Rhiza Labs FluTracker Forum

Table S3. Partial receptor-binding domain sequence of 16 1918 pandemic influenza virus hemagglutinin HA1s
Case (date of
death)
Strain
name* Partial HA protein sequence (residues 172-234 of HA1 domain)†
Source of sequence
(case no.)
EVLVLWGVHHPPTGTDQQSLYQNADAYVSVGSSKYNRRFTPEIAARPKVRDQAGRMNYYWTLL 1918 Consensus Sequence
Pre-pandemic
peak
05/11/1918 A/IA/1/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G . . . . . . . . . . . . This report (19180511)
06/02/1918 A/IA/2/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G . . . . . . . . . . . . This report (19180602)
06/24/1918 A/DC/1/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . This report (19180624)
07/22/1918 A/SC/2/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G . . . . . . . . . . . . This report (19180722)
Pandemic
peak
09/21/1918 A/NY/2/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . This report (19180921)
09/24/1918 A/NY/3/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G . . . . . . . . . . . . This report (19180924d)¶
09/26/1918 A/NY/1/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G . . . . . . . . . . . . Reid, et al. 1999 (1)
(19180926e)
09/26/1918 A/SC/1/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reid, et al. 1999 (1)
(19180926c)
09/26/1918 A/NY/4/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . This report (19180926d)
09/27/1918 A/VA/1/
1918
. . . . . . . . . . . . . . . . . R . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . This report (19180927a)
09/30/1918 A/VA/2/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . This report (19180930b)
10/01/1918 A/VA/3/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . This report (19181001e)
10/08/1918‡ A/AFIP/1/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . This report (19181008c)
Post-pandemic
peak
11/17/1918§ A/BM/1/
1918
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reid, et al. 1999 (1)
11/13/1918 A/London/
1/1918
. . . . . . . . . . . . . S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reid, et al. 2003 (2)
02/13/1919 A/London/
1/1919
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I . G . . . . . . . . . . . . Reid, et al. 2003 (2)
*Full influenza strain names assigned to these sequences: A/IA/1/1918: A/Iowa/1/1918 (H1); A/IA/2/1918: A/Iowa/2/1918 (H1); A/DC/1/1918: A/District of Columbia/
1/1918 (H1); A/SC/2/1918: A/South Carolina/2/1918 (H1); A/NY/2/1918: A/New York/2/1918 (H1); A/NY/3/1918: A/New York/3/1918 (H1); A/NY/1/1918: A/New
York/1/1918 (H1N1) (1); A/SC/1/1918: A/South Carolina/1/1918 (H1N1) (1); A/NY/4/1918: A/New York/4/1918 (H1); A/VA/1/1918: A/Virginia/1/1918 (H1); A/VA/2/
1918: A/Virginia/2/1918 (H1); A/VA/3/1918: A/Virginia/3/1918 (H1); A/AFIP/1/1918: A/Armed Forces Institute of Pathology/1/1918 (H1) [Location of case not
available]; A/BM/1/1918: A/Brevig Mission/1/1918 (H1N1) (1); A/London/1/1918: A/London/1/1918 (H1) (2); A/London/1/1919: A/London/1/1919 (H1) (2).
†Theoretical protein sequences (single letter code) translated from the determined cDNA 1918 sequences as aligned to the HA1 domain sequence of A/SC/1/
1918 [GenBank accession no. AAD17229.1], numbering from start of the HA1 domain (sequence aligns to residues 189-254 of open reading frame) (1). Gray
highlighted amino acids represent components of the receptor-binding domain (RBD) (3–5). Dots match consensus sequence. Sequences determined for this
study were deposited in GenBank (accession nos. JN620390–JN620401).
‡Case was accessioned at the AFIP in conjunction with other cases from September 22, 1918 through October 24, 1918; date of death was arbitrarily set as
October 8, 1918.
§The pandemic outbreak in Teller Mission (now Brevig Mission, AK) occurred between November 15–20, 1918; date of death was arbitrarily set as November 17,
1918 (6).
¶Sequence analysis of case 19180924d suggests a polymorphism at HA1 codon 222, with a theoretical translation of both glycine (G) and asparagine (N).
1. Reid AH, Fanning TG, Hultin JV, Taubenberger JK (1999) Origin and evolution of the 1918 “Spanish” influenza virus hemagglutinin gene. Proc Natl Acad Sci USA 96:1651e1656.
2. Reid AH, et al. (2003) 1918 influenza pandemic caused by highly conserved viruses with two receptor-binding variants. Emerg Infect Dis 9:1249e1253.
3. Glaser L, et al. (2005) A single amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding specificity. J Virol 79:11533e11536.
4. Stevens J, et al. (2006) Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities. J Mol Biol 355:1143e1155.
5. Srinivasan A, et al. (2008) Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses. Proc Natl Acad Sci USA 105:2800e2805.
6. Rozell N (2005) Villager’s remains lead to 1918 flu breakthrough. Alaska Science Forum http://www2.gi.alaska.edu/ScienceForum/ASF17/1772.html (University of Alaska, Fairbanks,
Fairbanks, AK).
Sheng

