Don't Blame Birds for 1918 Flu

[HenryN]

Re: Don't Blame Birds for 1918 Flu

Will you be attending the next Options meeting?

Probably.

[super_flu]

Re: Don't Blame Birds for 1918 Flu

In 2004 I said that 1918 was from human and swine H1N1 and presented the data at Options VI in Toronto (page 221 in abstract book) over two years ago (which your colleagues attended).

You should've submitted your paper for the proceedings. Maybe your arguments would be more convincing in a longer format. There's always another chance next year.

[gsgs]

Re: Don't Blame Birds for 1918 Flu

did they realize that shortly after such reassortments or species change
the mutation rate is usually higher for years ?

the evidence for 1957,1968 seems to be thin.

Can't they construct and publish their theoretical index-strains ?
("consensus") for the pandemic reassortments ?


3 strains cocirculating in 1918 and all surviving is not what we
usually see in pandemics, when one strain dominates and kills others.
So later strains from the 30s should be descendants

[gsgs]

Re: Don't Blame Birds for 1918 Flu

here is an older analysis from me for 1918 segments:
(always nucleotide-differences, since amino-acid differences can be
biased by functional constraints and are fewer)

http://www.setbb.com/fluwiki2/viewtopic.php?t=338&mforum=fluwiki2

assuming constant(time) nucleotide-mutation rates and
tracing the lines backward gives estimates for a common
ancestor of todays viruses and 1918 pandemic virus of:

segment H1N1 H3N2
-----------------------
 1      1880 1830
 2      1905 1700
 3      1905 1902
 4      1855
 5      1870 1893
 6      1900
 7      1900
 8

http://www.setbb.com/fluwiki2/viewtopic.php?t=424&mforum=fluwiki2

[super_flu]

Re: Don't Blame Birds for 1918 Flu

did they realize that shortly after such reassortments or species change
the mutation rate is usually higher for years ?

The clock model the authors used allows variable substitution rates among lineages. This is a similar method used in their recent Nature paper.

[super_flu]

Re: Don't Blame Birds for 1918 Flu

here is an older analysis from me for 1918 segments:
(always nucleotide-differences, since amino-acid differences can be
biased by functional constraints and are fewer)

http://www.setbb.com/fluwiki2/viewtopic.php?t=338&mforum=fluwiki2

assuming constant(time) nucleotide-mutation rates and
tracing the lines backward gives estimates for a common
ancestor of todays viruses and 1918 pandemic virus of:

segment H1N1 H3N2
-----------------------
 1      1880 1830
 2      1905 1700
 3      1905 1902
 4      1855
 5      1870 1893
 6      1900
 7      1900
 8

http://www.setbb.com/fluwiki2/viewto...forum=fluwiki2

This linear regression approach to estimating ancestral divergence dates has pretty much been replaced with the method used in this paper. A constant mutational rate does not take into account substitution rate changes that may result from inter-species transmission events.

[AlaskaDenise]

Re: Don't Blame Birds for 1918 Flu

....changes that may result from inter-species transmission events.

What are those changes?

.

[super_flu]

Re: Don't Blame Birds for 1918 Flu

What are those changes?

.

Cut my quote from above a little short...

...substitution rate changes that may result from inter-species transmission events.

It is generally believed that after an interspecies transmission event, such as transmission of avian influenza to humans, that nucleotide substitutions will accumulate at a higher rate due to viral adaptation to a novel host.

This phenomenon is observed throughout the genome, even though selection only takes place on the antigenic sites. I believe that codon usage bias is the reason we see increased rates on the internal genes as well. Mutations accumulate to look more like the novel hosts own genome - viral host mimicry. 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.

So, there are two reasons we often see substitution rates increase after an inter-species transmission event.

1. Antigenic escape
2. Codon usage bias

I'm sure someone will correct me if I've forgotten something.

[AlaskaDenise]

Re: Don't Blame Birds for 1918 Flu

Is that higher mutation rate, in the process of host adaptation, one of the reasons it's been difficult to make enough novel H1N1 egg-based vaccine?, i.e., the swine virus is naturally mutating to become a chicken virus and it would slow down the mass-production of swine-like virus.

