Spanish flu research

Last updated
Influenza A virus subtype H1N1
Reconstructed Spanish Flu Virus.jpg
An electron micrograph of the virus that caused the 1918 flu.
Virus classification OOjs UI icon edit-ltr.svg
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Negarnaviricota
Class: Insthoviricetes
Order: Articulavirales
Family: Orthomyxoviridae
Genus: Alphainfluenzavirus
Species:
Influenza A virus
Serotype:
Influenza A virus subtype H1N1
Sampled strains

Spanish flu research concerns studies regarding the causes and characteristics of the Spanish flu, a variety of influenza that in 1918 was responsible for the worst influenza pandemic in modern history. Many theories about the origins and progress of the Spanish flu persisted in the literature, but it was not until 2005, when various samples of lung tissue were recovered from American World War I soldiers and from an Inupiat woman buried in permafrost in a mass grave in Brevig Mission, Alaska, that significant genetic research was made possible.

Contents

Origin of virus

There are two prevailing theories usually postulated.[ citation needed ] One theory by Alfred W. Crosby 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 swine, [lower-alpha 1] this has since been cast into doubt. One researcher published in 2004 argued that the disease was found in Haskell County, Kansas, as early as January 1918. [2] A similar and even more deadly virus had been seen earlier at British camps in France and at Aldershot. [3]

Earlier investigative work published in 2000 by a team led by British virologist, John Oxford [4] of St Bartholomew's Hospital and the Royal London Hospital, suggested that a principal British troop staging camp in Étaples, France, was at the center of the 1918 flu pandemic or at least a significant precursor virus to it. There had been a mysterious respiratory infection at the military base during the winter of 1915–1916. [5]

Discovery of viral genomes

Dr. Jeffery Taubenberger and Ann Reid reviewing a genetic sequence from the 1918 Spanish flu virus. Jeffrey Taubenberger and Ann Reid.jpg
Dr. Jeffery Taubenberger and Ann Reid reviewing a genetic sequence from the 1918 Spanish flu virus.
Centers for Disease Control and Prevention as Dr. Terrence Tumpey examines a reconstructed version of the 1918 flu. Influenza virus research.jpg
Centers for Disease Control and Prevention as Dr. Terrence Tumpey examines a reconstructed version of the 1918 flu.

In 1995, Jeffery Taubenberger of the US Armed Forces Institute of Pathology (AFIP), wondered if it might be possible to recover the virus of 1918 flu pandemic from the dried and fixed tissue of victims. He and his colleagues, tested 10 slides of tissue sample and 2 came out positive. Taubenberger, Ann H. Reid and Thomas G. Fanning were able to amplify short segments of the viral nucleic acid using polymerase chain reaction (PCR). [6] The results were published in the journal Science in March 1997. [7]

On August 20, 1997, Johan Hultin 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. [8] He brought the samples to a team in Rockville, Maryland led by Jeffery Taubenberger of the US Armed Forces Institute of Pathology (AFIP). 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. [9] [lower-alpha 2]

The archived autopsy samples had been taken from WWI Army privates Roscoe Vaughan and James Downs. [11]

The 6 February 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 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 5 October 2005, Tumpey and other researchers at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and the Mount Sinai School of Medicine in New York, announced that the (~13 kbp) genetic sequence of the 1918 flu strain, a subtype of avian strain H1N1, had been reconstructed using historic tissue samples and a small part of the RNA from a modern strain. [12] [13] [14]

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. [15] 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. [16]

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." [17] Results reported by Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks.

In December 2008, research by Yoshihiro Kawaoka of University of Wisconsin showed the presence of the three specific genes (termed PA, PB1, and PB2) and a nucleoprotein derived from the H1N1 1918 flu samples was enough to trigger similar symptoms in animal testing. [18]

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. [13] 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. [19] [20] Taubenberger et al. responded to these letters and defended their original interpretation. [21]

Other research by Tumpey and colleagues who reconstructed the H1N1 virus of 1918 came to the conclusion that it was most notably the polymerase genes and the HA and NA genes that caused the extreme virulence of this virus. [14] 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. [22]

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 7 of the 10 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 found 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.