http://www.pnas.org/content/suppl/2011/ ... 1179SI.pdf

_________________
www.twitter.com/hniman

Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak
Zong-Mei Shenga, Daniel S. Chertowa, Xavier Ambroggiob, Sherman McCallc, Ronald M. Przygodzkid, Robert E. Cunninghame, Olga A. Maximovaf, John C. Kasha, David M. Morensg, and Jeffery K. Taubenbergera,1
+ Author Affiliations

aViral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases,
bBioinformatics and Computational Biosciences Branch,
fOffice of the Chief, Laboratory of Infectious Diseases, and
gOffice of the Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
cClinical Pathology Laboratory, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702;
dDepartment of Veterans Affairs, Washington, DC 20420; and
eDepartment of Biophysics, Armed Forces Institute of Pathology, Rockville, MD 20850
Edited* by Robert G. Webster, St. Jude Children's Research Hospital, Memphis, TN, and approved August 16, 2011 (received for review July 11, 2011)

Abstract
The 1918 to 1919 “Spanish” influenza pandemic virus killed up to 50 million people. We report here clinical, pathological, bacteriological, and virological findings in 68 fatal American influenza/pneumonia military patients dying between May and October of 1918, a period that includes ∼4 mo before the 1918 pandemic was recognized, and 2 mo (September–October 1918) during which it appeared and peaked. The lung tissues of 37 of these cases were positive for influenza viral antigens or viral RNA, including four from the prepandemic period (May–August). The prepandemic and pandemic peak cases were indistinguishable clinically and pathologically. All 68 cases had histological evidence of bacterial pneumonia, and 94% showed abundant bacteria on Gram stain. Sequence analysis of the viral hemagglutinin receptor-binding domain performed on RNA from 13 cases suggested a trend from a more “avian-like” viral receptor specificity with G222 in prepandemic cases to a more “human-like” specificity associated with D222 in pandemic peak cases. Viral antigen distribution in the respiratory tree, however, was not apparently different between prepandemic and pandemic peak cases, or between infections with viruses bearing different receptor-binding polymorphisms. The 1918 pandemic virus was circulating for at least 4 mo in the United States before it was recognized epidemiologically in September 1918. The causes of the unusually high mortality in the 1918 pandemic were not explained by the pathological and virological parameters examined. These findings have important implications for understanding the origins and evolution of pandemic influenza viruses.

archaevirologypostmortemimmunohistochemistry
Footnotes
↵1To whom correspondence should be addressed. E-mail: taubenbergerj@niaid.nih.gov. Author contributions: J.K.T. designed research; Z.-M.S., D.S.C., X.A., S.M., R.M.P., R.E.C., O.A.M., J.C.K., and J.K.T. performed research; X.A. and O.A.M. contributed new reagents/analytic tools; Z.-M.S., D.S.C., X.A., J.C.K., D.M.M., and J.K.T. analyzed data; and J.K.T. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession no. JN620390–JN620401).
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/p ... pplemental.

http://www.pnas.org/content/early/2011/ ... 8.abstract

_________________
www.twitter.com/hniman

Flu Study Shows No Strange Mutation Caused 1918 Pandemic
By Maggie Fox

Updated: September 19, 2011 | 11:08 p.m.
September 19, 2011 | 10:59 p.m.
Preserved tissue taken from 68 soldiers who died from flu in 1918 show the influenza virus did not undergo some strange mutation that made it especially deadly, U.S. researchers reported Monday.

