pharmaceutical industry?)…
…but don’t throw the baby out with the bathwater…I have fought this specific fight in the past…
…bacteria get on meat because of sloppiness…E coli can only get onto meat and into hamburger as a result of the bowel being perforated during slaughter and faeces contamination of the meat surface (for hamburger…surface contamination of grinding machines)
Listeriosis and Campylobacter and Salmonella result due to faeces contamination of the feathers and skin followed by sloppy slaughtering again…there have been real advances made in the Nordic countries that have not been followed in North America…
…not only are the solutions out there but 90 % of all influenza cases in North America each year are actually due to food poisoning…I wonder what the economic cost of sloppiness is to our economies…of course the food industry is a powerful lobby.
Bacteriophages work and the advantage of a viral version would be that they could be given at any time during disease progression …therefore specifically targeted to those worse case patients.
Vaccines are too broad based to be highly effective…many who get it won’t contact the disease and many others who are infected won’t be in the cytokine storm group but in the group that recovers without sophisticated medicines.
Antivirals only work in the early stages and have little effect if not given within 24 hours of symptoms.
An anti-toxin like substance whether viral-phage or something else directed at a molecular component of the cytokine storm…allows the unique opportunity to interject when no other treatments are effective…
…it may only be a hypothetical at this point but much of the groundwork was done in the early 1900′s before the discovery of antibiotics.
If these anti-toxin like treatments can be used in combination with prednisolone…we might have a chance to make a real difference to some young people’s lives. /:0)
Of course we need adequate supplies of broad spectrum antibiotics, oral electrolyte powders and anti-fever medications as well…which at the moment we don’t have any chance of having.
NS1 – at 18:57
Re: NF-kappaB
What does NF-kappaB need to function properly in an environment without H5N1? Maybe H5N1 provides something to NF-kappaB that it perceives as a need? Maybe by filling a demand to NF-kappaB, it is welcomed and ignored?
“NF-kappaB population is consistently engaged for cell differentiation in the pregnant and the young”
That might also explain the impact on the pregnant and the young.
spok-
NF-kB is bound by IkB in the cytoplasm. In order to be released, typically the kinase products IKKalpha and IKKbeta are involved in encouraging IkB to release the NF-kB.
If all goes well (the IKKs are OK and the IkB releases), then the free NF-kB translocates (moves) to the nucleus of the cell and begins to activate particular genes including a particular set that establishes the environment to release substances from the Interferon family (your bodies natural anti-viral).
In H5N1 and other similar viral strains using the NS1 (and NS3 at times) Interferon suppressors, I’m postulating that sometime between the virus breaching the cell wall (endocytosis) and the time that NF-kB would normally be released, something interferes in the process.
Now we search for the exact mechanism.
Feel free to examine the homework in the 3rd and 4th threads for a more detailed explanation.
And remember everyone . . .
Listen to Tom’s practical drive for the electrolytes and other basics!!!!’
NS1. The article on ‘viral junk’ was another one of those two by fours across the forehead…most likely do to unbelievable replication rates in H5N1 and N1N1 (1918)…
…If there was hypothetically, a way to filter the blood and remove this junk…I will bet you that the problem with the cytokine storm would be easily controllable…
…bottom line…it is playing a significant role and this problem is solvable. ……………………………………………………………..
Listen to Tom’s practical drive for the electrolytes and other basics!!!!’
Thanks for the support. I just want a fighting chance to save some kids.
Hey Tom, interesting discussion about bacteriophages, thanks! I had always thought that the phages were used to successfully kill bacteria…until a couple years ago when I read about a phage, the DNA from which contained coding for a toxin. So this morning I tried to find something about that. Here is an abstract about an E. coli phage which contains shiga toxin 2 (stx2). I don’t know under what biological circumstances this toxin-producing phage crosses over into normally harmless E. coli (that is, if it does cross over), or whether it involves recombination, or maybe presence of virus promoters floating around in genetically engineered feed, or other possible contributing factors. So little time and so much to read. For now though, we need to know that bacteriophages can sometimes contain coding for toxic factors.
