Structure of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus

Abstract

The 1918 "Spanish" influenza pandemic represents the largest recorded outbreak of any infectious disease. The crystal structure of the uncleaved precursor of the major surface antigen of the extinct 1918 virus was determined at 3.0 angstrom resolution after reassembly of the hemagglutinin gene from viral RNA fragments preserved in 1918 formalin-fixed lung tissues. A narrow avian-like receptor-binding site, two previously unobserved histidine patches, and a less exposed surface loop at the cleavage site that activates viral membrane fusion reveal structural features primarily found in avian viruses, which may have contributed to the extraordinarily high infectivity and mortality rates observed during 1918.

Crystal structure of the swine-origin A (H1N1)-2009 influenza A virus hemagglutinin (HA) reveals similar antigenicity to that of the 1918 pandemic virus

“…By contrast, the area of the basic patches (blue regions) is obviously larger in 09H1 than any other H1, including 18H1, due to its N/S46K and H285K substitutions. Although there has been no direct evidence till now, the increased basicity of the basic patch has been proposed to be related to enhanced virus membrane fusion and subsequent pathogenicity as proposed by Stevens et al (2004Stevens et al ( , 2006, and experimental testing of such a hypothesis is required.…”

“…Methods for the cloning, expression and purification of secreted 09H1 were based on those reported by Stevens et al (2004Stevens et al ( , 2006 and Ekiert et al (2009). Briefly, cDNA encoding amino acid residues 11-505 (11-329 (HA1) and 1-176 (HA2)) from the A/California/04/ 2009 HA ectodomain was amplified and cloned into the baculovirus transfer vector pAcGP67-B (BD Biosciences), containing a thrombin cleavage site, a trimerizing 'foldon' sequence and a his-tag.…”

Bacterial HA1 Vaccine against Pandemic H5N1 Influenza Virus: Evidence of Oligomerization, Hemagglutination, and Cross-Protective Immunity in Ferrets

“…However, it was not clear whether unglycosylated proteins will present antigenically relevant epitopes. Most of the influenza virus protective antigenic sites are conformation dependent and map primarily to the HA1 globular head (22,30). Previously, we used H5N1 whole-genome phage display libraries to map the antibody repertoires following human infection with HP H5N1 (A/Vietnam/1203/2004) AIV, as well as in post-H5N1 vaccination sera (11,12).…”

Influence of calcium on lipid mixing mediated by influenza hemagglutinin

“…However, at least in some HA strains vestigial esterase domain may play a role in fusion. For example, the vestigial esterase domain from the HA1 subunit of A/ Puerto Rico/8/34 [48,49] and A/South Carolina/1/18 strains [50] can be involved in fusion process. One can hypothesize that the vestigial esterase domain of HA1 of Udorn HA (used in our experiments) may play a role in membrane fusion as such domain of these two strains, and, hence, calcium-binding site in this domain can influence fusion.…”

“…Binding of calcium to the vestigial esterase domain may change the conformation of HA1, and such a conformational change may lead to the interaction of the fusion peptide cavity with basic HA1 residues. This interaction may hypothetically facilitate the release of the fusion peptide from the cavity [50].…”