In fact, the very same version of H1N1 flu was circulating for months before it finally sparked a pandemic that swept around the globe during World War I, killing as many as 50 million people, Dr. Jeffery Taubenberger of the National Institute of Allergy and Infectious Diseases and colleagues reported.

“These findings have important implications for understanding the origins and evolution of pandemic influenza viruses,” they wrote in their report, published in the Proceedings of the National Academy of Sciences.

The H1N1 virus that caused the 1918 pandemic is a distant ancestor of the H1N1 swine flu currently circulating, which caused a mild pandemic when it emerged in 2009. Researchers are worried that a new virus could emerge that would cause an even more deadly pandemic and are trying to learn as much as possible to help the world prepare before that happens.

The report has some reassurances. All 68 of the soldiers whose preserved tissue was studied also had infections with bacteria – called bacterial co-infections. In the days before antibiotics these could be highly deadly, but modern antibiotics make it much more unlikely a patient will die. However, many of the victims of the 2009 pandemic, which killed about 12,000 Americans, according to Centers for Disease Control and Prevention estimates, had bacterial co-infections.

Taubenberger’s team studied preserved samples from autopsies of the 68 soldiers. They managed to find pieces of genetic material of flu virus in 37, including four samples taken from the earliest known victims of the 1918 pandemic.

They found the virus was identical to viral samples taken from later in the pandemic. Their findings confirm theories that this particular strain of H1N1 flu virus circulated quietly for months before the pandemic really developed. But they don’t explain why the 1918 pandemic killed so many people – an estimated 3 percent of victims, a very high percentage for influenza.

Vaccines prevent flu very well and antiviral drugs can help patients with severe infections to recover. But scientists fear a completely new flu virus could emerge and spread quickly before a vaccine could be developed. Current processes for making flu vaccines take months. And flu viruses quickly evolve resistance to antiviral drugs, making them less useful.

http://www.nationaljournal.com/healthca ... c-20110919

_________________
www.twitter.com/hniman

Contact: Anne A. Oplinger
aoplinger@niaid.nih.gov
301-402-1663
NIH/National Institute of Allergy and Infectious Diseases

NIH scientists find earliest known evidence of 1918 influenza pandemic
Examination of lung tissue and other autopsy material from 68 American soldiers who died of respiratory infections in 1918 has revealed that the influenza virus that eventually killed 50 million people worldwide was circulating in the United States at least four months before the 1918 influenza reached pandemic levels that fall.

The study, using tissues preserved since 1918, was led by Jeffery K. Taubenberger, M.D., Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The researchers found proteins and genetic material from the 1918 influenza virus in specimens from 37 of the soldiers, including four who died between May and August 1918, months before the pandemic peaked. These four cases are the earliest 1918 pandemic influenza cases they know to be documented anywhere in the world, the scientists say.

The clinical disease and tissue damage seen in the pre-pandemic cases were indistinguishable from those evident in cases that occurred during the height of the pandemic. This suggests, says Dr. Taubenberger, that over the course of the pandemic, the virus did not undergo a dramatic change that could explain the unusually high mortality it ultimately caused.

In the current study, the autopsy materials showed that the virus replicated not only in the upper respiratory tract but also the lower respiratory tract, in a pattern very similar to that of the 2009 pandemic influenza virus. The team also found evidence that two virus variants were circulating in 1918. In one, a key viral protein called hemagglutinin bound well to receptors on human respiratory cells, while the hemagglutinin from the other variant bound less efficiently. Despite this difference in binding ability, both viruses caused similar disease symptoms and replicated in a similar pattern within cells lining the respiratory tract, suggesting that differences in hemagglutinin binding capacity alone do not fully explain the unusually high mortality seen in the 1918 pandemic.

