Don't Blame Birds for 1918 Flu

[KC]

So,

It could be possible that both a novel H1N1 virus (swine) and a novel H5N1 (avian) virus are circulating around the globe, and the common mixing vessels (swine or humans) are contributing to re-assortment and/or recombination? At the same time, normal seasonal influenza was/is also spreading.

Influenza is influenza.... it evolves... sometimes rapidly regardless of where the final pandemic origin spreads from.

My big question... and I've asked it many times here before and been shunned.... What might the effects of other endemic or epidemic non-influenza viruses that have similar structures have in the equation?

Could co-infections between an influenza virus and a non-influenza virus cause a problem if they share similar molecular traits?

[AlaskaDenise]

Originally Posted by super_flu

......mRNA's are often expressed on the surface of a cell. If a cell is infected with a virus it will express those mRNAs. If the mRNAs look similar to host sequences (ie. similar codon usage to that of the host) then the host will not recognize the infection...........

That was a great explanation of the increased mutation rate.

In thinking about this more, now I'm a little confused.

In "If a cell is infected with a virus it will express those mRNAs." - is "it" the new virons that will now have the host mRNAs on their (viron) surfaces?

Assuming the answer is yes, then....

In "If the mRNAs look similar to host sequences ..... then the host will not recognize the infection" - if the "baby" virons are disguished (using mRNA) to look like the host so they can escape detection, how does the immune system ever fight them off? (When I asked my self this question, I realized I might have misunderstood the explanation, hence this question)

.

[gsgs]

they (edit---the mRNAs) look just a tiny bit different, giving a slighly increased
probability to survive - the process goes over decades.

But nucleotides are not recognized by the immune system
as I understand, only amino-acids.
Nor are they expressed on the cell-surface (?)

mammalean flu acquires more A,T nucleotides over the
years,decades,centuries - but this is presumably another process


epitopes in the cell are transported to the surface, so the killer cells
can see which cells to kill

[HenryN]

Originally Posted by gsgs

they look just a tiny bit different, giving a slighly increased
probability to survive - the process goes over decades.

But nucleotides are not recognized by the immune system
as I understand, only amino-acids.
Nor are they expressed on the cell-surface (?)

mammalean flu acquires more A,T nucleotides over the
years,decades,centuries - but this is presumably another process


epitopes in the cell are transported to the surface, so the killer cells
can see which cells to kill

Interferon

[gsgs]

Brevig/1918 is more distant in PB2 to all other early human H1N1 than in PB1 or PA.
This indicates that it is not the ancestor of all these but rather
a reassortant.
But the same is true for Wilson-Smith/1933 , so there should be other reasons

Hickox/1940 seems to be from ~1945 rather than from 1940
Swine/Jamesburg/1942 seems to be from ~1932 rather than 1942

-----edit-------------
otoh, this (more mutations in PB2) is not seen in the swine linage
but the swine segments don't show any similarity with the human ones,
so there probably was no mixing human-swine after 1918

where should this new PB2 have come from ?

[AlaskaDenise]

Originally Posted by gsgs

they ........

??? What is the "they"?

What post are you referencing?

.

[Emily]

Originally Posted by KC

So,

It could be possible that both a novel H1N1 virus (swine) and a novel H5N1 (avian) virus are circulating around the globe, and the common mixing vessels (swine or humans) are contributing to re-assortment and/or recombination? At the same time, normal seasonal influenza was/is also spreading.

Influenza is influenza.... it evolves... sometimes rapidly regardless of where the final pandemic origin spreads from.

My big question... and I've asked it many times here before and been shunned.... What might the effects of other endemic or epidemic non-influenza viruses that have similar structures have in the equation?

Could co-infections between an influenza virus and a non-influenza virus cause a problem if they share similar molecular traits?

Is this along the lines of what you are wondering about?

http://pathmicro.med.sc.edu/mhunt/genet.htm
"Recombination enables a virus to pick up genetic information from viruses of the same type and occasionally from unrelated viruses or even the host genome

[kiwibird]

Really interesting Emily. Is this part of the answer to KC's question?

[gsgs]

> seasonal and classic swine H1N1 viruses were not derived directly
> from BM/1918, but their precursors co-circulated during the pandemic.

