AThe world’s most infamous flu pandemic (often called the Spanish flu), which raged from 1918 to 1920, scientists had very few tools available to help them fight the disease or understand it. Researchers did not even know that the virus was responsible for the disease until its causative agent was finally isolated in the laboratory in 1930. In subsequent years and decades, advances in technology have allowed researchers to look back and learn more about the often deadly pathogen, but questions remain about the course of the pandemic, especially about how and why the virus has changed over time.
A study published today (May 10) in The nature of communication fills some gaps in this amount of knowledge: researchers were able to obtain viral genomes from tissue samples of people infected with the 1918 pandemic flu in different years to show how the virus mutated over time to adapt to the human immune system. They concluded that the virus may have developed into a pathogen that circulated as seasonal flu after the pandemic.
“The Spanish flu of 1918 still remains a great mystery and mystery because there are so many questions [about] what actually happened at the time, ”study co-author Thorsten Wolf, a researcher on respiratory viruses at the Robert Koch Institute in Germany, told reporters at a news conference.
Studies of the nature and evolution of the 1918 pandemic virus have been limited by two main barriers: there are very few specimens of the virus, and those that do exist are in surviving, centennial specimens. Extracting them, experts say Scientistit is not a small feat.
Color image of the 1918 H1N1 influenza virus using an electron microscope
CDC / C. GOLDSMITH – LIBRARY OF GUARANTEED EMIRS № 11098
“When we started this work, there were only 18 copies. . . . There was no general genome information about the early [stage] pandemic, ”Sebastian Calvinyak-Spencer, also of the Robert Koch Institute, told a news conference. “Any new genome. . . can really complement our knowledge ”. But, he added, “these specimens had and still have a terrible reputation” as hard to work with.
Working with 13 formalin-fixed lung samples collected from people who died in Berlin between 1913 and 1920 from influenza or other bronchial diseases, Wolf, Calvignac-Spencer and their colleagues were able to obtain only one complete and two partial genomes. But they included the virus’s first genomes in history before the initial peak of the pandemic in 1918, which gave a new insight into the genetic changes the virus underwent when it first adapted to humans.
When researchers compared recently sequenced genomes with two previously sequenced genomes of the infamous influenza virus from 1918, researchers noticed that various mutations in the polymerase complex gene, an enzyme that mediates virus replication and is thought to be the main factor in the vast pathogenicity of the virus — were spread in different years, which allowed them to compile an elementary history of the evolution of influenza in a few waves.
“I think the coolest part of this work was that they were able to pull these sequences out of these formaldehyde-fixed tissues,” said Emily Bruce, a virologist at Larner College of Medicine at the University of Vermont who has not worked on the study. Scientist“And the fact that they found specific point mutations in the polymerase that they thought contributed to changes in virulence as the pandemic progressed.”
The team was able to recover this polymerase complex and link these and other mutations in the main gene to specific phenotypic changes, which they said are adaptive responses. For example, the team found many genetic changes that in some cases nearly doubled enzyme activity. Linking the prevalence of mutations in this sample to the month and year of death, the researchers found that mutations that increased the severity of the disease coincided with pandemic peaks, indicating a worsening of the pandemic after the virus adapted to its hosts. .
The team “found that there was a change in activity associated with adaptation processes,” Wolf said at a news conference, noting that the virus is trying to optimize replication. . . in the human population ”.
“The ability to take these archival medical samples and get really interesting genomic data from them to help answer some really important questions about the Spanish flu pandemic,” was the real conclusion from this work, “said Emma Loveday, a flu researcher from Montana. State University, which did not participate in the study.
Researchers also believe that the seasonal H1N1 flu virus, which began circulating after the 1918 pandemic (and continued to circulate) not yet displaced pandemic influenza H2N2 1957) is a direct descendant of the pandemic virus.
Earlier, scientists linked the 1918 pandemic to the next seasonal flu, but through different mechanisms. In the past, researchers have suggested that the seasonal H1N1 virus, which emerged after the pandemic, did so as the result of the reassortment, gene mixing among several viruses that infect the same host cell, meaning that the virus could become less deadly after exchanging genes with other influenza viruses. The authors write in a new paper that their results do not debunk the reassortment hypothesis; they simply indicate that H1N1 could have originated directly from the pandemic flu, and there is no need for reversal.
A public health poster published during the 1918 pandemic with advice to stop the spread of influenza
NATIONAL MEDICAL LIBRARY
Loveday tells Scientist that the idea that the seasonal H1N1 virus, which emerged after the 1918 pandemic, originated from a pandemic virus, is well established, but the underlying mechanism was less clear.
Wolf and Calvignac-Spencer say their future goal is to retrieve and analyze genomes from more specimens so they can refine what they describe as preliminary findings and answer additional questions about the 1918 pandemic virus. Because there have been no flu sequences for 15 or so years since the pandemic, a full picture of the virus’s evolution is not yet possible.
“Actually it’s very, very difficult [find] such samples, ”says Calvignac-Spencer. “We are insanely lucky to find several of these [Berlin Museum of Medical History] not far away.
Bruce says that, hypothetically, it would be interesting to see what scientists could learn if they recovered the virus at different stages of evolution, reproducing various mutations that have occurred over time, and testing their phenotypic effects in tissue and living animal cultures. “What to do [the various genetic changes over time] means the ability of a virus to transmit or cause disease? We know that polymerase is an important determinant of virulence, but we don’t know exactly how, ”she says.
But she acknowledges that this will require working in facilities with a higher level of biosafety than the current study, because the researchers only looked at polymerase, and that studying the viable virus would require more regulatory and logistical barriers.
Bruce notes that the findings predict humanity’s current experience with COVID-19, and that they may also help in understanding future pandemics. “What [the authors] “These mutations may be a hallmark of early human adaptation,” she said.
“Today we still have very poor information about genetic sequences throughout the period  a pandemic, ”she adds. Existing data can help “us understand things that may have been amazing to us in 2020.”