Bacterial co-infections were found in all 68 cases studied, the researchers noted. The role played by bacterial co-infections, such as bacterial pneumonia, in contributing to deaths in the 1918 pandemic was previously described by Dr. Taubenberger and his colleagues in a 2008 study. According to the study authors, the new data underscore the crucial role that bacterial infections can play in conjunction with any influenza virus, whether historic or future, and the need for public health officials to prepare to prevent, detect and treat bacterial co-infections during future influenza outbreaks.


###

ARTICLE: Z-M Sheng et al. Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak. Proceedings of the National Academies of Sciences DOI: 10.1073/pnas.1111179108 (2011).

Study co-authors Jeffery K. Taubenberger, M.D., Ph.D., Laboratory of Infectious Diseases, NIAID, and David M. Morens, M.D., Office of the Director, NIAID, are available to provide comment.

CONTACT: To schedule interviews, please contact Anne A. Oplinger, (301) 402-1663, aoplinger@niaid.nih.gov.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov/.

http://www.eurekalert.org/pub_releases/ ... 091911.php

_________________
www.twitter.com/hniman

The “Spanish” influenza was circulating in the population months before it peaked in the fall of 1918, according to a study published today (September 19) in the Proceedings of the National Academy of Sciences. The earlier cases could help reveal the flu’s geographic origin and how it evolved to be so infectious.

“They’ve done a really outstanding piece of work,” said Robert Webster, a virologist at St. Jude Children’s Research Hospital, who was not involved in the study. “This virus became extremely pathogenic in young men at about the time of the end of World War I,” and in order to do so it had to evolve to be more transmissible. “This paper shows how some of the changes occurred,” he added.

The 1918 influenza, which is thought to have evolved from an avian flu, began infecting young soldiers in September of 1918 and ultimately killed roughly 50 million people worldwide, said Jeffery Taubenberger, a viral pathologist at the National Institute of Allergy and Infectious Diseases. While some theories suggest the virus spread from water fowl to pigs on farms in the Midwest United States, where it emerged in its more deadly incarnation, no one knows for sure where the virus came from and how it became so virulent.

To find out, Taubenberger and his colleagues analyzed viral RNA from 68 autopsy samples of army recruits who had died in the months before and during the peak of the 1918 epidemic. Four of those samples came from the months of May to August, up to four months before the death toll started exploding. Consistent with later samples, early victims usually died because of pneumonia that took hold after being infected with the flu virus. The later cases didn’t seem to cause more severe disease than earlier ones.

But the researchers also found some key changes between the viruses isolated from earlier flu victims and those who died in the heat of the epidemic. Namely, in earlier cases, the hemagluttinin binding receptor, which helps the virus get a foothold in the body, was slightly more similar to that found in avian flu, while later cases showed a better fit with human hemagluttinin. Though the newer form of the receptor didn’t seem to make the disease replicate anymore quickly, “one possibility is that the form that predominates in the later fall case might have been more transmissible,” Taubenberger said.

The findings also show that the flu was circulating earlier than previously documented. In addition, the study offers a snapshot of how the virus was evolving, and further analyses may reveal what caused it to be so deadly.

Understanding what made this historic scourge so deadly could aid in designing treatments for modern flu, because all the flu pandemics that have occurred since are descendants of the 1918 version, Taubenberger said.

To get a more complete picture, Webster added, “it would be wonderful if they could obtain earlier clinical material for analysis to determine the precursors a little bit more about where these viruses came from.”

Z-M Sheng et al., “Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak,” Proceedings of the National Academy of Sciences, doi/10.1073/pnas.1111179108, 2011.


http://the-scientist.com/2011/09/19/191 ... fore-peak/

_________________
www.twitter.com/hniman

1918 was a recombinant between seasonal H1N1 and swine H1N1.