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. [23]

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. [24] Human H5N1 plasma may be an effective, timely, and widely available treatment for the next flu pandemic.[ citation needed ] A new international study using modern data collection methods, would be a difficult, slow process. Citing the months-long wait for a vaccine for the next pandemic, many flu experts are of the opinion that the 1918 method is something to consider. [25]

In the worldwide 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 showed any hint of success: Transfusing blood from recovered patients to new victims." [26]

See also

Footnotes

  1. ↑ Sometimes 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 'Spanish Flu' in 1918 appears to be entirely derived from an avian source." (Belshe, 2005) [1]
  2. ↑ Johan Hultin first attempted to recover samples from Brevig in 1951, but was unsuccessful. In 1997, by then a seventy-two-year-old retired pathologist, Hultin 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 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. [10]

Related Research Articles

<i>Influenza A virus</i> Species of virus

Influenza A virus (IAV) is a pathogen that causes the flu in birds and some mammals, including humans. It is an RNA virus whose subtypes have been isolated from wild birds. Occasionally, it is transmitted from wild to domestic birds, and this may cause severe disease, outbreaks, or human influenza pandemics.

<span class="mw-page-title-main">Avian influenza</span> Influenza caused by viruses adapted to birds

Avian influenza, also known as avian flu, is a bird flu caused by the influenza A virus, which can infect people. It is similar to other types of animal flu in that it is caused by a virus strain that has adapted to a specific host. The type with the greatest risk is highly pathogenic avian influenza (HPAI).

<span class="mw-page-title-main">Antigenic shift</span> Process by which two or more different strains of a virus combine to form a new subtype

Antigenic shift is the process by which two or more different strains of a virus, or strains of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains. The term is often applied specifically to influenza, as that is the best-known example, but the process is also known to occur with other viruses, such as visna virus in sheep. Antigenic shift is a specific case of reassortment or viral shift that confers a phenotypic change.

<span class="mw-page-title-main">Hemagglutinin (influenza)</span> Hemagglutinin of influenza virus

Influenza hemagglutinin (HA) or haemagglutinin[p] is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity.

<i>Orthomyxoviridae</i> Family of RNA viruses including the influenza viruses

Orthomyxoviridae is a family of negative-sense RNA viruses. It includes seven genera: Alphainfluenzavirus, Betainfluenzavirus, Gammainfluenzavirus, Deltainfluenzavirus, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in birds and mammals, including humans. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates. The Quaranjaviruses are also arboviruses, infecting vertebrates (birds) and invertebrates (arthropods).

Antigenic drift is a kind of genetic variation in viruses, arising from the accumulation of mutations in the virus genes that code for virus-surface proteins that host antibodies recognize. This results in a new strain of virus particles that is not effectively inhibited by the antibodies that prevented infection by previous strains. This makes it easier for the changed virus to spread throughout a partially immune population. Antigenic drift occurs in both influenza A and influenza B viruses.

<span class="mw-page-title-main">Influenza A virus subtype H5N1</span> Subtype of influenza A virus

Influenza A virus subtype H5N1 (A/H5N1) is a subtype of the influenza A virus which can cause illness in humans and many other species. A bird-adapted strain of H5N1, called HPAI A(H5N1) for highly pathogenic avian influenza virus of type A of subtype H5N1, is the highly pathogenic causative agent of H5N1 flu, commonly known as avian influenza. It is enzootic in many bird populations, especially in Southeast Asia. One strain of HPAI A(H5N1) is spreading globally after first appearing in Asia. It is epizootic and panzootic, killing tens of millions of birds and spurring the culling of hundreds of millions of others to stem its spread. Many references to "bird flu" and H5N1 in the popular media refer to this strain.

