Seasonal flu, possible descendant of Spanish flu

Preserved in formalin, genetically deciphered, early 20th-century European lung tissue provides new insight into the “Spanish” flu, of which one of the seasonal flu viruses may be a direct descendant, according to a study published Tuesday in the journal Nature.

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The most devastating respiratory pandemic of the 20th century, the 1918-1919 flu, known as “Spanish” — a misleading term because that pandemic was far from focused on Spain — is estimated to have killed between 50 and 100 million people in total.

Its viral origin was not confirmed until the 1930s, but later research identified the culprit: an influenza A virus of the H1N1 subtype.

But there are still mysteries surrounding the Spanish flu. Geneticists have been trying to dissect them for twenty years, but their task is limited by the small number of victim samples to analyze.

After fifteen unsuccessful steps, Sébastien Calvignac-Spencer, a specialist in viral evolution at the Robert Koch Institute (Germany), says he and his colleagues were “extremely lucky”. They had access to 13 lung specimens preserved in formalin in museums in Berlin and Vienna from 1901 to 1931, including six from 1918-1919.

And they discovered RNA fragments of the Spanish flu virus in three samples from 1918.

These researchers managed to sequence large parts of the virus that infected two people, but also an entire genome in the third case. Previously, “there were only sequences of 18 specimens worldwide, two complete genomes in the United States” and “no genetic information on the first phases of the pandemic,” stressed Sébastien Calvignac-Spencer during a press conference.

The Spanish flu actually experienced three major waves. The second and third were particularly deadly, more than the first having developed by the spring of 1918.

In particular, her work has uncovered genomic variations in the course of the pandemic and its global trajectory through round trips facilitated by the deployment of soldiers at the end of World War I.

Since the earliest days of the Spanish flu, a gene in the virus appears to have evolved to counteract the human immune response.

Most importantly, “these new analyzes are consistent with the scenario of a purely pandemic origin of seasonal influenza viruses,” a direct lineage, according to the study.

This undermines other hypotheses about the origin of seasonal influenza, notably the idea known as “reasortment” that current viruses consist of multiple fragments of heterogeneous ancestors.

On the other hand, it is difficult to describe how the flu pandemic of 1918 gradually developed into a seasonal virus “due to a lack of data”, especially in the 1920s, explained Thorsten Wolff, virologist at the Robert Koch Institute.

Can this research provide some keys to the development of COVID?

According to Sébastien Calvignac-Spencer, if we cannot compare these two pandemics in the face of “different viruses, very different conditions of spread, differently organized and connected people”, certain similarities could exist.

“For example, the 1918 flu had multiple waves like COVID, but unlike the COVID pandemic, where the waves are associated with new variants, according to our study, that was probably not the case for the 1918 pandemic,” he noted.

The study in Nature has a limitation, however, its “very small sample size,” its authors acknowledge, and emphasize that their results remain “preliminary.”

“Additional genomes from pandemic-era samples, as well as phenotypic characterization of several 1918 viruses in vitro and in vivo will undoubtedly allow for more robust analysis,” they say.

It remains to find new preserved pathological specimens.

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