225G Worldwide Tracking & Evaluation

[sharon sanders]

Re: 225G Preliminary Worldwide Tracking & Evaluation

hat tip FT Resident SusanC -

<table width="100%"><tbody><tr><td> Receptor Binding and Evolutionary Trends of H1N1 HAs

by: SusanC

Sat Nov 21, 2009 at 23:28:40 PM EST


</td> </tr> <tr> <td>
</td> </tr> <tr> <td class="theFlip"> SusanC :: Receptor Binding and Evolutionary Trends of H1N1 HAs</td> </tr> <tr> <td>There's been much interest recently in the revelation of 'mutations' in the HA of the 2009 H1N1 virus, specifically, a 'change' at position 225 from D to G (see codon table for coding). I put the words mutation and change in quotes for reasons that will become obvious as you read further. I thought I might as well take this opportunity to review the issue of mutations that favor different patterns of receptor binding, from 1918 to now. The bulk of the following discussion is based on 2 papers:

1. Stevens 2006 Glycan Microarray Analysis of the Hemagglutinins from Modern and Pandemic Influenza Viruses Reveals Different Receptor Specificities
2. Shen 2009 Evolutionary Trends of A(H1N1) Influenza Virus Hemagglutinin Since 1918.

Here's a quote from Stevens et al that summarizes, in a much simplified form, the issue of receptor binding:

Receptor binding specificity is primarily distinguished by recognition of the terminal sialic acid and its linkage to the vicinal galactose of carbohydrates in these tissues. Avian viruses preferentially bind to receptors with an a2-3 linkage, whereas human adapted viruses are specific for the a2-6 linkage.3,4 The subtle switch from a2-3 to a2-6 receptor specificity is thought to be a critical step in the adaptation of avian viruses to a human host.

First, findings from Stevens et al:

1. Using glycan microarray (ie binding to sugars on slides, basically), they found 2 positions where changes resulted in shifting of receptor binding preference, 190 and 225
2. In position 190, avian viruses had E, and viruses from humans (including 1918) had a D. The former binds to a2,3 sites, the latter binds to a2,6 sites. Very straight-forward. One single change completely changes the receptor binding from avian to human.
3. For position 225, in 1918, there were 2 variants, D and G. These 2 existed both early and late in the pandemic. The 2 sequences tested in this paper were from 2 soldiers who died on the same day, one in NY, one in South Carolina. The SC one had HAs with a D in position 225, the NY one had a G.
4. In the glycan microarray test, the SC HA (with D at 190 and D at 225), bound exclusively to a2,6 (ie preferential for human), whereas the NY HA (with D at 190 and G at 225) had mixed specificity, for both a2,3 and a2,6 (both avian and human)
5. However, the authors noted that despite these differences in receptor binding preference in the lab, these 2 variants showed no difference in virulence or transmissibility

Second, from Shen et al, just published:
<center></center>

1. During a pandemic, in 1918 and in 2009, position 190 is strictly conserved, ie 100% D.
2. In interpandemic years, there is some selection pressure on position 190, away from D (to what, they didn't say. Or at least I didn't find it).
3. For position 225, during a pandemic, in both 1918 and 2009, both variants are present.
4. In interpandemic years, in samples that have been passaged through eggs (ie egg-adapted) there is selection pressure from D to G.
5. For interpandemic samples that are not egg-adapted (from 1979-2008), 98.2% of samples had D, but changes in this position did not fulfill their criteria for having been under selection pressure. Nevertheless, D at 225 is highly conserved, in interpandemic years.

COMMENTS, on position 225:

1. The 2 variants in position 225, co-existed in 1918. We are now finding the same variants in 2009.
2. In between pandemics, ie after the virus has jumped to humans, position 225 tends to become highly conserved, as D.
3. There is no evidence of evolutionary pressure (ie 'change') from D to G, either in 1918, in 2009, or in all the years in between. If one were to infer any selection pressure, it would be from G to D, since in samples that are not egg-adapted, D was almost exclusively found, eg 1979-2008.
4. In any case, a D225G change in 1918 resulted in lower preference to human receptors. (see Stevens et al, above)
5. And, in 1918, these 2 variants were not associated with differences in virulence or transmissibility. As far as we know, that appears to be the case as well, in 2009, since both variants have been found from the earliest days of this pandemic, since April, and in many countries. (more here)

Receptor binding is by no means the only or even the most important driver of virulence. In the 2003-04 flu season, a new subclade of H3N2 emerged which was very virulent and caused much higher fatality (as discussed here). This virus had exactly the same HA as one that had been circulating before as a minor (ie non-dominant) strain, the only differences are in the polymerase genes. Yet, whereas the previous version caused mild disease and was not able to wipe out other strains, the new one (with exactly the same HA) both became dominant and was much more virulent.
See Memoli 2009 Recent human influenza A/H3N2 virus evolution driven by novel selection factors in addition to antigenic drift. and my comments here and here
</td></tr></tbody></table>

[Commonground]

225G Preliminary Worldwide Tracking &amp; Evaluation

Blog
2009-11-23

This report is preliminary and will be reviewed for corroboration as the official documents become available.

