Spanish flu research

Spanish flu research has long included many theories about the origins and progress of the Spanish flu, but it wasn't until 2005, when various samples recovered from American World War I soldiers and an Inuit woman buried in the Alaskan tundra, that significant research has been possible.

Origin of Virus

One theory is that the virus strain originated at Fort Riley, Kansas, by two genetic mechanisms — genetic drift and antigenic shift — in viruses in poultry and swine which the fort bred for local consumption. Though initial data from a recent reconstruction of the virus suggested that it jumped directly from birds to humans, without traveling through swineSometimes a virus contains both avian adapted genes and human adapted genes. Both the H2N2 and H3N2 pandemic strains contained avian flu virus RNA segments. "While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the '1918 flu' in 1918 appears to be entirely derived from an avian source (Belshe 2005)." (from [http://www.influenzareport.com/ir/ai.htm Chapter Two : Avian Influenza by Timm C. Harder and Ortrud Werner] , an excellent free on-line Book called "Influenza Report 2006" which is a medical textbook that provides a comprehensive overview of epidemic and pandemic influenza.)] , this has since been cast into doubt. One researcher argues that the disease was found in Haskell County, Kansas as early as January 1918. [ [http://www.translational-medicine.com/content/2/1/3 The site of origin of the 1918 influenza pandemic and its public health implications] ]

Discovery of viral genomes

In February 1998, a team led by Jeffery Taubenberger of the US Armed Forces Institute of Pathology (AFIP) recovered samples of the 1918 influenza from the frozen corpse of a Native Alaskan woman buried for nearly eight decades in permafrost near Brevig Mission, Alaska. Brevig Mission lost approximately 85% of its population to the 1918 flu in November 1918. One of the four recovered samples contained viable genetic material of the virus. This sample provided scientists a first-hand opportunity to study the virus, which was inactivated with guanidinium thiocyanate before transport. This sample and others found in AFIP archives allowed researchers to completely analyze the critical gene structures of the 1918 virus. "We have now identified three cases: the Brevig Mission case and two archival cases that represent the only known sources of genetic material of the 1918 influenza virus", said Taubenberger, chief of AFIP's molecular pathology division and principal investigator on the project. [ [http://news.bbc.co.uk/2/hi/health/6271833.stm Lethal secrets of 1918 flu virus] ; BBC] [According to Gina Kolata's 1999 account of the pandemic, 'Flu', pp. 255-65 : Johan Hultin first attempted to recover samples from Brevig in 1951, but he was unsuccessful. In 1997, by then a seventy-two year old retired pathologist, he decided that science had advanced enough to make another attempt worthwhile. Taubenberger had already recovered RNA of limited quality from samples of two servicemen who had died in the pandemic, and Hultin wrote offering offering his services to try to get better quality samples from Brevig permafrost. Taubenberger accepted, and Hultin went alone to Brevig in August 1997, and recovered the sample from the Alaskan woman, which Taubenberger and his team then analysed.]

The February 6 2004 edition of "Science" magazine reported that two research teams, one led by Sir John Skehel, director of the National Institute for Medical Research in London, another by Professor Ian Wilson of The Scripps Research Institute in San Diego, had managed to synthesize the hemagglutinin protein responsible for the 1918 flu outbreak of 1918. They did this by piecing together DNA from a lung sample from an Inuit woman buried in the Alaskan tundra and a number of preserved samples from American soldiers of the First World War. The teams had analyzed the structure of the gene and discovered how subtle alterations to the shape of a protein molecule had allowed it to move from birds to humans with such devastating effects.

On October 5, 2005, researchers at the Mount Sinai School of Medicine in New York announced that the genetic sequence of the 1918 flu strain, a subtype of avian strain H1N1, had been reconstructed using historic tissue samples. [ Special report at "Nature" News: [http://www.nature.com/news/2005/051003/full/437794a.html The 1918 flu virus is resurrected] , Published online: 5 October 2005; Doi|10.1038/437794a] [cite journal|last=Taubenberger|first=Jeffery K. |coauthors=Ann H. Reid, Raina M. Lourens, Ruixue Wang, Guozhong Jin and Thomas G. Fanning|year=2005|title=Characterization of the 1918 influenza virus polymerase genes|url=|journal=Nature|issn=|volume=437 |issue=|pages=889–893|doi=10.1038/nature04230] [Also: cite journal|last=Tumpey|first=Terrence M.|coauthors=Christopher F. Basler, Patricia V. Aguilar, Hui Zeng, Alicia Solórzano, David E. Swayne, Nancy J. Cox, Jacqueline M. Katz, Jeffery K. Taubenberger, Peter Palese and Adolfo García-Sastre|year=2005|title=Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus|url=|journal=Science|issn=|volume=310|issue=|pages=77–80|doi=10.1126/science.1119392|pmid=16210530]

Characteristics of virus

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The H5N1 virus has mutated into a variety of types with differing pathogenic profiles; some pathogenic to one species but not others, some pathogenic to multiple species. [cite journal|last=Kou|first=Z.|coauthors=F. M. Lei, J. Yu, Z. J. Fan, Z. H. Yin, C. X. Jia, K. J. Xiong, Y. H. Sun, X. W. Zhang, X. M. Wu, X. B. Gao and T. X. Li|year=2005|title=New genotype of avian influenza H5N1 viruses isolated from tree sparrows in China|url=|journal=Journal of Virology|issn=|volume=79|issue=|pages=15460–15466|pmid=16306617|doi=] The ability of various influenza strains to show species-selectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types. [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16226289&query_hl=1 Evolution of the receptor binding phenotype of influenza A (H5) viruses] by A. Gambaryan, A. Tuzikov, G. Pazynina, N. Bovin, A. Balish and A. Klimov in "Virology" (2005) electronic release on October 11 ahead of print publication.] This doesn't mean one amino acid substitution can cause a pandemic but it does mean one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans.

