Influenza Mutation from Equine to Canine

Abstract

In their report “transmission of equine influenza virus to dogs” (21 Oct. 2005, p. [482][1]), P. C. Crawford et al. observed an unprecedented interspecies transfer of a complete equine influenza virus to the dog and the emergence of a new canine-specific influenza virus associated with acute respiratory disease. They noticed that a viral hemagglutinin (HA), a critical determinant of host species specificity of influenza virus, differs mainly in four residues (N83S, W222L, I328T, and N483T) between the equine and canine HA orthologs, out of which only one (W222L) is exposed to the serum and is most likely involved in receptor binding. Our analysis revealed an additional important mutation (N54K) located in the antibody-binding region of HA ([1][2]). This residue is highly conserved in all noncanine (94) HA sequences of the subtype H3N8 (see multiple sequence alignment at ). In contrast, a leucine residue observed in the canine HA at position 222 is also present in three equine orthologs deposited in GenBank. The figure presents a comparison of the three-dimensional models of the equine and the canine HAs created with 1HA0 ([2][3]) and 1KEN ([3][4]) structures as templates. Highlighted areas show that the N54K mutation changes the electrostatic potential on the protein surface significantly. Moreover, it is placed in the middle of an N glycosylation motif (Asn-X-Ser) and likely increases the probability of the posttranslational modification of the preceding asparagine ([4][5]). The glycosylation of HA has been shown to enable the virus to mask its antigenic sites ([5][6]). We suggest that this mutation may help the virus escape the dog's immune defense and may be part of the minimal repertoire of changes required for the host specificity transition in the observed case. ![Figure][7] The ribbon representation ( A ) and the protein surface colored by electrostatic potential ( B , C ) of 3D models of the canine (A, B) and the equine (C) influenza hemagglutinins. Five dog-specific mutations are marked (A) with visible amino acid side chains. Highlighted areas (B, C) show the highest differences in electrostatic potential caused by the N54K mutation. This picture was created with Swiss PDB Viewer. 1. 1.[↵][8] 1. D. Fleury, 2. R. S. Daniels, 3. J. J. Skehel, 4. M. Knossow, 5. T. Bizebard , Proteins (2000) 40, 572. 2. 2.[↵][9] 1. J. Chen 2. et al. , Cell (1998) 95, 409. 3. 3.[↵][10] 1. C. Barbey-Martin 2. et al. , Virology (2002) 294, 70. 4. 4.[↵][11] 1. S. H. Shakin-Eshleman, 2. S. L. Spitalnik, 3. L. Kasturi , J. Biol. Chem. (1996) 271, 6363. 5. 5.[↵][12] 1. J. J. Skehel 2. et al. , Proc. Natl. Acad. Sci. U.S.A. (1984) 81, 1779. 6. 6. M.v.G. is a fellow of Foundation for Polish Science. # Response {#article-title-2} Glycan camouflaging of HA antigenic sites is certainly a successful strategy of the human influenza virus in evasion of antibody responses elicited by previous influenza infections in adult populations. Canine influenza is a newly emerging pathogen and dogs are immunologically naive to the virus. Without the selective pressure applied by preexisting antibodies, the role of the amino acid substitution at position 54 in virus escape from antibody neutralization is probably not as important in either adaptation to or maintenance of the virus in the canine population at this time. We agree with von Grotthuss and Rychlewski that, in addition to the four amino acid substitutions we described, the N54K substitution in the HA may have contributed to the successful transfer of equine H3N8 virus to the dog. However, the effects of these amino acid mutations on HA function are undefined and are likely multifactorial. It will be very interesting to monitor the evolution of these five sites of the HA as the virus becomes endemic in the dog population and herd immunity develops from infection or vaccination. [1]: /lookup/doi/10.1126/science.1117950 [2]: #ref-1 [3]: #ref-2 [4]: #ref-3 [5]: #ref-4 [6]: #ref-5 [7]: pending:yes [8]: #xref-ref-1-1 View reference 1. in text [9]: #xref-ref-2-1 View reference 2. in text [10]: #xref-ref-3-1 View reference 3. in text [11]: #xref-ref-4-1 View reference 4. in text [12]: #xref-ref-5-1 View reference 5. in text