Scientists Describe Structure of Receptor on Surface of
Virus That Caused Deadly 1918 Flu Epidemic
By Jason Socrates
A team of scientists at The Scripps Research Institute has
described for the first time the structure of a protein from
the deadly 1918 "Spanish Flu" virusa virus that took
more lives than World War I and became the largest and deadliest
influenza outbreak in recorded history. Their work reveals
some of the virus's deadly secrets.
"Why was this so devastating an outbreak?" asked lead investigator
Ian Wilson, a molecular biology professor and a member of
The Skaggs Institute for Chemical Biology at Scripps Research.
Seeking the answer led Wilson, Senior Scripps Research Associate
James Stevens, Scripps Research Associate Adam Corper, and
several colleagues, including Jeffery K. Taubenberger from
the Armed Forces Institute of Pathology in Washington, D.C.,
and Christopher F. Basler and Peter Palese of Mount Sinai
Institute of Medicine in New York, to describe the structure
of a protein called hemagglutinin from the 1918 flu virus.
This "antigenic" surface protein is the first structure of
this extinct virus to be solved.
Their research will be published in an upcoming issue of
the journal Science.
A Devastating Infection
Influenza is a common viral infection of the lungs that
affects millions of people annually and is a leading cause
of death in the United States, contributing to around 50,000
deaths per year. Influenza outbreaks like the one in 1918
occur when a virus adapted to birds jumps directly into humans
or reassorts and infects another species, such as the pig,
and then jumps into humans. Similar outbreaks occurred in
1957 and 1968.
The 1918 outbreak was remarkable not only because it caused
such a large number of deaths675,000 in the United
States and up to 40 million worldwidebut also because
it inflicted such high mortality rates, reaching 70
percent in some communities.
Research on the molecular biology of the virus that caused
the 1918 outbreak was complicated by the fact that in 1918,
the cause of the disease was not known. Viruses were not identified
as the cause of influenza until the 1930s, and lung tissue
samples taken in 1918 are generally unreliable sources because
the virus degrades easily.
However, biopsies from soldiers who died from influenza
in 1918 were preserved and maintained in the Armed Forces
Institute of Pathology. Another sample was taken from an Inuit
woman who had succumbed to the infection and had been buried
in the Alaskan permafrost.
Together, these samples yielded a number of pieces of RNA
from the virus. A few years ago, Taubenberger and his colleagues
at the Armed Forces Institute of Pathology were able to piece
together enough fragments to reconstruct the sequence of the
gene that coded for the viral protein hemagglutinin. These
are the oldest viral sequences that have been reconstructed
Then Basler and Palese at Mount Sinai Institute of Medicine
in New York managed to construct an expression system that
allowed them to make the hemagglutinin protein. Finally, Wilson
and Stevens developed their own systems and made enough of
the protein to crystallize and solve the structure using x-ray
The structure of the hemagglutinin protein, one of only
a handful of proteins made by the virus, reveals details that
may be crucial to understanding the 1918 outbreak.
The Hemagglutinin Receptor
A large, glycosylated protein that forms from three identical
550 amino acid chains, hemagglutinin is abundantly displayed
on the surface of the influenza virus. It is the receptor
responsible for the virus infecting cells of the host organism.
During an infection, the virus enters the airways and travels
to the epithelial cells lining the lungs. There, the hemagglutinin
on the surface of the virus binds to lung epithelial cell
receptors containing sialic acid, which allows the virus to
be internalized into the epithelial cell, through something
known as the endosomal pathway, and this establishes an infection.
Hemagglutinin is also the main antigenic determinant on
the virusit is what the human immune system primarily
recognizes and responds to by making antibodies and mounting
an immune defense. How deadly an individual influenza infection
is depends on how well one person's immune system recognizes
One of the questions the researchers asked was whether the
Spanish Flu entered human populations from pigs or some other
mammal that contracted it from an avian source or whether
it jumped directly from birds to humans. In order to address
this, Stevens, Wilson, and their colleagues solved the structure
of the 1918 influenza hemagglutinin, compared it to hemagglutinin
proteins from other human, avian, and pig viruses, and described
all of this in their Science paper. Another article
in this week's Science (by S.J. Gamblin et al) describes
the structure of 1918 hemagglutinin and two closely related
hemagglutinin proteins with receptor analogues.
The structure that Stevens, Wilson, and their colleagues
solved has features primarily found in avian viruses. "It
looks more like an avian viruswith some human characteristics,"
says Wilson. This suggests why the virus may have been so
deadly. Avian-to-human transmission is rare and because of
this has the potential to be more deadly. Because the surface
proteins of the 1918 virus were different from those found
on other flu viruses, people's immune systems were unaccustomed
to them and unable to fight off the Spanish Flu.
An avian origin of the virus also suggests an explanation
for one of the most unusual features of the 1918 outbreakthat
mortality was particularly high among young adults, the age
group that is usually least impacted by the flu. Influenza
is normally more deadly to the elderly and preadolescents
within a population, but in 1918, there were a surprising
number of deaths among 15 to 34 year olds. The avian nature
of the structure suggests the older age group may have been
partially protected by exposure to a similar virus in an earlier
The research article, "Structure of the uncleaved human
H1 hemagglutinin from the extinct 1918 influenza virus," is
authored by James Stevens, Adam L. Corper, Christopher F.
Basler, Jeffery K Taubenberger, Peter Palese, and Ian A. Wilson
and appears in Science Express on February 5, 2004.
Science Express provides rapid electronic publication
of selected papers in the journal Science. Print versions
of these papers will appear in Science after several
weeks. See: http://www.sciencemag.org/sciencexpress/recent.shtml.
The research was funded by the National Institutes of Health,
an Ellison Medical Foundation New Scholarship in Global Infectious
Diseases, an Ellison Medical Foundation Senior Scholarship,
the intramural funds of the Armed Forces Institute of Pathology,
and the Skaggs Foundation for Research.