|SSRL Science Highlight - August 2004|
Stevens1 and Ian A. Wilson1,2
1Department of Molecular Biology and 2Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037
In 1918, a Great Flu Pandemic swept the world, killing an estimated 20-40 million people, thus making it the largest and most destructive outbreak of any infectious disease in recorded history. This virus was unusual not only in its higher than average mortality rate, but also in the age groups that it attacked. Unlike other outbreaks it targeted not only the very young and old, but also young adults (20-40 year olds). Why the 1918 virus was so devastating is still a mystery. A thorough molecular understanding is now sought to offer reasons why this influenza virus was so pathogenic and how it managed to evade the immune system so effectively. Unfortunately, no intact virus survived, since the pandemic struck before viruses were even identified as the causative agent. Only fragments of the viral genome survived in both Alaskan victims buried in the permafrost and in fixed and archived autopsy material and these have been used to sequence and assemble a number of genes from this virus.
One of the most important viral proteins is the virus coat protein, hemagglutinin (HA). This surface glycoprotein is responsible for virus binding to host cell receptors, and subsequent membrane fusion events within the endosomal pathway in the infected cell. HA is also the most abundant antigen on the surface of the virus and harbors the primary neutralizing epitopes for antibodies. In line with its importance, this viral antigen has been the initial focus of our research on the 1918 flu.
The ectodomain of the HA gene from the 1918 influenza virus1 A/South Carolina/1/18 was cloned and expressed in a baculovirus expression system as the pre-infective HA0 form (see Figure 1 legend). Protein was produced as trimers using a trimerizing sequence ('foldon') from the bacteriophage T4 fibritin. HA0 crystallized at pH 5.5 and its structure was recently solved by molecular replacement (MR) to 3.0 ┼ resolution from data collected at beamline 9-2 at SSRL (pdb:1RD8)2. 18HA0 is ~135 ┼ in length with two distinct domains (Figure 1). The cylindrical trimer has a tightly intertwined 'stem' domain at its membrane proximal base. The dominant feature of this stalk region is a long triple-stranded coiled-coil. This region also contains the cleavage site where host enzymes cleave HA0 to its infective HA1/HA2 form. The membrane-distal domain consists of a globular 'head' which contains the host receptor binding site and major epitopes for neutralizing antibodies.
Although phylogenetic analyses place the 1918 HA sequence at the base of the
evolutionary tree of human viruses, analysis of this structure revealed that it
is more closely akin to avian forms. A number of species- and serotype-specific
features have been identified:
Thus, these and other as yet unidentified features may have contributed to the extraordinarily high infectivity and mortality rates observed during 1918.
|Last Updated:||20 AUG 2004|
|Content Owner:||Ian A. Wilson|
|Page Editor:||Lisa Dunn|