Diversity of stx2 converting bacteriophages induced from Shiga-toxin-producing Escherichia coli strains isolated from cattle.
The presence of bacteriophages encoding Shiga toxin 2 (stx(2) phages) was analysed in 168 strains of Shiga-toxin-producing Escherichia coli (STEC) isolated from cattle…Most phages carried the stx(2) gene, while a few carried stx(2) variants. Infectivity of the phages depended on the different hosts, although O157 : H7 was preferentially infected by phages induced from O157 strains. The results show that inducible stx(2) phages are common among STEC of animal origin and that they may enhance the spread of stx(2).
PMID: 15347754
beehiver.
So little time and so much to read. Agreed but nobody else is doing it so we might as well…I have a lot of faith in the intelligence of this team on flu wiki…I honestly don’t think there is anything that couldn’t be solved.
In my years, I have found that no matter the problem, in retrospect the problem and solution to the problem was simple and straightforward….
…all we have to do is Stay Calm…Be Brave…Wait For The Signs (written by Tom King…Native Canadian writer)
For now though, we need to know that bacteriophages can sometimes contain coding for toxic factors. Is this a good or a bad thing?
For now though, we need to know that bacteriophages can sometimes contain coding for toxic factors. Is this a good or a bad thing?
Sorry Tom, got in a hurry. Phage-encoded Shiga toxin is definitely a bad thing, it’s what causes the hemolytic uremic syndrome - as recently seen in some of the folks who ate infected spinach. The mechanism is clearly explained on this page in the section called “Site of Action”.
Here is access to another free article: Sequence of Shiga toxin 2 phage 933W from Escherichia coli O157:H7: Shiga toxin as a phage late-gene product. Abstract snip says: “Lysogenic bacteriophages are major vehicles for the transfer of genetic information between bacteria, including pathogenicity and/or virulence determinants. In the enteric pathogen Escherichia coli O157:H7, which causes hemorrhagic colitis and hemolytic-uremic syndrome, Shiga toxins 1 and 2 (Stx1 and Stx2) are phage encoded.”
Actually Tom, I am fascinated by your idea of what we might call a “toxic factor” against our favorite virus. I am trying to get some reading and thinking done about this, including what’s in previous pages of this thread. It takes a lot of time…and like many, I have to fit it between other responsibilities…
This was posted on Effect Measure this a.m. - Hope I am not doing a bad thing re copying it here?? If so, Mods please delete.
The Nature paper on the 1918 virus and immune reaction Category: Bird flu • biology Posted on: September 29, 2006 7:13 AM, by revere
We’ve now had a chance to take a look at a new paper in Nature (advance online publication 27 September 2006 | doi:10.1038/nature05181) on increased host immune and cell death responses in mice infected with the reconstructed 1918 virus compared to other viruses with only some of the 1918 gene segments. It is a very interesting paper.
The authors (Kash et al.) infected mice intranasally (through the nose) with four viruses, one a currently circulating human H1N1 virus, A/Texas/36/91, dubbed Tx91 for short, and three others, two produced by replacing first two of the eight gene segments of tx91 with the corresponding ones from the 1918 virus (HA and NA, thus designated 2:6 1918) and then five of the eight gene segments of Tx91 (HA, NA, M, NP and NS, 5:3 1918). tx91 was also an H1N1 virus so no new sub-type was produced. Kash et al. also infected the mice with the fully reconstructed 1918 H1N1 virus (r1918), that is, an H1N1 that had all of the original eight of the 1918 gene segments.
The most lethal combination was r1918. Moreover the pathology of the lung lesions looked distinctly different with r1918 compared to the other viruses, suggesting that the pathology and virulence of the virus is not due to specific genes but rather the cooperation or combinations of proteins from genes on different segments. Kash et al. also looked at which genes of the mouse immune system might be activated by the different viruses. Other studies had shown that the increase in cytokines in mouse lung infected with the 2:6 1918 could be attributed to the increased number of inflammatory and scavenger cells, suggesting the increase in cytokines was an effect rather than a cause. The same phenomenon was seen in this study with r1918, i.e., an increase in cytokines from increased recruitment of white blood cells and macrophages (a kind of scavenger cell) in the lungs. The microarray method used to detect which genes were upregulated during infection could not distinguish what kind of lung cell was involved, but did show that that the severe disease produced by r1918 was correlated with genes involved in inflammatory response. Similar findings have been seen with H5N1, suggesting that H5N1 shares some ominous similarities in pathogenic mechanisms with the 1918 virus, features it doesn’t share with contemporary H1N1 human viruses.
