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S227N and Changes in the H5N1 Receptor Binding Domain
Recombinomics Commentary
February 13, 2006
Dr Nabarro has asked nations to prepare for a pandemic
The bird flu virus is only two mutations away from a form that can spread easily between people, sparking a pandemic in which millions could die.
The above comments almost certainly refer to changes in the receptor binding domain of H5N1. H5N1 has been highly pathogenic in confirmed cases identified by WHO. However, the efficiency of H5N1 infections in humans is low.
The human serotypes are H1, H2, and H3. In the past these serotypes have been characterized for differences in the receptor binding domain.
A recent paper used a glycan microarray to look at receptor binding for various HA sequences, including HA from two isolates from the 1918 pandemic. Changing two positions in the receptor binding domain, E190D and G225D, could dramatically increase the affinity for human receptors. H5N1 has not been identified with either of these two changes, but the paper showed that only two changes were required.
A change in the receptor binding domain that has been identified on HA H5N1 is S227N (also called S223N). This change was initially found in two isolates from Hong Kong residents who had traveled to Fujian Province in China and developed bird flu symptoms. H5N1 was isolated from the father and son and both had S227N. Recent studies have shown that this change could increase the affinity for human receptors and decrease the affinity for avian receptors. This change was also found in an isolated from a patient in Vietnam, but all isolates were from human cases.
In October, 2005, donor sequences were identified in H9N2 isolates that could recombine with the Qinghai strain of H5N1 and create S227N. A warning of such a recombination was issued because H5N1 was migrating into the Middle East, where H9N2 was endemic in local poultry. Infection of the poultry with H5N1 would allow for homologous recombination and creation of S227N. This acquisition would increase the affinity of HA for human receptors and would lead to increased efficiency of human infections.
At the time of the warning, the Qinghai version of H5N1 had not been confirmed in human infections. In late December of 2005, patients with bird flu symptoms in eastern Turkey were identified. In 2006 H5N1 was confirmed in three of the patients, S227N was found in the index case. The familial cluster involved at least three families. At least 16 of the family members were hospitalized and 7 of the 16 were confirmed to be H5N1 positive. The four fatal cases, including the index case, were among the seven H5N1 positive patients.
S227N is in the receptor binding domain. It is adjacent to other changes that increase the affinity for human receptors (Q226L and G228S).
Additional changes at these positions would be cause for concern. As H5N1 expands its geographical reach, additional opportunities for recombination exist. These opportunities to acquire changes in the receptor binding domain, like S227N, are predictable.
They are not due to random mutations, but they are cause for concern.
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