Although confirmation is not yet complete on this item, the American CDC has apparently issued an alert to physicians concerning hemorrhagic pneumonia in the United States. The North Carolina Medical Society has published a description of the CDC alert and has identified a reporting point in their state.

The PF11 viral reservoir is extending and revising in important areas concerning trait enhancements. Since the early part of the pandemic, this viral reservoir has exhibited exceptional abilities to damage the human body due to Influenza Flux; however, we may now be moving into deeper water if this alert is validated. While no one may say exactly where this virus is going, we are able to track the genetics and the human clinical outcomes correlated to those genetics.

Deep lung involvement appears to be supported as a trait enhancement via the D225G polymorphism on the viral Hemagglutinin. 225G is not a new incursion into ΣPF11, but now paired with 206T is becoming a higher concern. The US and Mexico demonstrated 225G with 206S early in the pandemic. 206T, as predicted, has now become fixed or consensus in many geographies. Recent studies on the Ukraine, Russia, China and Norway show 225G in the Hemagglutinin to be circulating alongside the dangerous 225E and the wildtype 225D bearing strains.

Heightened surveillance is being required from the medical community while the general public is receiving communications with an alternate message? Moms and Dads will want to get ahead of this issue by gathering accurate and complete information as soon as possible. PF11 will be with us for a long time.

Gather and Solve.

For additional background on the clinical and epidemiological observational facts concerning Pandemic Influenza H1N1, please refer to the Table of Contents for PF11 Trends & Issues, Mid-Term.

http://pf11-trends-and-issues.blogspot.com/2009/11/hemorrhagic-pneumonia-cdc-issues-alert.html

[sharon sanders]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

2009-11-23

Hong Kong reports 225G in Fully Recovered 1 Year Old Male from July at Prince of Wales Hospital

225G is not new.

The public perception of 225G and the media linkage to hemorrhagic pneumonia is new.

These Hydra Effect viral backgrounds carrying 225G within ΣPF11 are, in fact, very dangerous strains for what they are doing now and, more importantly, for where they are going . . . no question exists about that risk tendency. The only question is why hasn't the science community driven the clinical linkages to the forefront before this week? Fatal outcomes have been documented on record since July in multiple cases from Brasil.

Prince of Wales Hospital in Hong Kong, notable for their handling of the SARS epidemic and additional limited waves in the following years, has released data today concerning the very popular polymorphism, 225G. A one year old male child presented on July 25 and was reported to have exhibited symptoms as early as July 22. The report indicates a discharge 3 days after admittance with recovery.

One week of illness. One important discussion point for those characterising 225G as essentially a high morbidity polymorphism.

We certainly do not impeach the idea of higher morbidity. Biasing any induction solely on singular reports like this Hong Kong case is errant logic, but the evidence does suggest that patience and some exertion may be required to accurately surmise the effector mechanisms of PF11 with and without the pairing of 206T and 225G. Proceeding with a data basis will slowly build the well-supported pyramidal steps required to undertake a capstone solution against this genetically simple, yet clinically complex disease.

We expect to see another half dozen of the major research areas also report 225G, not because the change is new, but because they’ve had the reins lightened, the leash lengthened, on this particular revision and are now encouraged to report this popular news item. This polymorphism, 225G, is seeded around the world.

225G is not as wide or as deeply penetrating as 225E. Our team expected and predicted this Hydra Effect with multiple, human-fit strains on diverse genetic backgrounds that would co-circulate in an emerging pandemic due to Influenza Flux during the pre-PF11_Ω phases. An enterprising question might be, “How many Hydra strains will co-circulate in each phase?”

Numerous sub-species are spreading according to the genetic databases, including TamiFlu Resistant and epitope variant strains. The lead US public health agency reports again this week an instance of a low reactor against the antisera. Additionally, silent spread may be expected due to the wide geography of consistent SNP genetics. The present stock explanation of spontaneous random "mutation" will soon be replaced with more rigourous descriptions based on patterns found in factual data.

