By Heather Rock Woods
Researchers have literally unearthed clues as to why the
1918 influenza pandemic was so deadly. Using fragments of the flu genome
from Army autopsy tissues and a body buried in the freezing Alaskan
permafrost, researchers have assembled genes from the 1918 flu virus.
SSRL’s x-ray beams then revealed the structural secrets of a protein
encoded by one of the genes.
A ‘ribbon’ representation created from data taken
at SSRL shows part of the hemagglutinin (HA) protein from the 1918
influenza virus. The receptor binding site is where the flu protein
attaches to human lung cells. The two patches—one found only in bird
forms of the protein—may have contributed to increased infection
rates during the 1918 pandemic. (Image courtesy of James Stevens and
Ian Wilson, The Scripps Research Institute)
"It’s been known for many years that the 1918 pandemic was
one of the greatest killers ever seen," said Ian Wilson (Scripps Research
Institute). Between 20 and 40 million people died worldwide, including an
abnormally high proportion of healthy young adults, who rarely die from
At the time, people did not know influenza was caused by a
virus. To find surviving samples of genetic material, Jeffery Taubenberger
(Armed Forces Institute of Pathology) and colleagues searched through the
Army’s large set of preserved autopsy tissues and took biopsies from
Alaskans buried in the permafrost. "Whole villages were wiped out by the
flu," Wilson said.
Genetic Information Revealed
From those samples, Taubenberger figured out the sequence
of the flu’s genetic information. The virus has eight gene segments that
give instructions for making at least 11 proteins. Wilson and James
Stevens (Scripps Research Institute) produced one of the viral proteins,
called hemagglutinin (HA), and used SSRL’s protein crystallography beam
line to see the coils, stalks and heads that make up HA’s structure. Their
results appeared in the journal Science.
The intricate shape helps explain why the 1918 flu virus
was unusually virulent. HA is the most abundant protein on the virus’s
surface, making it the main target for the immune system to recognize and
attack. HA binds to human lung cells and enables the virus to get into the
cell inside sacs called vesicles. HA then undergoes a change in shape and
helps the viral and vesicle membranes to fuse, allowing the infection to
Avian Flu Mixes with Human Flu
The structural analysis shows that the 1918 HA protein is
more closely related to avian (bird) forms than previously believed. Flus
that infect birds and pigs also have eight gene segments, corresponding to
human flu, but the proteins look somewhat different.
"That’s one of the reasons influenza is so successful,"
Wilson said. "It can re-sort these segments from different sources, say
one from a bird and the rest from a human." The mixture is devastating
because our immune system has no protective antibodies to avian or swine
proteins that it has never seen before being infected. In the three flu
pandemics last century, Wilson said the HA gene and a second viral gene
were replaced by segments from pigs or aquatic birds. "For the 1918 flu,
we were interested to see if it’s more avian-like or has features of both,
to see why it was so virulent," he said.
Two features in HA’s shape particularly stand out as
potentially contributing to the extraordinarily high infection and
mortality rates observed in 1918. The receptor binding site (for the virus
to attach to human cells) is narrow, and is only a single mutation away
from a known swine-avian virus. The mutation makes the binding site
slightly larger, which could increase affinity for human cells.
The researchers also observed two patches rich in
histidine (an amino acid) which may boost the ability of HA to fuse to the
vesicle membrane in order to escape and replicate itself inside human
cells. One of the patches is found only in avian forms of HA. "[This]
provid[es] tantalizing evidence of a direct jump of this virus from birds
to the human naïve population," Wilson added.
"There are 11 gene products involved, and they probably
all play a role," he said. "This is just a start as far as we’re