MRC National Institute for Medical Research, London
Science for Health
A more virulent form of swine flu
03 November 2010
Although most cases of the 2009-2010 influenza pandemic were mild, the 'swine flu' virus has also caused a substantial number of severe and fatal infections. Some variants of the virus carried mutations in its receptor-binding site, and mutants with a D222G substitution have been observed to correlate with cases of severe or fatal disease
Cell surface receptors for influenza viruses differ in distribution in the tissues and cells of different species. The receptors are differentially recognized by the haemagglutinin proteins of human and animal influenza viruses and are critical determinants of host range and tissue tropism. Previous studies have indicated that amino acid substitutions in the hemagglutinin at position 222 may affect the specificity of receptor binding and thereby determine the range of cell types in human respiratory tissues infected by the viruses.
Steve Wharton (pictured right) and Rod Daniels (pictured below), from NIMR’s Division of Virology and the WHO Influenza Centre, collaborated with Mikhail Matrosovich, at Philipps University in Marburg, and Ten Feizi, at Imperial College London, to examine the influence of the D222G substitution on the cell tropism of the pandemic A(H1N1) viruses. They showed that 222G variants infected a higher proportion of ciliated cells in cultures of human airway epithelium than did viruses with other substitutions, which targeted mainly nonciliated cells. Carbohydrate microarray analyses showed that 222G variants bind a broader range of receptor sequences of a type expressed on ciliated bronchial epithelial cells and on epithelia within the lung. These features of 222G mutants may contribute to exacerbation of disease.
Whether the selection of the D222G mutations is a cause or a consequence of more severe lower respiratory tract infection is still to be resolved. It is evident, however, that its emergence is likely to exacerbate the severity of disease. The altered receptor specificity and distinctive cell tropism of the D222G mutants of H1N1pdm are hallmarks of a more dangerous pathogen, emphasizing the importance of close monitoring of the evolution of these viruses.
Although, thankfully, the occurrence of the pandemic H1N1 strains that are associated with a more severe disease have remained sporadic, this research highlights the potential for emergence of more virulent forms and emphasizes the importance of monitoring the binding properties as well as the sequence and antigenicity of novel strains of the pandemic virus.
Steve Wharton
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Difference in the binding of pandemic H1N1 viruses to receptor analogues using the carbohydrate microarray system. A/Moldova/G186/2009 with an aspartic acid (D) at position 222 in the haemagglutinin resulted in a non-fatal infection whereas A/Norway/3206-3/2009 with a glycine (G) substitution at position 222 caused a fatal infection. The 222G virus bound more strongly to 2,3 linked sialic acid analogues.
Original article
Liu Y, Childs RA, Matrosovich T, Wharton S, Palma AS, Chai W, Daniels R, Gregory V, Uhlendorff J, Kiso M, Klenk HD, Hay A, Feizi T, Matrosovich M. (2010)
Altered Receptor Specificity and Cell Tropism of D222G Hemagglutinin Mutants Isolated from Fatal Cases of Pandemic A(H1N1) 2009 Influenza Virus.
Journal of Virology 84:12069-74. Fulltext
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