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The 1918 influenza pandemic killed tens of millions of people in just two years. Image © Library of Congress, Prints & Photographs Division, photograph by Harris & Ewing, LC-DIG-hec-14088
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The seasonal influenza virus may be the descendent of one of the most lethal viruses in human history.
Samples taken in the early years of the 1918 influenza pandemic, also known as Spanish flu, can help scientists understand how modern viruses evolve as they spread across the world. 
The most deadly pandemic in recent history may have given rise to the influenza viruses that circulate every year.
Analysis of newly discovered samples from the 1918 influenza pandemic found that every section of the virus’ genome could have given rise to seasonal flu. While more samples are needed to confirm this conclusion, it suggests the virus may have become significantly less virulent in the years following its initial outbreak.
Dr Thorsten Wolff, the co-author of the study published in Nature Communications, says, ‘Spanish influenza is still a riddle in virology because there are many open questions that we still don’t know the answers to. 
‘Our analysis of the Berlin samples allowed a complete genome sequence of the virus to be uncovered, which had a number of differences from other samples in genes relating to viral reproduction. This included two changes in the viral nucleoprotein, which shields viral genetics from the cell’s defences, which had previously been seen only in avian influenza.
‘This suggests that the function of these changes allows human viruses to counteract an important anti-viral defence known as the Mx8 proteins. This could have been an early signature of these viruses that changed during the course of the pandemic.’ 
The newly studied 1918 influenza virus samples were uncovered in the collection of the Berlin Museum of Medical History. Image © Navena Widulin, Berlin
The 1918 influenza pandemic, caused by the H1N1 subtype of the influenza A virus, is the second most deadly pandemic ever. Only the 14th century Black Death, caused by bubonic plague, is thought to have killed more people. 
The influenza pandemic occurred in three to four waves between 1918 and 1920, during which time it is believed to have killed anywhere between 17 to 100 million people. Striking in the closing months of the First World War and the following years, the movement of military personnel is believed to have accelerated its spread.
Countries fighting in the war generally censored news about the spread of the virus to maintain public morale. As Spain was neutral in the conflict, this meant that it was one of the few countries to report freely on the flu’s spread, giving the impression that the virus had begun there.
But while the pandemic was called the Spanish flu, to this day no one knows where the outbreak began. Despite the first confirmed cases coming from the USA, it is likely to have spread for months or years beforehand without being detected.
Despite how widespread the pandemic was, at the time its causes were not well understood. Influenza had variously been attributed to the spread of bacteria, mosquitos, and even cannon fire. It would not be until 1933 that the influenza virus was first isolated.
As a result, samples containing the virus are rare, making it hard to identify exactly what it would have looked like.
Co-author Dr Sébastien Calvignac-Spencer says, ‘When we started the work, there were only 18 specimens from which genetic sequences were available, and only two complete genomes. Most of these were from the USA, and only two from London. 
‘There was also no genome wide information about the early phase of the pandemic, so any new genomes documenting new locations and periods can really add to our knowledge of this pandemic.’
The discovery of three new samples from the first wave of the 1918 influenza virus in the collection Berlin Museum of Medical History has helped scientists unpick just how the virus became one of the world’s most deadly. 
The 1918 influenza virus was found to have adapted its ability to replicate as the pandemic progressed. Image © CDC/Dr. Terrence Tumpey/Cynthia Goldsmith, licensed under Public Domain via CDC.
After recovering a complete genome and two partial sequences from the three samples, the researchers looked at how the Berlin samples compared to a complete sequence of the virus isolated in Alaska during the disease‘s second wave. 
They found that most of the genetic differences were in the polymerase genes, which control the replication of a virus, and not the haemagglutinin genes which allow it to bind to a cell. 
‘It was a surprise that the virus haemagglutinin was conserved and that most of the changes took place in the polymerase enzyme,’ Thorsten says. ‘When we assessed these changes, we found the Alaskan virus was up to twice as active as the Berlin variant, which may be related to the virus’ adaptive processes as it spread through the human population.
‘After the pandemic, there were years where there was still increased mortality but it is difficult to distinguish whether this was from an increase in immunity or a decrease in virulence. 
‘From the reconstruction, it suggests that this was a substantially more virulent virus with significant differences from seasonal flu. However, whether a gradual decline or a sudden drop was responsible for the change is impossible to tell from our current data.’
Instead, the researchers were able to investigate how samples of different 1918 influenza viruses were related. They found that European and American samples were distributed among different branches of the virus’ family tree, suggesting that the virus was circulating internationally.
The different waves that spread these viruses were found not to have been caused by different variants of the virus replacing each other, as has occurred in the COVID-19 pandemic, but repeatedly by the same lineage of influenza.
The evolution of the virus was further investigated using a molecular clock model, which is used to assess the timeline of evolution. The scientists found that the eight segments of RNA which make up the seasonal influenza virus’ genome could have directly descended from the pandemic virus.
However, they couldn’t rule out that seasonal virus may have resulted from the process of viral reassortment, where a host being infected by more than one virus at a time can lead to the production of a virus which contains genetics from both.
The scientists also regard their findings as provisional due to the low sample size of 1918 influenza genetic sequences. In future, they hope to identify more specimens to learn more about this pandemic, in the hope it can give us more information about how future pandemics could develop.
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