> the 1918 H1N1 pandemic virus most likely was generated by
> reassortment between mammalian viruses and a previous human
> strain and was not a pure avian virus.

then it would have been much different and we would see it in BM/18

> the BM/1918 virus H1, N1, PB1, PA, and NP genes clustered with human
> H1N1 influenza A viruses, whereas its PB2, M, and NS genes
> clustered with swine.

differences in promille in the 8 segments:
BM/18-WS/33 : 48,32,37,81,42,68,27,29
BM/18-SW/31: 44,46,51,65,44,51,39,45

so I'd say there were more mutations in humans in HA and NA (because of immunity)
and more mutations in swine in the other 6 segments

> TMRCA:1903,1914,1914,1916,1909,1913,1896?,1908

reassortments are rare, so multiple reassortments in different years are even rarer

AT-score in the 8 segments: (the longer in mammals, the higher the score)

BM/18:5568,5665,5620,5614,5310,5751,5152,5465
WS/33:5621,5772,5720,5878,5354,5630,5340,5563
Ma/54:5740,5856,5784,5791,5368,5848,5266,5622
Sw/57:5620,5772,5754,5942,5456,5874,5246,5649

> (Table 1) suggest those genes (1,5,8)
> have circulated in humans since the 1889 H3 influenza pandemic

H3N8 ? The same virus which is still in horses,dogs. That virusis rare in birds,
did it go from birds to humans in 1889 in all segments ?
Still 19 years to gain in AT-score, which apparantly hasn't happened (?)

> However, our results suggest that the same NP gene lineage has
> been circulating in human influenza A viruses since the 19th
> century, consistent with the report by Gammelin et al. (19). [from 1990]


> Taken together, our results indicate that it is unlikely that the
> BM/1918 virus could have resulted from adaptation of an entire
> avian virus introduced directly into humans shortly before the
> pandemic. More likely, it was generated by reassortment between
> previously circulating swine and human strains and introduced
> avian viruses over a period of years.


> Phylogenetic relationships between BM/1918 and classic swine
> H1N1 virus PB2, M, and NS genes also indicate that classic swine
> H1N1 is a reassortant between BM/1918 and an unknown virus.

which segments from BM/1918 ?

> As such, classic swine H1N1 is derived partially from BM/1918
> and is not a precursor of the 1918 pandemic virus (Fig. 1 and
> Figs. S1–S8) (9).


I don't believe it (yet).
I haven't looked at the phylo-graphs or the 1957,1968 data yet.
But this looks even more doubtful to me, that 1957,1968
should have been created years ago


http://www.setbb.com/fluwiki2/viewtopic.php?p=1229

[super_flu]

Originally Posted by AlaskaDenise

That was a great explanation of the increased mutation rate.

In thinking about this more, now I'm a little confused.

In "If a cell is infected with a virus it will express those mRNAs." - is "it" the new virons that will now have the host mRNAs on their (viron) surfaces?

Assuming the answer is yes, then....

In "If the mRNAs look similar to host sequences ..... then the host will not recognize the infection" - if the "baby" virons are disguished (using mRNA) to look like the host so they can escape detection, how does the immune system ever fight them off? (When I asked my self this question, I realized I might have misunderstood the explanation, hence this question)

.

The answer is no.

The host cell will express mRNAs on its surface. Regardless of whether viral or not. It's a mechanism for host cells to monitor its cells are behaving correctly. During infection viral genetic material and proteins are produced at high levels. Some of these RNAs are placed on the surface of the host cell. Other cells may recognize these RNAs as not self and kill the cell. If viruses accumulate mutations to account for codon usage bias this will make the viral genome appear more like its host. This does not necessarily result in new phenotypes. In other words, these are silent mutations that do not result in new amino acids. They just use codes for the same amino acid that are similar to the host species.

[super_flu]

Originally Posted by gsgs

they (edit---the mRNAs) look just a tiny bit different, giving a slighly increased
probability to survive - the process goes over decades.