Can I assume these details also describe vaccination-driven mutation?

.

[AlaskaDenise]

Re: Don't Blame Birds for 1918 Flu

Mean TMRCA estimates of each gene segment of H1N1 viruses shows that the components of the 1918 pandemic strain were circulating in
mammalian hosts, i.e., swine and humans, at least 2 to 15 years
before pandemic occurrence.

Various sources say that severe swine flu wasn't known until 1918. I'm not sure about the correctness of that statement, but given the above excerpt from the new PNAS paper, would it make sense that a low path swine flu would circulate for 2 to 15 years and only become noticeably-severe at the same time as a severe human influenza?

.

[super_flu]

Re: Don't Blame Birds for 1918 Flu

Is that higher mutation rate, in the process of host adaptation, one of the reasons it's been difficult to make enough novel H1N1 egg-based vaccine?, i.e., the swine virus is naturally mutating to become a chicken virus and it would slow down the mass-production of swine-like virus.

Can I assume these details also describe vaccination-driven mutation?

.

Oooh, good question!

In egg we do not see immune driven selection. Rather, in this case everything has to do with efficient replication. More specifically, how well does the cellular machinery and the viral RNP complex work in the specific environment. Egg adapted mutations do exist. However, as far as I know, there has been no examination of viral substitution rates during egg adaptation or even quasi-species diversity within a single egg. Hopefully some enterprising young scientist will conduct some experiments to answer these questions. I think they're very interesting.

With vaccine development, the viruses used are adapted to grow well in mammalian cells. Often a virus needs to be engineered so that it's safe to work with and grows efficiently, but is still similar enough that it's still suitable for vaccine use. However, the evolutionary pressure of growing in egg is minimal - one reason to use eggs for vaccine development. Both mechanisms I described in the previous post are driven by the immune system.

[AlaskaDenise]

Re: Don't Blame Birds for 1918 Flu

Both mechanisms I described in the previous post are driven by the immune system.

Yes - I didn't think long enough - an egg hasn't developed enough to have an immune system.

.

[AlaskaDenise]

Re: Don't Blame Birds for 1918 Flu

Rather, in this case everything has to do with efficient replication

If they put a "K" in position 627 of the PB2 and set the oven for 98.6F would it speed up vaccine production?

.

[super_flu]

Re: Don't Blame Birds for 1918 Flu

Various sources say that severe swine flu wasn't known until 1918. I'm not sure about the correctness of that statement, but given the above excerpt from the new PNAS paper, would it make sense that a low path swine flu would circulate for 2 to 15 years and only become noticeably-severe at the same time as a severe human influenza?

.

Swine flu wasn't isolated until 1930. But the data suggests that the precursor genes for the 1918/classic swine/seasonal H1N1 were present in some mammalian host. Based on what we know about the current outbreak I would suspect that host may have been swine.

The data also suggests that 2 variants, seasonal and the 1918 virus both co-circulated. This might help explain the less lethal spring wave followed by the more lethal second wave. It's possible they were caused by two different viruses.

[Evelyn]

Re: Don't Blame Birds for 1918 Flu

Cut my quote from above a little short...

...substitution rate changes that may result from inter-species transmission events.

It is generally believed that after an interspecies transmission event, such as transmission of avian influenza to humans, that nucleotide substitutions will accumulate at a higher rate due to viral adaptation to a novel host.

This phenomenon is observed throughout the genome, even though selection only takes place on the antigenic sites. I believe that codon usage bias is the reason we see increased rates on the internal genes as well. Mutations accumulate to look more like the novel hosts own genome - viral host mimicry. 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.

So, there are two reasons we often see substitution rates increase after an inter-species transmission event.

1. Antigenic escape
2. Codon usage bias

I'm sure someone will correct me if I've forgotten something.

Super_flu, thank you for that clear and extremely helpful explanation. I really appreciate it.