The epidemiology of this virus did not suddenly change, just the perception. The only thing that has changed in the last few days is that the leading public health agencies have allowed public reporting of the 225G revision. This particular popular 225G with commensurate background of 206T has been in active circulation since May after emerging in April, vectored from both New York and Georgia, and is on record with documented fatal cases since July.

Nothing new there.

Why are the offical public health agencies raising awareness only now? While we do applaud the release of information and the present focus on matching clinicals to the sequences, we also caution against obverse speculation. A primary topic of concern is Cytokinic Dysregulation. Reliance on inspecific terms like "Cytokine Storm" in the media will only continue to misinform the public on a process that is far less understood than the lead investigators would like to admit.

All of which returns us to the basic categories:

• What we do know?
• What we don't know?

What we do know?

Now that matched clinical data is available, however limited, a potential correlation is being drawn on lung tropism. The standing bench studies, including the Palese and JKT team collaboration in 2006, detailing variant tropism based on differential HA reception at α2-3 and α2-6-linked sialic acids evaluated correlative to protein 225 lend evidence to the concept of deep lung involvement though the experiments were conducted by varying permutations of proteins 190 and 225 on 1918 variants. Whereas, we stand in 2009 with quite different genetics that require cross-validation prior to citation with applicability to PF11.

Tissue type targets are compelling studies and this particular superarray protocol may prove even more useful on PF11 than 1918 samples. We note that though 1918 and PF11 now share 190D and 225G, that all 1918 public sequences show 206S. 206T continues to emerge and conserve regionally in PF11. All 225G bearing strains after April show 206T, except the July CatNS1706 and the undated Vladivostok01.

Reproducing the glycan microarray procedure with the contemporary and ideal dataset including Brasil and Catalonia may bring a tigher focus onto today's issues. We couldn't ask for a more balanced set of control factors with Catalonia offering sequences less than one week apart demonstrating both important pairings: 206S/225G and 206T/225G . . . a bench review made to order.

We also do know that a proper immune response, that is a timely and regulated innate immune response, is not occurring in certain of these patients. When the n +1 generations of the virus progeny begin to lyse the host cells, that failure of innate immune function to have responded early leads to an undetected and massive viral load due to the rapid replication trait of PF11. The cell detritus and the density of moving viral particles elicit a host-driven, limited “self-destruct” series of events because the multiple levels of early detection parameters have been bypassed leaving the core essentially defenseless.

What we don’t know?

Though Cytokinic Dysregulation is occurring in most cases at some level of interchange, the 225G and 225E strains may potentially interfere at a more profound level with the early innate response by amplifying the PF11 conserved effect of the NS1 paired Glutamates at aa96 & 97 that suppresses the IFN synthesis instantiation cycle. Influenza bench researchers don’t know exactly where the failure is occurring or at which combination of cell-to-cell signalers in PF11 or the PF11 225G strains. Until those identification studies are designed, undertaken and reproduced, discussion at this point is stark hypothesis based frequently on the speaker’s sheer lack of present research content mastery. Apparently, saying “I don’t know?” and then returning to the bench to design and gather a proper foundation of data is a skill rarely encouraged in our “Science for Hire” era.

Our team is unimpressed that the wider science community, with such broad analytical skills and exceptional equipment, relies on pseudo-explanation, this cloud of diversion, by invoking the “Cytokine Storm” phrase. More than 20 well-characterised and 100 identified distinct molecular signal functions are at work in the early immune response, including cytokines, but not limited to that class of communicators. Tagging a term for PR purposes is much simpler than tagging a molecule for tracking, but you received your instruments because you can think, not for your ability to improvise inventive talk.

Think.

Eighty billion dollars in research should arrive at a better answer with higher specificity and actionability than the blanket “Cytokine Storm” tome. Data and procedure discover Facts. Anything less is purely Public Relations.

Our team continues to hold an opinion that we first described in 2006 concerning Cytokinic Dysregulation and the NS1 protein of Influenza. Succinctly, the viral ability to suspend innate immunity for up to two days post-infection, as characterised by Mount Sinai this year, prevents the early and required pro-inflammatory Cytokinic Response to viral detection. That blunting, taken in conjunction with detailed studies around adaptive immunity, may result not only in failure to clear the virus from some patients in a timely fashion, but also in failure to produce a useful quantity and competence of memory T-cells and Ab. The early failure to clear a rapidly replicating virus like H5N1 or PF11 results in a frank trauma to the immune system when the first generations of viral progeny lyse their host cells after being undetected and flood the tissues with virii and toxic cell detritus. That disorderly surge of human and viral proteins en masse activates a late and cascading pro-inflammatory response that frequently fails to down-regulate properly.