In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Robert Webster of the St Jude Children's Research Hospital, Memphis, Tennessee, reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity". [ [http://www.pnas.org/cgi/content/abstract/0403212101v1 The evolution of H5N1 influenza viruses in ducks in southern China] by H. Chen, G. Deng, Z. Li, G. Tian, Y. Li, P. Jiao, L. Zhang, Z. Liu, R. G. Webster and K. Yu in "Proceedings of the National Academy of Sciences of the United States of America" (2004) volume 101, pages 10452-10457.] Results reported by Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks.

Research of viral pathogenesis

Recent research of Taubenberger "et al" has suggested that the 1918 virus, like H5N1, could have arisen directly from an avian influenza virus. [Recent research of Taubenberger "et al" has suggested that the 1918 virus, like H5N1, could have arisen directly from an avian influenza virus in:
*Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature. October 6, 2005;437(7060):889-893] However, researchers at University of Virginia and Australian National University have suggested that there may be an alternative interpretation of the data used in the Taubenberger "et al." paper. [ [http://www.nature.com/nature/journal/v440/n7088/full/nature04823.html Was the 1918 pandemic caused by a bird flu? - Gibbs and Gibbs] Nature. April 27, 2006;440:E8] [ [http://www.nature.com/nature/journal/v440/n7088/full/nature04824.html Was the 1918 flu avian in origin? - Antonovics et al.] Nature. April 27, 2006;440:E9] Taubenberger "et al" responded to these letters and defended their original interpretation. [ [http://www.nature.com/nature/journal/v440/n7088/full/nature04825.html Molecular virology: Was the 1918 pandemic caused by a bird flu? Was the 1918 flu avian in origin? (Reply)] ]

Other research by Tumpey and colleagues who reconstructed the H1N1 virus of 1918 came to the conclusion that it is was most notably the polymerase genes and the HA and NA genes that caused the extreme virulence of this virus. [Tumpey TM, Basler CF, Aguilar PV, Zeng H, Solorzano A, Swayne DE, Cox NJ, Katz JM, Taubenberger JK, Palese P, Garcia-Sastre A. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science. October 7, 2005;310(5745):77-80] The sequences of the polymerase proteins (PA, PB1, and PB2) of the 1918 virus and subsequent human viruses differ by only 10 amino acids from the avian influenza viruses. Viruses with seven of the ten amino acids in the human influenza locations have already been identified in currently circulating H5N1. This has led some researchers to suggest that other mutations may surface and make the H5N1 virus capable of human-to-human transmission. Another important factor is the change of the HA protein to a binding preference for alpha 2,6 sialic acid (the major form in the human respiratory tract). In avian virus the HA protein preferentially binds to alpha 2,3 sialic acid, which is the major form in the avian enteric tract. It has been shown that only a single amino acid change can result in the change of this binding preference. Altogether, only a handful of mutations may need to take place in order for H5N1 avian flu to become a pandemic virus like the one of 1918. However it is important to note that likelihood of mutation does not indicate the likelihood for the evolution of such a strain; since some of the necessary mutations may be constrained by stabilizing selection.

On 18 January 2007, Kobasa "et al" reported that infected monkeys ("Macaca fascicularis") exhibited classic symptoms of the 1918 pandemic and died from a cytokine storm. [ [http://www.nature.com/nature/journal/v445/n7125/full/nature05495.html Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus] "Nature". 18 January 2007;445:319]

Blood plasma as an effective treatment

In the event of another pandemic, US military researchers have proposed reusing a treatment from the deadly pandemic of 1918 in order to blunt the effects of the flu. Some military doctors injected severely afflicted patients with blood or blood plasma from people who had recovered from the flu. Data collected during that time indicates that the blood-injection treatment reduced mortality rates by as much as 50 percent. Navy researchers have launched a test to see if the 1918 treatment will work against deadly Asian bird flu. Results thus far have been inconclusive. Human H5N1 plasma may be an effective, timely, and widely available treatment for the next flu pandemic. A new international study using modern data collection methods, would be a difficult, slow process. But many flu experts, citing the months-long wait for a vaccine for the next pandemic, are of the opinion that the 1918 method is something to consider. [ [http://www.npr.org/templates/story/story.php?storyId=5731688 npr.org] [http://www.history.navy.mil/library/online/influenza_main.htm history.navy.mil] ]

In the world wide 1918 flu pandemic, "physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call "Hemophilus influenzae"—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success." [ [http://darwin.nap.edu/books/0309095042/html/62.html The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) (free online book)] page 62]

ee also

*1918 flu
*Influenza research
*Mark Sykes

ources and notes