<span class="mw-page-title-main">Swine influenza</span> Infection caused by influenza viruses endemic to pigs

Swine influenza is an infection caused by any of several types of swine influenza viruses. Swine influenza virus (SIV) or swine-origin influenza virus (S-OIV) refers to any strain of the influenza family of viruses that is endemic in pigs. As of 2009, identified SIV strains include influenza C and the subtypes of influenza A known as H1N1, H1N2, H2N1, H3N1, H3N2, and H2N3.

<span class="mw-page-title-main">Influenza A virus subtype H1N1</span> Subtype of Influenza A virus

In virology, influenza A virus subtype H1N1 (A/H1N1) is a subtype of influenza A virus. Major outbreaks of H1N1 strains in humans include the 1918 Spanish flu pandemic, the 1977 Russian flu pandemic and the 2009 swine flu pandemic. It is an orthomyxovirus that contains the glycoproteins hemagglutinin (H) and neuraminidase (N), antigens whose subtypes are used to classify the strains of the virus as H1N1, H1N2 etc. Hemagglutinin causes red blood cells to clump together and binds the virus to the infected cell. Neuraminidase is a type of glycoside hydrolase enzyme which helps to move the virus particles through the infected cell and assist in budding from the host cells.

<span class="mw-page-title-main">Influenza pandemic</span> Pandemic involving influenza

An influenza pandemic is an epidemic of an influenza virus that spreads across a large region and infects a large proportion of the population. There have been six major influenza epidemics in the last 140 years, with the 1918 flu pandemic being the most severe; this is estimated to have been responsible for the deaths of 50–100 million people. The 2009 swine flu pandemic, resulted in under 300,000 deaths and is considered relatively mild. These pandemics occur irregularly.

<span class="mw-page-title-main">Influenza A virus subtype H2N2</span> Subtype of Influenza A virus

Influenza A virus subtype H2N2 (A/H2N2) is a subtype of Influenza A virus. H2N2 has mutated into various strains including the "Asian flu" strain, H3N2, and various strains found in birds. It is also suspected of causing a human pandemic in 1889. The geographic spreading of the 1889 Russian flu has been studied and published.

<span class="mw-page-title-main">Transmission and infection of H5N1</span> Spread of an influenza virus

Transmission and infection of H5N1 from infected avian sources to humans has been a concern since the first documented case of human infection in 1997, due to the global spread of H5N1 that constitutes a pandemic threat.

<span class="mw-page-title-main">H5N1 genetic structure</span>

H5N1 genetic structure is the molecular structure of the H5N1 virus's RNA.

<span class="mw-page-title-main">Fujian flu</span> Strains of influenza

Fujian flu refers to flu caused by either a Fujian human flu strain of the H3N2 subtype of the Influenza A virus or a Fujian bird flu strain of the H5N1 subtype of the Influenza A virus. These strains are named after Fujian, a coastal province in Southeast China.

<span class="mw-page-title-main">Human mortality from H5N1</span>

Human mortality from H5N1 or the human fatality ratio from H5N1 or the case-fatality rate of H5N1 is the ratio of the number of confirmed human deaths resulting from confirmed cases of transmission and infection of H5N1 to the number of those confirmed cases. For example, if there are 100 confirmed cases of humans infected with H5N1 and 10 die, then there is a 10% human fatality ratio. H5N1 flu is a concern due to the global spread of H5N1 that constitutes a pandemic threat. The majority of H5N1 flu cases have been reported in southeast and east Asia. The case-fatality rate is central to pandemic planning. Estimates of case-fatality (CF) rates for past influenza pandemics have ranged from to 2-3% for the 1918 pandemic to about 0.6% for the 1957 pandemic to 0.2% for the 1968 pandemic. As of 2008, the official World Health Organization estimate for the case-fatality rate for the outbreak of H5N1 avian influenza was approximately 60%. Public health officials in Ontario, Canada argue that the true case-fatality rate could be lower, pointing to studies suggesting it could be 14-33%, and warned that it was unlikely to be as low as the 0.1–0.4% rate that was built into many pandemic plans.