This explanation is contrary to "pop" science reports that a normal and robust immune response over-generates cytokines and attacks self indiscriminately. We hold that, by the time the virus has lysed thousands of cells and released millions of virii, that most adjacent tissue areas are "fair game" for immune response due to toxic cell detritus and viral travel. That flooding of antigen and waste matter, widespread and instantaneous to the immune system, may further interact with some virally induced derangement of the alternative pathway of complement and generate the intensive up-regulation of signaling, pro-inflammation cascades and the resultant tissue damage described in the clinicals as DIC, DAH and ARDS.

Ergo, the findings of massive tissue damage on necropsy is the result of a failed early innate immune response, not a normal robust response. A normal, properly up- and down-regulated robust innate response clears infection in more than 90&#37; of various infections (viral, fungal and bacterial) and proceeds to generate Ab in short order via the adaptive arm of immunity.

When viral hosting cells properly detect intrusion, flag themselves for apoptosis (cell death) and are then assisted by cytotoxic T-cells, the injection of fragmentins via perforin "tubes" induces an endogenous apoptotic program literally cutting DNA into 200 base multimers (fragments) and eventually condensing chromatin. That organised molecular result is far less inflammatory and far more useful for antigen identification than the disorderly outcome of a virally "exploded" cell. Now you can see why proper genetic expression during each phase of this programmed cell death guarantees a lower pathology than the chaotic and toxic outcome of lytic host cell destruction resulting from viral NS1-induced, delayed genetic expression.

A confluence of PF11 traits (failed early detection, multi-tropism and rapid replication) against the host-pathogen interface may force a limited "self-destruct" in the host upon eventual detection in an attempt to save the organism. That limited "self-destruct" is not the desired outcome of a normal and robust immune response, but occurs due to a failure of the immune system to detect and respond early in the process.

Timing matters.

Individual viral genetics and individual host immune genetic expression are primary effectors that must no longer be discounted under the clouds of some nebulous "Cytokine Storm" or Mysterious Mutation.

May we see the sequences paired with the clinicals?

[Digger]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

Kudos Florida1.

I have been following NS1 for quite some time. At first I was skeptical about the NS1 blog because of the use of his very peculiar synonyms

I wasn't, at first reading, sure of the motives of NS1.

Since then, I have found reading NS1 to be very accurate, informative, logical and actually enjoyable.

Reading NS1 is like reading a Genetic "Who Dunn-it Mystery Novel".

NS1's out of the box approach in describing the faces of "PF11" allows one to rise high above the current situation. Even to the understanding that "PF11" may not, in the end, be the ultimate or only threat before us. It is only the beginning of a journey down a long road.

In your post, Florida1, NS1, so systematically describes the frustration of a great portion of followers of Flu and viruses in general.

And that is:

Here we are in 2009 with an incredible arsenal of resources and tools. One of the most efficient means of communicating and networking in human history, with a host of millions of willing investigators and observers......And our genetic and clinical field surveillance Stinks.

Political and Social barriers must be removed or "The Next Time" will be disastrous. Not to say that "The Next Time", isn't already here and come upon us.

This is the tragic irony of our dilemma, is it not? "The Next Time" may have already begun........


____

[Twall]

Re: Norway - H1N1 &quot;Mutation&quot; Announced by Health Department

does this indicate this flu is now moving in the wrong direction?


2009-11-24

Norway: 1 Mixture of 225D/225G, 5 of 25 have 225E; Spain: 7 of 19 have 225E

225E is becoming fixed.

GenBank Deposits 2009-11-23

Norway: 5 of 25 have 225E
Spain : 7 of 19 have 225E

A/Norway/2924, sampled on 2009-08-10 from a 40F, is a mixture of wt 225D and 225G after canine cell passage. The sample also carries the prevalent 206T.

The data collection must begin in earnest after this development. The first data quality improvement might be to release the sample location and the patient outcome please.

We have no evidence that the cases discussed here are related to the three previously reported instances in Norway of 1 serious illness and 2 fatalities. Sweden is also today reporting 2 cases of 225G that were serious and treated via ECMO during the summer. No outcomes noted as yet on Sweden.

