A complete influenza A virus genome recovered from a Swiss patient who died in July 1918 already contained key mutations associated with human adaptation during the earliest phase of the pandemic, according to a recent study.
Researchers in Switzerland reconstructed a complete and precisely dated influenza A virus (IAV) genome using a ligation-based RNA sequencing protocol applied to a formalin-fixed specimen collected during the early weeks of the 1918 influenza pandemic. The genome, recovered from an 18-year-old patient who died on July 15, 1918, was sequenced with an average coverage of 64 times. The study evaluated this ligation-based protocol alongside a previously published phenol- and chloroform-free random hexamer-based protocol. Both methods yielded comparable viral genome coverage, but the ligation-based protocol produced a higher proportion of short RNA fragments and retained strand orientation.
The ligation-based protocol, published in BMC Biology, successfully recovered viral RNA fragments from historical autopsy specimens, including sample ZH1502, which contained mutations previously associated with adaptation to the human host. Notable substitutions were identified at nucleoprotein positions 16 and 283 (D16 and P283), which have been reported to confer reduced susceptibility to the human antiviral protein MxA. These substitutions were not found in other first-wave European genomes from June 1918, suggesting genetic variation among circulating strains during that period. The HA gene of ZH1502 encoded the D222 residue, which is associated with preferential binding to human-type sialic acid receptors. This residue was also present in other early European IAV genomes and may have been common during the initial pandemic wave.
Phylogenetic analysis placed ZH1502 within a clade containing IAV genomes from the first and second pandemic waves in Europe and North America. A comparison of genomic divergence between the 1918 and 2009 pandemics found greater diversity in three gene segments (PB2, PA, and HA) among 1918 genomes. The presence of divergent polymerase segments with otherwise similar HA sequences in 1918 genomes may reflect reassortment or varying selection pressures, although the limited number of genomes precludes definitive conclusions.
The sequencing approach-maintained RNA fragment orientation and yielded short fragments consistent with expectations for degraded historical RNA. The study protocol recovered short viral RNA fragments and preserved RNA strand information from formalin-fixed historical autopsy tissue.
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