But nucleotides are not recognized by the immune system
as I understand, only amino-acids.
Nor are they expressed on the cell-surface (?)

mammalean flu acquires more A,T nucleotides over the
years,decades,centuries - but this is presumably another process


epitopes in the cell are transported to the surface, so the killer cells
can see which cells to kill

The process can happen much much much faster than decades. RNA viruses are amongst the fastest evolving genetic populations known. These mutations may accumulate in relatively few replication cycles.

If swine hosts have a similar codon usage bias as humans, yet with shorter life spans and relatively few symptoms from influenza infection it suggests that these hosts would be perfect to mediate mammalian adaptation. Add human handlers for frequent close contact and increased probability of interspecies transmissions

[super_flu]

Originally Posted by gsgs

>


I don't believe it (yet).
I haven't looked at the phylo-graphs or the 1957,1968 data yet.
But this looks even more doubtful to me, that 1957,1968
should have been created years ago

I'm surprised you're skeptical. Especially considering we're all concerned about a novel virus that has taken as long as 30 years (the M and Na genes were introduced into Eurasian swine in 1979) for all the viral segments to be in the correct host at the same time to emerge and cause our current pandemic.

[gsgs]

if some early H1N1 X in some segment was not derived directly from BM/18,
then there should have been avian viruses which are closer to that virus X
in that segment than to BM/18.
Or should at least have unusually many mutations which coincide with
X in the positions where X differs with BM/18.

Some such avian viruses should still be around or should have been isolated
in the years since 1918.

But I found none. (except some turkeys which obviously caught a recent
swine virus)


-------------edit--------------
sorry, this is not true what I said , I made a thought error.
If there was just one introduction from birds
to humans in -say- 1903 and then it developed independently
to BM/18 and WS/33, then all birds should be more distant from
WS/33 than from BM/18.
But the time of the introduction may be estimated from these
differences

[super_flu]

Originally Posted by gsgs

if some early H1N1 X in some segment was not derived directly from BM/18,
then there should have been avian viruses which are closer to that virus X
in that segment than to BM/18.
Or should at least have unusually many mutations which coincide with
X in the positions where X differs with BM/18.

Some such avian viruses should still be around or should have been isolated
in the years since 1918.

But I found none. (except some turkeys which obviously caught a recent
swine virus)

There's no reason to suspect that further reassortment happened with avian viruses. In fact, currently we have a pandemic H1N1 virus which is antigenically similar to a seasonal H1N1 virus but contains gene segments most closely related to another seasonal subtype H3N2. All three of these viruses currently co-circulate in humans. There is no reason to suspect that further reassortment will can not happen with these viruses. In fact this is a major worry that researchers are monitoring (as well as a million other worries). Who knows what will be circulating in 30 years and how they'll be related to say California/04/2009

The phylogenies and date estimates, however, do suggest that prior to the emergence of the 1918 virus their was reassortment and the gene segments may not have been introduced as a single intact particle.

This might be the best idea we get of how the 1918 virus was generated. I suspect that ideas surrounding the generation of the 1918 virus will always be contentious.

BM/1918 is only one virus in a population and there is no reason to suspect that this was typical of those circulating. The search for this virus did not look to sample the diversity of viruses circulating at that time, but rather to search for the most lethal example. In Brevig Mission I believe the virus was extremely fatal and all but three people died (my memory might be wrong on the number of survivors).

[gsgs]

wherever it (1918 panflu) had come from, originally it was in birds, as all flu-A.
Whether it went into mammals 1918 or 1890, doesn't matter so much.(---edit--- for this analysis)
There should still be some bird-sequence showing it, being closer to
~1930s-sequences than to BM/18. (if that 1930s sequences did not
directly come from BM/18 as the paper suggests)

BM/18 is not so unique. We have 3 viruses from 1918 and one from 1919.
Partial sequences only, but they coincide with BM/18.

You suggest the pandemic strain had died and some unnoticed
seasonal strain did take over ? Any example that this ever happened ?

Local differences of the strain are presumably small, as was seen in other pandemics.
H3N2 did reassort a couple of times with segments from old H2N2 between 1968-1972,
though. But not many differences in the single segments.