This post will be updated as corroborationg data is made available.

[tropical]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

#49 PF11 news text

I don't know about "pop" science,
but I know about decades of sterile scientific diatribes with studies and counter studies, which never gave an fast-on-the-field shielding answer.

Now, even if it is perfectly reasonable to put the individual gens and bodies as the primary reason how our health response will be,
could we reasonable said scientificaly,
that an organism with a healthy body, plentifull of power and strenght,
never had a flu, and not easy prone to infections,
have an immune system unable to clear rapidly replicating viruses?

And that at the same time,
organisms with weakened immune systems by combating some chronic illnesses or other reasons,
have an immune system able to clear rapidly replicating viruses?

What with immune systems in bodies having auto-immune diseas,
are they a "fast clearing virus immunity", or not?

Could we easy measure in advance by blood tests such "fast clearing immunity"?

If we look at the recent FT thread: Peterborough, Ontario man in coma from H1N1

Could we said scientificaly that even such healthy strong man have "not a normal and robust immune response",
but a "failed early innate immune response"?

If yes, than what will be the anti-pandemic primer, without a matched vaccine,
to augment by add enhancers the immunity no matter the response type, or not?

Any practical therapy scientific practical survival advice,
from PF11 site or anywhere,
or always a global scientific studies diatribes saga only?

__________________________________________
<table width="100&#37;" border="0" cellpadding="0" cellspacing="6"><tbody><tr><td nowrap="nowrap"> Roehl_JC <script type="text/javascript"> vbmenu_register("postmenu_322189", true); </script>
Senior User
</td> <td width="100%">
</td> <td valign="top" nowrap="nowrap">


</td> </tr> </tbody></table> <!-- / user info --> <!-- message, attachments, sig --> <!-- icon and title --> Peterborough, Ontario man in coma from H1N1
<hr style="color: rgb(204, 204, 204); background-color: rgb(204, 204, 204);" size="1"> <!-- / icon and title --> <!-- message --> Peterborough native in coma after contracting H1N1 virus
...
Traviss Primeau's family describes him as a hulking, strapping young man — a snowmobile enthusiast and transport truck driver who was "tough as nails" and "healthy as a horse" who would often greet his mother with a bear hug that would lift her off her feet.
After contracting the H1N1 virus earlier this month, however, the 32-year-old Peterborough native is fighting for his life.
...
"I want people to be aware of the severity of this virus," Lisa says. "My brother was very healthy and strong and this virus just took him over."
...
His family says he's the kind of man who rarely gets sick — he's a non-smoker who keeps in shape with his job as a truck driver, often hauling bags of cement, and he chops his own wood for his home's fireplace. They say he has no underlying medical conditions.

Traviss called his father on Nov. 10 to wish him a happy birthday.

The next day, he got flu-like symptoms including a cough and fever.

His parents say he hadn't yet gotten a flu shot because, at the time, the H1N1 vaccines were for high-priority groups only.

When he started struggling to breathe two days later, his wife took him to an Ottawa hospital where doctors ordered an X-ray and told Traviss he had "a touch of the flu."

He was sent home without a prescription, his parents say.

His wife was sick too, they say, although not as severely.

When he still wasn't better by Nov. 16, his wife, who was getting healthier, was already planning to take him back to the hospital when a hospital official called saying he should be readmitted because something wrong was seen on his X-ray.
...
He hasn't improved since being there, his parents say.

Traviss is hooked up to tubes; his lungs are filled with fluid.
...
Fred says he urges everyone to learn from his family's story and get vaccinated.

"Err on the side of caution," Fred says. "Because this thing can hit you like a sledgehammer."

ebower@peterboroughexaminer.com

Article ID# 2189323

http://www.thepeterboroughexaminer.c...aspx?e=2189323
"
___

http://pf11.blogspot.com/


2009-11-23

Hong Kong reports 225G in Fully Recovered 1 Year Old Male from July at Prince of Wales Hospital
...
The early failure to clear a rapidly replicating virus like H5N1 or PF11 results in a frank trauma to the immune system when the first generations of viral progeny lyse their host cells after being undetected and flood the tissues with virii and toxic cell detritus.

This position is contrary to "pop" science reports that a normal and robust immune response over-generates cytokines and attacks self indiscriminately.
...
Ergo, the findings of massive tissue damage on necropsy is the result of a failed early innate immune response, not a normal robust response.
...
A confluence of PF11 traits (failed early detection, multi-tropism and rapid replication) against the host-pathogen interface may force a limited "self-destruct" in the host upon eventual detection in an attempt to save the organism.