_________________
www.twitter.com/hniman

TORONTO - The virus responsible for the worst flu pandemic in known history was circulating in the United States for several months before it was recognized, new research published Monday shows.

It has been believed for years that infections in the spring of 1918 in the U.S. were a so-called "herald wave" of the Spanish flu pandemic, which eventually killed upwards of 50 million people worldwide.

But because the pandemic occurred before viruses could be isolated — before viruses were even known to exist — there hasn't been actual proof that the early cases seen in American military camps and elsewhere were caused by the same virus that wreaked such havoc on the world starting in the fall of that year.

This new study, published in the journal Proceedings of the National Academy of Sciences, provides that evidence.

Painstaking work on preserved lung tissue samples from 68 soldiers who died of influenza in 1918 reveals that the Spanish flu virus was circulating at least as early as May, said Dr. Jeffery Taubenberger, the scientist who led the work.

Nine of the deaths occurred between mid-May and early August, before the start of the major fall wave that was so deadly in North America and Europe.

Taubenberger headed the team that first found and sequenced the 1918 virus. He did that work while at the now-defunct American Forces Institute of Pathology, where the lung samples that form the basis of the new study were archived.

Taubenberger now runs a lab at the National Institutes for Allergy and Infectious Diseases in Bethesda, Md., which funded this research.

For years Taubenberger has been trying to solve the mysteries of the 1918 virus, attempting to tease out of preserved lung tissue answers to questions about the animal origins of the virus and why it was so extraordinarily lethal.

"Since the 1918 virus was this horrible, horrible, horrible virus, everyone wants to know everything about it," he said in an interview.

"Where did it come from? How did it spread? How did it start? How did it work? And yet we're dealing with something that occurred almost 100 years ago, in the pre-virology era."

An interesting feature of this work is that it showed the 1918 virus caused the same type of damage to the lungs of those who succumbed to it as did the virus behind the 2009 pandemic, which was a far more mild disease outbreak.

While that might seem counterintuitive, Taubenberger said, it probably makes sense that a fatal influenza infection would cause the same damage in the lungs, regardless of the virus responsible for it.

The work also provides some hints that the virus might have been in transition in the spring. Viruses from some of the spring cases have receptors that bind to avian cells. More of the fall cases were caused by viruses that bore receptors designed to lock onto the cells of the human respiratory tract.

Taubenberger said there isn't enough evidence to say with certainty that the spring viruses were still adapting to human hosts, but there is a suggestion that might have been the case.

Still, given the similar patterns of damage to the lungs of the fatal cases in the spring and fall, he said the findings point away from the hypothesis that the virus underwent changes in the summer of 1918 that made it more lethal.

"The answer to the mystery of why the 1918 virus killed tens of millions of people, especially young healthy adults, does not apparently live in the tissues that we look at under the microscope," he said.

However, the changing pattern of the receptors — if indeed it did occur — may have played a role in how transmissible the virus was in humans, Taubenberger said.

He insisted it's still important to figure out why the Spanish flu virus claimed so many lives.

"Because it happened once and we would certainly not want to see something like this happen again. So everything we can do to understand the past will help us prepare for the future."


http://www.winnipegfreepress.com/arts-a ... 58593.html

_________________
www.twitter.com/hniman

Niman, do you think there may still be a recurrence of our current H1N1 pandemic strain this flu season, with D225G causing high fatality rates?

I often wonder whether the H1N1 pandemic really is "over."

Note that earlier data identified D225G in 2/4 post peak samples. The new daat finds D225G in 3/4 pre-peak and 1/7 post peak. These difference may be linked to collection / viral load issues.

_________________
www.twitter.com/hniman

Actually, D225G is in trH3N2, which is evolving via H1N1. This pandemic is just getting revved up.

It is only over in the media and press releases from the CDC and WHO (and neither trH3N2 not pandemic H1N1 read press releases).

_________________
www.twitter.com/hniman