Digging Deep: Study reveals 100-year-old virus genomes responsible for Spanish Flu

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Comparisons with the 1918 Spanish Influenza outbreak have long been drawn ever since Covid-19 began in Dec 2019. Now, a study published in Nature Communications sheds light on the genome of the Influenza A H1N1 virus that was responsible for the pandemic outbreak.

Patrono et al. (2022) combed through multiple museums in Europe for tissues that would yield RNA fragments of the H1N1 virus. Out of the thirteen lung tissue samples sourced from medical archives in Germany (Berlin and Munich) and Austria (Vienna), the researchers report one complete and two partial influenza A virus (IAV) genomes (ie a total of three).

This is not the first time the virus’s genome has been sequenced from preserved tissues. Working independently, Xiao et al. (2013) and Taubenberger et al. (2019) reconstructed complete influenza A virus (IAV) genomes from two individuals who had died in New York (Sep 1918) and Alaska (Nov 1918) respectively. While these genomes conclusively established an origin in birds, they had a bit of a drawback. Both these genomes were of individuals who died in autumn 1918, that is, the second wave of the pandemic, and, therefore, revealed nothing about the mutations the virus would have gone through during the first wave.

The IAV genome shows a unique capability of gene reassortment. The genome consists of eight genes, and in the event of a cell being infected by more than one strain of a gene, the genome can rearrange the order in which the genes appear by 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 new lethal 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 this virus pathogenicity.’

The genomes from the European samples – also the first known genome sequences from a time 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 the Alaskan one. 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 connection: the changes in the viral polymerase gene complex could have been responsible for making the virus more lethal.

But, how does one accurately underpin the trajectory of genetic reassortments for something like a viral genome, that typically evolves at different rates in each species? For instance, the IAV evolves slowly in horses and rapidly in pigs. Plus, the virus must have made 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 amongst human populations between 1918 and the 1930s. The task of ascertaining the rate of evolution is made even more difficult due to the unavailability of sequences from the 1920s.

While making connections between IAV genomes temporally – that is, across different periods of the 1918 pandemic. While examining the HA sequences, it was observed that the virus characteristic of the peaks did not descend ‘from a single global replacement of pre-pandemic peak viruses.’ Instead, they find that many ‘pre-pandemic peak lineages survived into the following pandemic months.’

Focusing on the geographical 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 in the HA sequences from samples in Europe and North America going back to the period of the pandemic – and its reconstruction ‘showed the interspersed clustering of the three German sequences with the North American ones’. The study theorises that this could be because of the widespread trans-Atlantic movement in the backdrop of the First World War. Both these characteristics – sharing of lineages over time and space – have much in common with the 2009 H1N1 outbreak.

While Patrono et al. (2022) assert that advances in genetic sequencing have enabled biologists to discern lessons from previous pandemics and inform policy measures for the ongoing pandemics, they also highlight that the exorbitant cost of maintaining medical archives means that museums are fast doing away with these historically preserved tissues. Regardless of technological advances, the paucity of readily available medical archives carrying historical pathogens will be a serious impediment to similar research in the future.

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

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