Timing matters.

Individual viral genetics and individual host immune genetic expression are primary effectors that must no longer be discounted under the clouds of some nebulous "Cytokine Storm" or Mysterious Mutation.

May we see the sequences paired with the clinicals?

[sharon sanders]

Re: Norway - H1N1 &quot;Mutation&quot; Announced by Health Department

does this indicate this flu is now moving in the wrong direction?


2009-11-24

Norway: 1 Mixture of 225D/225G, 5 of 25 have 225E; Spain: 7 of 19 have 225E

225E is becoming fixed.

GenBank Deposits 2009-11-23

Norway: 5 of 25 have 225E
Spain : 7 of 19 have 225E

A/Norway/2924, sampled on 2009-08-10 from a 40F, is a mixture of wt 225D and 225G after canine cell passage. The sample also carries the prevalent 206T.

The data collection must begin in earnest after this development. The first data quality improvement might be to release the sample location and the patient outcome please.

We have no evidence that the cases discussed here are related to the three previously reported instances in Norway of 1 serious illness and 2 fatalities. Sweden is also today reporting 2 cases of 225G that were serious and treated via ECMO during the summer. No outcomes noted as yet on Sweden.

This post will be updated as corroborationg data is made available.

It means that all the hype about the change to 225G is not accurate. The 225 position is becoming fixed with E - glutamic acid.

[JJackson]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

In reply to Tropical's post and PH11.
I give you Goldilocks and the three bears.

<link rel="File-List" href="file:///D:&#37;5CDOCUME%7E1%5CADMINI%7E1%5CLOCALS%7E1%5CTe mp%5Cmsohtml1%5C01%5Cclip_filelist.xml"><o:smartta gtype namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="stockticker"></o:smarttagtype><!--[if gte mso 9]><xml> <o:OfficeDocumentSettings> <o:RelyOnVML/> <o:AllowPNG/> </o:OfficeDocumentSettings> </xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> <w:UseAsianBreakRules/> </w:Compatibility> </w:WordDocument> </xml><![endif]--><!--[if !mso]><object classid="clsid:38481807-CA0E-42D2-BF39-B33AF135CC4D" id=ieooui></object> <style> st1\:*{behavior:url(#ieooui) } </style> <![endif]--><style> <!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-GB;} @page Section1 {size:612.0pt 792.0pt; margin:72.0pt 90.0pt 72.0pt 90.0pt; mso-header-margin:35.4pt; mso-footer-margin:35.4pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> </style><!--[if gte mso 10]> <style> /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman";} </style> <![endif]--> The innate immune system is a flawed compromise. If it is too aggressive in attacking suspect non-self items the result is auto-immune disease, if it is too conservative then genuine invaders get more of a foothold and therefore become more difficult to clear.
<o:p> </o:p>
The argument being made in the text box above (from pf11.blogspot.com) is not mutually exclusive with the ‘pop science’ the author is deriding. In both cases the damage done in the lungs is being attributed to a combination of lyses – as a direct result of viral infection – and damage done by an overly robust immune response (AKA cytokine storm). In apoptosis there is an orderly dismantling and recycling of the cells contents. As part of this process if the cause of cell death is a pathogen parts of the pathogen are presented to the immune system by being bound to proteins on the exterior of the cell wall. This flags the infection to the immune system in a controlled manner and will initiate an immune response. If the virus replicates too fast this controlled cell death is replaced by lyses in which the cell ruptures. This uncontrolled release will lead to a massive immune response as not only all the partially built viral proteins are attacked but many of the host cells own proteins are also subject to attack as they are now not where they are supposed to be.
This is the story of Goldilocks and the three bears too weak an immune response and the virus runs wild (baby bear), too strong – after initially not spotting the attack – and the combined immune plus viral damage is catastrophic or just right – spotted early, good <st1:stockticker>MHC</st1:stockticker> presentation to promote controlled response, gradual controlled escalation leading to combined innate and adaptive immune system clearance of the virus.
The moral of the story is slow and steady wins the race (Thanks Aesop).

[gsgs]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

is E better then D ?
it can still goto G

[tropical]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

The moral of the story is slow and steady wins the race (Thanks Aesop).

Thank you JJ. for the gived answer/suggestion.

So, if we take it:
slow but enaugh steady powerfull immune response,
could win the race.

That means also the slow, but weaker not steady immune systems, could loose.

