Dig deep: Study reveals 100-year-old virus genomes responsible for Spanish flu

Comparisons to the 1918 Spanish flu epidemic have long been drawn since the start of Covid-19 in December 2019. Now a study published in Nature Communications sheds light on the genome of the influenza A H1N1 virus which was responsible for the pandemic epidemic.

Patrono et al. (2022) combed several museums in Europe for tissues that would produce RNA fragments of the H1N1 virus. Of the thirteen lung tissue samples from medical archives in Germany (Berlin and Munich) and Austria (Vienna), the researchers report a complete genome and two partials of the influenza A virus (IAV) (a total of three ).

This is not the first time the virus genome has been sequenced from preserved tissue. Working independently, Xiao et al. (2013) and Taubenberger et al. (2019) reconstructed the complete influenza A virus (IAV) genomes of two people who died in New York (September 1918) and Alaska (November 1918), respectively. Although these genomes conclusively established an origin in birds, they had a slight drawback. These two genomes came from individuals who died in the fall of 1918, that is to say the second wave of the pandemic, and therefore revealed nothing about the mutations that the virus would have undergone during the first wave.

The IAV genome shows a unique capacity for gene reassortment. The genome is made up of eight genes, and in the case of a cell infected with more than one strain of a gene, the genome can rearrange the order in which the genes appear through a process called reassortment. Worobey et al. (2014) established that reassortment had taken place between the 1918 H1N1 virus and another virus, which created a deadly new virus with more pathogenicity. Additionally, previous research had also shown that the hemagglutinin (HA) gene and the polymerase complex gene “were likely major determinants of the pathogenicity of this virus.”

The genomes of the European samples – also the first known genomic sequences from a period before the second wave – are distinct from the American samples. In particular, the researchers observed that the viral polymerase gene complex in the European samples was markedly different from that in Alaska. When their functions were compared in the laboratory, the Alaskan polymerase gene complex was twice as active as the European version. Therein lies a possible link: changes in the viral polymerase gene complex may have been responsible for making the virus more deadly.

But how do you accurately document the trajectory of genetic reassortments for something like a viral genome, which typically evolves at different rates in each species? For example, IAV progresses slowly in horses and rapidly in pigs. In addition, the virus must have done quite a few “host jumps” during its evolutionary history.

When Patrono et al. (2022) examined the phylogenetic trees of the virus, they noticed a long branch along which the virus evolved much faster than other branches. The branch corresponds to unsampled viruses that were transmitted among human populations between 1918 and the 1930s. The task of determining the rate of evolution is made even more difficult due to the unavailability of sequences from the 1920s.

While establishing links between IAV genomes over time, i.e. different periods of the 1918 pandemic. When examining HA sequences, it was observed that the virus characteristic of peaks was not descended from “a single global replacement of pre-pandemic peaks viruses”. Instead, they find that many “pre-pandemic peak lines survived the subsequent pandemic months.”

Focusing on the geographic spread of the 1918 influenza A virus, the study found that there was no geographic segregation between continents. For this, they again examined the genetic variability of HA sequences from samples in Europe and North America dating back to the pandemic period – and its reconstruction “showed the interspersed clustering of the three German sequences with the north- American”. The study hypothesizes that this could be due to the widespread transatlantic movement in the context of the First World War. These two characteristics – the sharing of lineages in time and space – have much in common with the H1N1 epidemic of 2009.

While Patrono et al. (2022) argue that advances in genetic sequencing have enabled biologists to discern lessons from previous pandemics and inform policy action for ongoing pandemics, they also point out that the exorbitant cost of maintaining medical records means that Museums are quickly disposing of these historically preserved fabrics. Regardless of technological advances, the paucity of readily available medical records containing historical pathogens will be a serious impediment to similar research in the future.

The author is a researcher at the Indian Institute of Science (IISc) in Bengaluru and a freelance science communicator. He tweets at @critvik