BioWorld International Correspondent

LONDON - The mystery of how the influenza virus that killed around 20 million people worldwide in 1918 was able to wreak such havoc has been solved by a joint team of scientists working in the UK and the U.S.

Their study shows how one of the proteins on the surface of the 1918 influenza virus had a different shape, allowing it to bind to and attack human cells more vigorously than other strains. The scientists said their findings demonstrate how subtle alterations in the infectivity of the influenza virus can influence its spread.

The findings are the result of a long-term collaboration between John Skehel, of the Medical Research Council's National Institute for Medical Research in London, and the late Don Wiley, a Howard Hughes Medical Institute investigator at Harvard University in Cambridge, Mass.

An account of the study appears in the Feb. 5, 2004, version of Sciencexpress, the online edition of Science, titled "The Structure and Receptor-Binding Properties of the 1918 Influenza Hemagglutinin."

Skehel said: "This paper is important because of the knowledge it brings about how these viruses, which originate in birds, can jump to humans. This allows us to track and monitor the changes in the virus for public health purposes, even though it does not allow us to predict or prevent future forms of flu."

Influenza viruses are categorized according to the hemagglutinin (H) and neuraminidase (N) proteins on their surfaces. The H proteins recognize and bind to receptors on the host-cell surface. The binding of those receptors causes pores to open in the host cells, allowing the virus to pass through.

The receptors on the host cells are sialic acids, which are linked to galactose, one of the components of cell-surface glycoproteins and glycolipids. The linkage of the sialic acid to the galactose can take two forms, either alpha2,3 or alpha2,6.

Which of those types of linkage the H protein of a given influenza strain can bind to will determine which species it can infect. For example, avian influenza viruses bind preferentially to sialic acid in alpha2,3-linkage, and that type of linkage predominates in the lining of the avian gut. Swine influenza viruses can bind to sialic acid in both alpha2,6- and alpha2,3-linkage, and both types of linkage can be detected in porcine trachea. The main form of sialic acid found in the human respiratory tract is alpha2,6-linked, and the subtypes of human influenza virus that caused the pandemics of 1918, 1957 and 1968 all bind to that form.

Skehel, Wiley and their colleagues aimed to find out how the 1918 version of the H protein could bind to receptors on human cells and yet still retain many of the characteristics of its avian precursor virus.

The H protein of the 1918 virus, which was the first to cause a pandemic, was called H1. The influenza viruses that caused later pandemics had distinctively different hemagglutinin structures, called H2 for the Asian influenza that began in 1957, and H3 for the Hong Kong strain, which began in 1968.

Skehel said: "What was interesting was that, although all three of these subtypes came from birds, the H1 was quite different from H2 and H3, having hardly changed from what it was in the avian virus."

The researchers set out to explore that difference in detail. They worked from DNA sequence information that other researchers had obtained from viral material isolated from autopsy specimens taken from people who died in the 1918 pandemic.

Using that sequence data, Wiley, Skehel and their colleagues synthesized the gene for the H1 hemagglutinin and used it to produce the protein itself. They then crystallized the protein and used X-ray crystallography to determine its structure.

Skehel said: "The structure revealed how the H1 group could still resemble the avian binding site but nevertheless infect humans. We found basically that two sides of the hemagglutinin receptor-binding site are in slightly different positions in the 1918 hemagglutinin, in comparison with the Hong Kong protein. This subtle difference allows the human receptor to bind in an antigenically favorable way."