But both the responses will loose if the supposed virus 225G/E changes starts to circulate largely, and if proved to be more right the scientific theory of the viral ability to suspend innate immunity for up to two days post-infection.

Such viral ability (if proved) could be directly linked with the viral distress (or cytokine storm) which appears few days after, with haemorhage.

In the above case, there will be no help with additional prior immune enhancing of the body to escape the illness, because the virus will not start the body response for the first few days.

The second consequence is that the body will not send any unusual alarm (symptoms) the first few days during which the lungs fastly filled up with viruses,
so no antivirals will be administrated in the optional time schedule of 2 days of lungs filling.

Old mutation, G/E/..., now widening and spreading more, or new ones, if the result of them are the above, that seems an dangerous route of that chimera virus.

The decisional responsability of not trying to slow/break its early dissemination by any measure at the begining, is now augmenting.

___

#49, PH11:
Our team continues to hold an opinion that we first described in 2006 concerning Cytokinic Dysregulation and the NS1 protein of Influenza. Succinctly, the viral ability to suspend innate immunity for up to two days post-infection, as characterised by Mount Sinai this year, prevents the early and required pro-inflammatory Cytokinic Response to viral detection. That blunting, taken in conjunction with detailed studies around adaptive immunity, may result not only in failure to clear the virus from some patients in a timely fashion, but also in failure to produce a useful quantity and competence of memory T-cells and Ab. The early failure to clear a rapidly replicating virus like H5N1 or PF11 results in a frank trauma to the immune system when the first generations of viral progeny lyse their host cells after being undetected and flood the tissues with virii and toxic cell detritus.

[Heather]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

FINLAND AND SWEDEN not on WHO's list of mutated virus countries - wonder why ? :



H1N1 virus in a changed form was observed in Finland in July
published today at 12:57 pm, last updated today at 15:21


In Norway, the recently observed swine influenza virus variant has been found in Finland, too - several months ago. Health and Welfare (THL) says that the same virus variant was found in July 2009 infected patients.

THL says transformation is typical of the influenza virus. In Norway or elsewhere in the observed variations do not affect the essential characteristics of the virus: virulence is a former, anti-viral drugs and vaccines do still have a great power, says a press release, THL.

WHO and the European Center for Disease According to these modifications have been observed since the spring around the world.

Wales and the USA is currently being examined viral drug-resistant strains can spread from person to person. Health and Welfare will monitor the situation constantly.

YLE News

http://yle.fi/uutiset/kotimaa/2009/11/h1n1-viruksen_muuttunutta_muotoa_myos_suomessa_1180282.html

http://www.smittskyddsinstitutet.se/nyhetsarkiv/2009/angaende-variant-av-den-nya-influensan-i-norge/

Sweden
Subject variant of the new flu in Norway

Norwegian authorities reported November 20 that it has found a new variant of flu that may cause more severe disease. Virus Strains with this mutation has previously been detected in other parts of the world since the month of April in severely and mildly ill. Although other mutations in the same location in the viral genome was detected in both hard as mildly ill.

Although variation existed long have not seen any widespread dissemination of and only found it in a few of all those seriously ill patients. On one of WHO laboratories have already shown that the vaccine also protects against this variant. Therefore, assessing Smittskyddsinstitutet not to find in Norway is currently a cause for greater concern.

The Norway-based parties fear that this virus variant is more serious in that it found material from the two deaths, and from a patient who was seriously ill. In a previous study of a different influenza A virus has been shown that this particular mutation, allowing it to bind to cells in the lungs. Normally, influenza virus binds primarily to the upper respiratory tract, and pneumonia as seen in the new flu is attributed to the H1N1 pandemic has a greater ability to bind to lung cells than seasonal influenza. It has not shown that the described mutation in the H1N1 pandemic makes this particular variant binds easier further down the respiratory tract than other pandemic H1N1 variants circulating. In Sweden, the variant was detected in two patients who were cared for in ECMO in July and in August.

[sharon sanders]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

The D225G change in 2009 H1N1 influenza virus is not a concern

by Vincent Racaniello on <abbr class="published" title="2009-11-24">24 November 2009</abbr>





The Norwegian Institute of Public Health recently identified a mutation in 2009 H1N1 influenza virus isolated from two patients who died and one with severe disease. It has been suggested that this mutation, which causes a change from the amino acid aspartic acid to glycine at position 225 of the viral HA protein (D225G), could make the virus more likely to infect deeper in the airways and cause more severe disease. What is the basis for this concern and does it have merit?


