1918 influenza pandemic caused by highly conserved viruses with two receptor-binding variants

Abstract

The “Spanish influenza pandemic swept the globe in the autumn and winter of 1918–19, and resulted in the deaths of approximately 40 million people. Clinically, epidemiologically, and pathologically, the disease was remarkably uniform, which suggests that similar viruses were causing disease around the world. To assess the homogeneity of the 1918 pandemic influenza virus, partial hemagglutinin gene sequences have been determined for five cases, including two newly identified samples from London, United Kingdom. The strains show 98.9% to 99.8% nucleotide sequence identity. One of the few differences between the strains maps to the receptor-binding site of hemagglutinin, suggesting that two receptor-binding configurations were co-circulating during the pandemic. The results suggest that in the early stages of an influenza A pandemic, mutations that occur during replication do not become fixed so that a uniform “consensus” strain circulates for some time.

Figure

Partial HA1 domain cDNA sequences from five 1918–19 cases. A 563-bp fragment encoding antigenic (19,20) and receptor-binding (21) sites of the HA1 domain is shown, with the sequences aligned to A/Brevig Mission/1/1918 (BREVIG18) (15). Dots represent sequence identity as compared to BREVIG18. The numbering of the nucleotide sequence is aligned to A/PR/8/1934 (GenBank accession no. NC_002017) and refers to the sequence of the gene in the sense (mRNA) orientation. The partial HA1 translation product for BREVIG18 is shown above its cDNA sequence. Amino acid numbering is aligned to the H3 HA1 domain (15). Boxed amino acids indicate potential glycosylation sites as predicted by the sequence (15). Residues that have been shown experimentally to affect receptor-binding specificity in H1 HAs, D77, A138, P186, D190, L194, and D225 (–23) are indicated by a ◇ symbol above these six residues. Residues defining four antigenic sites are indicated: C_b (●), S_a (■), S_b (◆), and C_a (▲) (19,20). Residues that have been mapped to both receptor-binding and antigenic sites (positions 194 and 225) are marked with two symbols. When a nucleotide change as compared to BREVIG18 results in a changed amino acid, the resultant amino acid is shown in lower case to the right of the BREVIG18 residue. Strain abbreviations and GenBank accession numbers: A/Brevig Mission/1/1918 (BREVIG18, # AF116575), A/South Carolina/1/1918 (SC18, # AF117241), A/New York/1/1918 (NY18, # AF116576), A/London/1/1918 (LONDON18, # AY184805), and A/London/1/1919 (LONDON19, # AY184806).