---------edit--------
sorry, I made a mistake, see my post above

[HenryN]

Originally Posted by super_flu

There's no reason to suspect that further reassortment happened with avian viruses. In fact, currently we have a pandemic H1N1 virus which is antigenically similar to a seasonal H1N1 virus but contains gene segments most closely related to another seasonal subtype H3N2. All three of these viruses currently co-circulate in humans. There is no reason to suspect that further reassortment will can not happen with these viruses. In fact this is a major worry that researchers are monitoring (as well as a million other worries). Who knows what will be circulating in 30 years and how they'll be related to say California/04/2009

The phylogenies and date estimates, however, do suggest that prior to the emergence of the 1918 virus their was reassortment and the gene segments may not have been introduced as a single intact particle.

This might be the best idea we get of how the 1918 virus was generated. I suspect that ideas surrounding the generation of the 1918 virus will always be contentious.

BM/1918 is only one virus in a population and there is no reason to suspect that this was typical of those circulating. The search for this virus did not look to sample the diversity of viruses circulating at that time, but rather to search for the most lethal example. In Brevig Mission I believe the virus was extremely fatal and all but three people died (my memory might be wrong on the number of survivors).

There are several 1918 isolates and all are virtually identical.

[HenryN]

Commentary

[Mamabird]

Originally Posted by super_flu

... In fact, currently we have a pandemic H1N1 virus which is antigenically similar to a seasonal H1N1 virus but contains gene segments most closely related to another seasonal subtype H3N2.....

I'm sorry, but which seasonal H1N1 are we talking about here? From every indication, the current Swine Flu is not antigenically related to seasonal flu. In fact, the closest we can come to similarities is that the Swine Flu HA segment is related to the old 1918 HA segment that has been resident in swine for the last 90 years. In the human population this HA was relplaced by H2 in 1957.

[AlaskaDenise]

Originally Posted by niman

Commentary

Commentary

1918 Pandenic H1N1 Human/Swine Recombination

Recombinomics Commentary 14:41
July 14, 2009

It has become almost common wisdom that the virus that caused the 1918 flu pandemic was an avian strain introduced into the human population shortly before the pandemic erupted. But a new study disputes that hypothesis, arguing instead that genes of the 1918 virus had circulated in mammalian hosts, most likely pigs and humans, for several years before 1918.

The origins of the 1918 virus, which is estimated to have killed at least 20 million people, are still controversial. After painstakingly piecing together the genome of the extinct strain, a team led by virologist Jeffery Taubenberger, then at the Armed Forces Institute of Pathology in Washington, D.C., concluded in 2005 that the virus most closely resembled viruses of avian origin; the team suggested it had become transmissible between humans after a couple of key changes

The above comments on the recent PNAS paper as well as the Nature paper in 2005 provides some background on the data supporting a human / swine origin of 1918. The sequence of a 1917 avian isolate clearly demonstrated that avian sequences in 1917 were similar to current avian sequences and easily distinguished from mammalian sequences, such as pandemic 1918 H1N1, seasonal H1N1 and swine H1N1.

The Nature paper of 2005 identified 10 polymorphisms which were said to be pandemic -specific because they were in the 1918 pandemic sequence but not avian sequences. However, these markers were simply mammalian markers and were not only in the H1N1 1918 pandemic sequence but also in seasonal H1N1 and swine H1N1. Thus, the markers did not identify changes that created a pandemic strain, but instead provided additional data supporting a human / swine origin of 1918, as had been seen from phylogenetic analysis.

The swine origin is also supported by the recent Nature paper showing that sera from patients alive in 1918 had antibodies that not only saw the 1918 pandemic H1N1 strain, but also the current 2009 pandemic strain which is a swine H1N1. Thus, both the antibody data as well as phylogenetic analysis support a mammalian (human and swine) origin of 1918.

However, detailed analysis of the 8 gene segments of the 1918 virus show that it is a recombinant with alternating blocks of swine and human polymorphisms. In fact approximately 90% of the polymorphisms in each of the eight gene segments can be found in two parental sequences, WSN/33 representing human H1N1 and swine/Iowa/15/1931 representing swine H1N1. Although there are some avian polymorphisms, the vast majority of polymorphisms is mammalian and can in fact be found in two isolates from the early 1930's.