Attachment of all influenza A virus strains to cells requires sialic acids. There are a number of chemically different forms of sialic acids, and influenza virus strains vary in their affinity for them. Human influenza A strains bind preferentially to sialic acids linked to galactose by an alpha(2,6) bond, while avian and equine strains prefer alpha(2,3) linked sialic acids.


The type of sialic acid preferred by influenza viruses is controlled by amino acids in the HA protein. Amino acids 190 and 225 are important determinants of receptor binding specificity of the 1918 H1 hemagglutinin. The HA of the 1918 strain A/South Carolina/1/18 prefers alpha(2,3) linked sialic acids; the New York variant, isolated in September 1918, binds both alpha(2,3) and alpha(2,6) sialic acids. These two H1 hemagglutinins differ only by a single amino acid, position 225, which is aspartic acid (D) in the South Carolina strain and glycine (G) in the NY strain. When amino acid 190, which is D in both strains, is changed to E in the NY HA, the virus (AV18) preferentially binds alpha(2,3) sialic acids. These findings are summarized in the table.

Different isolates of the 2009 H1N1 influenza virus have D at HA at amino acid 190 and mostly D at amino acid 225. The virus prefers to bind to alpha(2,3) linked sialic acids. The amino acid change D225G would be expected to produce a virus with preference for both alpha(2,3) and alpha(2,6) linked sialic acids.


In the human respiratory tract, alpha(2,6) linked sialic acids are dominant on epithelial cells in the nasal mucosa, paranasal sinuses, pharynx, trachea, and bronchi. Alpha(2,3) linked sialic acids are found on nonciliated bronchiolar cells at the junction between the respiratory bronchiole and alveolus, and on type II cells lining the alveolar wall.


Based on these considerations, it could be hypothesized that the D225G change would allow the 2009 H1N1 virus to replicate deeper in the respiratory tract. But 2009 H1N1 virus without this amino acid change can already replicate deep in the respiratory tract of ferrets, and probably also in humans. Cells with alpha(2,6) linked sialic acids are present in the lower respiratory tract of humans. So it’s not clear if any effect on virulence would be conferred by the ability of the 2009 H1N1 strain to bind alpha(2,3) linked sialic acids.


An important consideration is that the D225G amino acid change has a negative impact on transmission. The change from D to G at amino acid 225 of the 1918 HA significantly impairs transmission among ferrets. When both D225G and D190E are present, transmission is abolished. These changes do not impair viral replication or virulence in the respiratory tract of inoculated animals.


Transmissibility is clearly a positive selection factor for viral evolution. There may be selection for increased virulence only if there is no negative impact on viral transmission. Given these considerations, the choice between an H1 HA amino acid at position 225 that allows efficient transmission (D225) or one that impairs transmission and might or might not allow multiplication deeper in the lung (D225G) seems obvious.


Tumpey, T., Maines, T., Van Hoeven, N., Glaser, L., Solorzano, A., Pappas, C., Cox, N., Swayne, D., Palese, P., Katz, J., & Garcia-Sastre, A. (2007). A Two-Amino Acid Change in the Hemagglutinin of the 1918 Influenza Virus Abolishes Transmission Science, 315 (5812), 655-659 DOI: 10.1126/science.1136212
Shen J, Ma J, & Wang Q (2009). Evolutionary Trends of A(H1N1) Influenza Virus Hemagglutinin Since 1918. PloS one, 4 (11) PMID: 19924230

[sharon sanders]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

Welcome Heather!

[Digger]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

In summary, I believe NS1 currently stands uncorrected and has been on target.

If you follow the blog thread, NS1 has systematically predicted this outcome based on comparing the genetic trail with the known genetic and clinical path of predecessors.

NS1, whoever your are, if you are reading........, , .....Thanks!

A great excellent benchmark example of proper use of scienticfic observation and analysis methods.

JimO--

Hang in there. Your family will be OK. I prayed and have already given thanks for the answer. In addition, I think there were more than 2 of us that were doing the same

Digger


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[sharon sanders]

Re: 225G Preliminary Worldwide Tracking &amp; Evaluation

is E better then D ?
it can still goto G

from NS1 via email -

"We do not have enough clinical evidence to correlate 225E.

When a virus changes at this phase of Influenza Flux, either host-adapting or base species-reverting, and if the change is new to that reservoir, the change creates an opportunity for higher pathology. In a few words, change at this point of zoonosis is generally bad."