The interplay of functional components of the immune system appears very complicated, either because it is or because we have yet to unravel the simpler coupled relationships that produce its complicated dynamics. This study tried to tease out some of these inter-relationships. The overall picture is that the virus causes the body to turn on a pro-inflammatory response and also to initiate a programmed cell death response. Whether the latter is a result of the former, or vice versa or they are independent or partially independent is not known. Programmed cell death (apoptosis) is different than a cell being killed by some exogenous agent. Apoptosis is a cell suicide routine, and like the inflammatory response, is part of the protective and development repertoire of normal cells. Cells can be induced to kill themselves if their death is required by shaping an organ system during development or to protect the host from an infected or cancerous cell. But like inflammation, which is meant to recruit infection-fighting cells to an area of microbial invasion, apoptosis can do much damage if uncontrolled. It appears that something like this may be part of the devastating pathology of r1918 and probably H5N1.
In this study the FAS and caspase cascade are upregulated. They are part of the cell death program. Researchers are still trying to tease out the convoluted chain of events related to programmed cell death and it appears there may be several different parallel chains capable of initiating it. One of them involves the cell’s energy generator, the sub-cellular organelle called the mitochondrion. Caspase-9 which is one of the upregulated proteins in this study, is activated in the cell death routine by one of the contents of the mitochondrion, cytochrome c. Recent work indicates that a protein coded by an alternate reading frame of the PB1 gene segment of the influenza virus affects the mitochondrion in ways that might increase release of cytochrome c. An alternate reading frame is a way to make a different protein from a gene sequence by shifting where one starts to code the protein’s amino acids. Amino acids are coded by triples of gene bases but there is no spacing or punctuation to indicate where to start the triple. If you move over one base you will get a different sequence of triples and produce a different protein. That is what happens with the PB1-F2 segment which takes the PB1 gene segment and translates it again slightly differently. It is of interest that none of the viruses in this study, other than r1918, used the PB1 gene segment, i.e., none of tx91, 2:6 1918 or 5:3 1918 had the 1918 PB1 that was in r1918. It would be of interest to do the same experiment with an incomplete 1918 genome but one that included PB1.
This paper is an important contribution to understanding the role of host immune responses in virulent influenza infections. So far it appears the full 1918 genome is needed to produce the catastrophic response we associate with 1918 H1N1 and the current H5N1 subtype. We have yet to discover what parts of the 1918 virus are mirrored by current strains of H5N1 now circulating in many areas of the world in birds, with sporadic cases in humans, and incomplete knowledge of other possible reservoirs. It is possible that these virulence factors of 1918 are all present, given the clinical picture in humans. The question would then shift to those factors which govern the transmissibility of the virus from bird to human and human to human, since H5N1 currently is not easily transmitted to people as the 1918 virus was.
The basic science of influenza virology is moving relatively quickly, but the pace of science, no matter how rapid, is slow compared to the possible time frame of an emerging pandemic. It’s a race whose outcome we don’t as yet know.
Thanks g…Thanks Beehiver.
Tom DVM – at 08:19
I seem to recall tranfusions being mentioned from time to time as part of the treatment modality. Tremendous risk for the HCW. Probably too late once the virus is in the blood.
Too bad we can’t vacuum the lungs with some attractant that binds the intercellular viral particles?
Don’t try this at home!
NS1 – at 16:47 — A good clean-up job, blood, lungs,… Racter will tell you nanobots are on his wish list :-) - and yet… I keep thinking, what if? After all, some scientists even tried the water respiration thing where you still manage to breathe with your lungs full of water or also with some gases (for divers).
FrenchieGirl,
I was thinking exactly the same when I wrote the post! Not really a good idea at all, but it has been tried.