These data have important implications for the current pandemic strain, because it is a swine H1N1 which can efficiently transmit in humans. It has spread throughout the human population worldwide, and now is in position for further adaptation to human host via recombination with seasonal H1N1, which is well adapted to humans.

There are several obvious candidates in seasonal H1N1 which could significantly impact swine H1N1. One of the 10 markers identified in the 2005 Nature paper was PB2 E627K. This polymorphism is in virtually all influenza A seasonal flu isolates. It allows for most efficient replication at 33 C, which leads to upper respiratory infections and a preference for seasonal spread, when cold temperatures keep the human nose close to the optimal temperature for E627K. In contrast, the avian version, E627, allows for most efficient replication at 41 C, the body temperature of birds. Since the swine H1N1 PB2 is avian, it has E627, which may lead to less efficient transmission in the winter, but higher transmission in the summer, and associated replication the lower respiratory tract. E627K was reported in one isolate in Shanghai but was only found in the sequences from the original sample as well as the first clone. The second clone had reverted back to E627.

Another potential acquisition from seasonal H1N1 is H274Y. Although this isn't a mammalian specific polymorphisms, it is present on almost 100% of seasonal H1N1 and has a history of jumping from one genetic background to another. It has been reported in three pandemic swine isolates, including a patient traveling from San Francisco to Hong Kong who had not received oseltamivir, raising concerns of a fit pandemic H1N1 with H274Y. Moreover, this isolate and other related isolates without H274Y also have a receptor binding domain change D225E, which may be important in establishing dominance via genetic hitching. A change at the same position, D225N, was associated with the establishment of H3N2 seasonal flu with adamantane resistance, S31N.

Thus, the movement of swine H1N1 into the human population creates the environment for rapid adaptation to human hosts and the acquisition of key polymorphisms from seasonal H1N1, which could cause significant problems in the upcoming months.

.

[super_flu]

Originally Posted by niman

There are several 1918 isolates and all are virtually identical.

Sure, but we're discussing reassortment and therefore need to know the genomic constellation of these viruses.

[super_flu]

Originally Posted by Mamabird

I'm sorry, but which seasonal H1N1 are we talking about here? From every indication, the current Swine Flu is not antigenically related to seasonal flu. In fact, the closest we can come to similarities is that the Swine Flu HA segment is related to the old 1918 HA segment that has been resident in swine for the last 90 years. In the human population this HA was relplaced by H2 in 1957.

I'm not saying that these different subtypes are antigenically cross-reactive. But both of these molecules are H1 and N1 subtypes. they have related evolutionary histories, even if this history is 90+ years removed, and they have similar shapes. Seasonal H1N1 from 2008 is not cross-reactive with seasonal H1N1 from 2000. But they are both related.

[super_flu]

Originally Posted by gsgs

wherever it (1918 panflu) had come from, originally it was in birds, as all flu-A.
Whether it went into mammals 1918 or 1890, doesn't matter so much.(---edit--- for this analysis)
There should still be some bird-sequence showing it, being closer to
~1930s-sequences than to BM/18. (if that 1930s sequences did not
directly come from BM/18 as the paper suggests)

BM/18 is not so unique. We have 3 viruses from 1918 and one from 1919.
Partial sequences only, but they coincide with BM/18.

Actually, it does matter. Taubenberger et al suggested that this virus emerged in the human population as an intact particle from the avian gene pool directly shortly before the 1918 pandemic. The analysis in this paper and your own analysis suggest that these viruses did not emerge simultaneously. If it wasn't simultaneous introduction of genes then it was sequential introduction with reassortment.

The 1919 goose influenza sequence is phylogenetically distantly related to the pandemic.

Originally Posted by gsgs

You suggest the pandemic strain had died and some unnoticed
seasonal strain did take over ? Any example that this ever happened ?

I don't think it's impossible. The phylogenetic evidence suggests that these viruses (1918, classic swine, seasonal H1N1) are all different viruses. The date estimates suggests that these all co-circulated. If I can think of better evidence I'll let you know.

Originally Posted by gsgs

Local differences of the strain are presumably small, as was seen in other pandemics.
H3N2 did reassort a couple of times with segments from old H2N2 between 1968-1972,
though. But not many differences in the single segments.