Jeffery K. Taubenberger is an American virologist. With Ann Reid, he was the first to sequence the genome of the influenza virus which caused the 1918 pandemic of Spanish flu. He is Chief of the Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Taubenberger's laboratory studies a number of viruses, including influenza A viruses (IAVs), which are the pathogens that cause yearly flu epidemics and have caused periodic pandemics, such as the 1968 outbreak that killed an estimated one million people. His research aims to inform public health strategies on several important aspects of flu: seasonal flu; avian flu, which circulates among birds and has infected humans in the past; swine flu, which circulates among pigs and has infected humans in the past; and pandemic flu, which can arise from numerous sources and spread quickly because humans have little to no immunity to it.

<span class="mw-page-title-main">Influenza</span> Infectious disease, often just "the flu"

Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin from one to four days after exposure to the virus and last for about 2–8 days. Diarrhea and vomiting can occur, particularly in children. Influenza may progress to pneumonia, which can be caused by the virus or by a subsequent bacterial infection. Other complications of infection include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.

Johan Hultin was a Swedish-born American pathologist known for recovering tissues containing traces of the 1918 influenza virus that killed millions worldwide.

<span class="mw-page-title-main">Pandemic H1N1/09 virus</span> Virus responsible for the 2009 swine flu pandemic

The pandemic H1N1/09 virus is a swine origin influenza A virus subtype H1N1 strain that was responsible for the 2009 swine flu pandemic. This strain is often called swine flu by the public media. For other names, see the Nomenclature section below.

<span class="mw-page-title-main">H5N1 vaccine</span> Vaccine designed to provide immunity against H5N1 influenza

A H5N1 vaccine is an influenza vaccine intended to provide immunization to influenza A virus subtype H5N1.

References

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  4. ↑ "Dr. John Oxford". EU Research Profile. Archived from the original on 26 December 2008.
  5. ↑ Connor, Steve (8 January 2000). "Flu epidemic traced to Great War transit camp". The Independent . UK. Archived from the original on 8 August 2009. Retrieved 26 March 2020. An investigation into the global epidemic of influenza in 1918, which killed an estimated 40 million people, has shown it almost certainly started in an army camp in France in the middle of the First World War.
  6. ↑ "Resurrecting 1918 Flu Virus Took Many Turns". The Washington Post . 2005-10-10. ISSN   0190-8286 . Retrieved 2020-07-25.
  7. ↑ Taubenberger, Jeffery K.; Reid, Ann H.; Krafft, Amy E.; Bijwaard, Karen E.; Fanning, Thomas G. (1997-03-21). "Initial Genetic Characterization of the 1918 "Spanish" Influenza Virus". Science. 275 (5307): 1793–1796. doi:10.1126/science.275.5307.1793. ISSN   0036-8075. PMID   9065404. S2CID   8976173.
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  9. ↑ "Lethal secrets of 1918 flu virus". BBC News.
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  16. ↑ Gambaryan A, Tuzikov A, Pazynina G, Bovin N, Balish A, Klimov A (January 2006). "Evolution of the receptor binding phenotype of influenza A (H5) viruses". Virology. 344 (2): 432–438. doi: 10.1016/j.virol.2005.08.035 . PMID   16226289.
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  21. ↑ Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG (April 2006). "Molecular virology: Was the 1918 pandemic caused by a bird flu? Was the 1918 flu avian in origin? (Reply)". Nature. 440 (7088): E9–E10. Bibcode:2006Natur.440E...9T. doi:10.1038/nature04825. S2CID   4308033.
  22. ↑ Kobasa D, Jones SM, Shinya K, Kash JC, Copps J, Ebihara H, et al. (January 2007). "Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus". Nature. 445 (7125): 319–323. Bibcode:2007Natur.445..319K. doi: 10.1038/nature05495 . PMID   17230189. S2CID   4431644.
  23. ↑ "Influenza (main)". history.navy.mil.
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