The seasonal diversity of H1N1 and H3N2 is high enough to need new vaccines annually. There is no reason to suggest that local diversity would be lower. What pandemics are you referring to? I'm not sure I understand what you are suggesting here. Could you clarify?

[Mamabird]

Originally Posted by super_flu

I'm not saying that these different subtypes are antigenically cross-reactive. But both of these molecules are H1 and N1 subtypes. they have related evolutionary histories, even if this history is 90+ years removed, and they have similar shapes. Seasonal H1N1 from 2008 is not cross-reactive with seasonal H1N1 from 2000. But they are both related.

Got it. Thanks!

[AlaskaDenise]

From new PNAS paper:

“Here we provide the first evidence that seasonal H1N1 viruses
were not derived directly from BM/1918 but co-circulated during
the pandemic. This evidence may be relevant to the current
emergence and potential pandemicity of swine-derived H1N1
viruses in humans (1).”

Can we interpret this to disagree with “experts” advice that those of us born before 1957 have some protection against the novel H1N1, because of our exposure to the earlier H1N1?

-------------------------

Regarding the “BEAST” - can this system be aimed “forward” to look at the current pandemic & derive some information that would assist in reducing severe illness and death? (e.g., some data regarding choice of an appropriate anti-viral therapy)

If they had strategic samples could the system perform a “forward-analysis”?

.

[gsgs]

my argument above that there should be birds to test the
hypothesis was flawed, I edited it.
I'm thinking about other ideas to test it
(that WS/33 and SW/31 and others did not descend from BM/18
in some segment)

All previous known pandemics were caused by one new virus
which was introduced and after some years this virus killed
previously existing human flu-A viruses.

[blacknail]

With the ferret studies showing that the pandemic strain replicates deeper in the lungs and is harder to detect in nasal swabs than the seasonal strain, I'm thinking that the 41 degree replication is the reason. Patients immediately get a high fever which would normally ward off the seasonal strain, but actually works against the patient with this strain which can replicate most effectively at 41 degrees C. Probably younger patients are able to mount a higher temperature which is one reason they are more likely to succumb as they are simply making their lungs more hospitable for the virus to replicate. My guess is that if the pandemic strain picks up the 33 degree gene it will be less severe.

[blacknail]

Also, there were reports that patients cared for outdoors fared much better than those treated in the hospitals in 1918. Some people speculated that this was due to Vitamin D exposure, but perhaps these people were breathing in colder air which lowered the temperature in the lungs just enough to slow the virus replcation. Kind of like croup can be relieved with cold air.

[HenryN]

Originally Posted by gsgs

my argument above that there should be birds to test the
hypothesis was flawed, I edited it.
I'm thinking about other ideas to test it
(that WS/33 and SW/31 and others did not descend from BM/18
in some segment)

All previous known pandemics were caused by one new virus
which was introduced and after some years this virus killed
previously existing human flu-A viruses.

Phylogentic analysis can be done on each gene segement and there is NO doubt that all 8 gene segments came from recombination between swine H1N1 and human H1N1 (denying this is along the same lines as the avian origin, hocus pocus to maintain a hypotheses that is DOA - the DATA are VERY clear).

[HenryN]

Originally Posted by blacknail

Also, there were reports that patients cared for outdoors fared much better than those treated in the hospitals in 1918. Some people speculated that this was due to Vitamin D exposure, but perhaps these people were breathing in colder air which lowered the temperature in the lungs just enough to slow the virus replcation. Kind of like croup can be relieved with cold air.

1918 virus had E627K (human version that grows best at 33 C).

[super_flu]

Originally Posted by niman

Phylogentic analysis can be done on each gene segement and there is NO doubt that all 8 gene segments came from recombination between swine H1N1 and human H1N1 (denying this is along the same lines as the avian origin, hocus pocus to maintain a hypotheses that is DOA - the DATA are VERY clear).

Phylogenetic analysis can not detect the recombination that you've described in other posts. If you truly believe that you can, then I realise that the issue is not one where you have your own agenda, but rather you don't understand the methods you're using