- Email: [email protected]
D225G mutation in the hemagglutinin protein found in 3 severe cases of 2009 pandemic influenza A (H1N1) in Spain
Available online at www.sciencedirect.com
Diagnostic Microbiology and Infectious Disease 67 (2010) 207 – 208 www.elsevier.com/locate/diagmicrobio
D225G mutation in the hemagglutinin protein found in 3 severe cases of 2009 pandemic influenza A (H1N1) in Spain☆ Andrés Antóna,⁎, María Ángeles Marcosa , Miguel Julián Martíneza , Susana Ramóna , Anna Martínezb , Neus Cardeñosab , Pere Godoyb , Nuria Tornerb , Patricia De Molinaa , Ricard Isantaa , María Teresa Jiménez de Antaa , Tomàs Pumarolaa a
b
Microbiology Laboratory, Hospital Clínic, 08036 Barcelona, Spain Department of Health, Generalitat de Catalunya, 08005 Barcelona, Spain Received 21 January 2010; accepted 2 February 2010
Abstract From 27 April to 16 December 2009, we analyzed the hemagglutinin gene sequence of 2009 pandemic influenza A (H1N1) virus in 189 respiratory specimens. We only found the D225G mutation in 3 severe cases. However, it was not found in samples from other cases with or without clinical criteria of severity. The biologic significance of this mutation remains still unclear. © 2010 Elsevier Inc. All rights reserved. Keywords: Pandemic; Influenza; D225G mutation
The binding of influenza viruses to their target cells is mediated by the viral hemagglutinin (HA), which recognizes cell surface glycoconjugates containing terminal sialic acid (SA) residues. Receptor specificity plays an important role in the viral cell and tissue tropism because human influenza viruses bind preferentially to SAs linked to galactose by an α(2,6) linkage (α2,6 SA), whereas avian and equine strains prefer α(2,3) linkage (α2,3 SA) (Reina 2002). Whereas α2,6 SA expression is abundant in the upper respiratory tract and α2,3 SA is scarce (van Riel et al., 2007), both α2,6 SA and α2,3 SA expression in the distal lung regions is significant (Gagneux et al., 2003; Shinya et al., 2006). Amino acids at positions 190 and 225 (H3 numbering) in the 1918 pandemic influenza A virus HA appear to determine its receptor binding specificity because changes at these positions caused a switch in preference from the α2,6 SA to the α2,3 SA. However, these mutant 1918
☆ This work was partially supported by Fondo de Investigación Sanitaria, grant FIS 08/0118, from Ministry of Health, Spain. ⁎ Corresponding author. E-mail address: [email protected] (A. Antón).
0732-8893/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2010.02.002
pandemic influenza A viruses demonstrated a low transmissibility (Tumpey et al., 2007). A mutation at position 225 of the viral HA protein where aspartic acid (D) is changed to glycine (G) might make a virus with double preference, for both α2,3 SA and α2,6 SA. Severity of the respiratory disease might be due to a deeper infection of the respiratory tract. Otherwise, an influenza virus without this amino acid change could probably replicate deep in the respiratory tract in humans as well, because cells with α2,6 SA are also present in the lower respiratory tract of humans (Tumpey et al., 2007). The mutant D225G 2009 pandemic influenza A (H1N1) virus has been also observed in other countries like Norway, Brazil, China, Japan, Mexico, Ukraine, and the United States. These mutations appear to occur sporadically and spontaneously without spreading (http://www. who.int/csr/disease/swineflu/notes/briefing_20091120/en/ index.html). As the Spanish National Influenza Centre in Barcelona, we monitor HA, NA, M, and PB2 sequences of the circulating 2009 pandemic influenza A (H1N1) viruses in Catalonia. Further than studying weekly some random positive samples for pandemic influenza from our influenza surveillance network in Catalonia (Spain), the study of
208
A. Antón et al. / Diagnostic Microbiology and Infectious Disease 67 (2010) 207–208
additional samples from cases with severe outcomes has special interest. From 27 April to 16 December 2009, a total of 189 samples were analyzed for mutations in HA gene, of which 8 samples corresponded to 7 severe cases. No mutations were found at position 190 in all analyzed samples. However, we found the D225G in viruses from 2 fatal cases of pandemic influenza and 1 patient with severe illness who finally recovered successfully. These 3 cases were the first infected patients by mutant D225G 2009 pandemic influenza A (H1N1) viruses in Spain. There was neither epidemiologic relationship among these strains nor humanto-human transmission (sporadic cases as occurred worldwide). This mutation was not found in any sample from nonsevere cases. Moreover, we also found a different mutation (D225E) at this position in 61 samples, not only from severe cases, but also from patients from the influenza surveillance network. Thus, these data enhance the idea that this mutation does not confer any virologic advantage for the virus.
Although these mutations (D225G and D190E) could affect the virulence of 2009 pandemic influenza A (H1N1) virus, the biologic significance remains still unclear. References Gagneux P, Cheriyan M, Hurtado-Ziola N, van der Linden EC, Anderson D, McClure H, Varki A, Varki NM (2003) Human-specific regulation of alpha 2-6–linked sialic acids. J Biol Chem 278:48245–48250. Reina J (2002) Factors affecting the virulence and pathogenicity of avian and human viral strains (influenza virus type A). Enferm Infecc Microbiol Clin 20:346–353. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y (2006) Avian flu: influenza virus receptors in the human airway. Nature 440:435–436. Tumpey TM, Maines TR, Van Hoeven N, Glaser L, Solórzano A, Pappas C, Cox NJ, Swayne DE, Palese P, Katz JM, García-Sastre A (2007) A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science 315:655–659. van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus AD, Kuiken T (2007) Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals. Am J Pathol 171:1215–1223.
Diagnostic Microbiology and Infectious Disease 67 (2010) 207 – 208 www.elsevier.com/locate/diagmicrobio
D225G mutation in the hemagglutinin protein found in 3 severe cases of 2009 pandemic influenza A (H1N1) in Spain☆ Andrés Antóna,⁎, María Ángeles Marcosa , Miguel Julián Martíneza , Susana Ramóna , Anna Martínezb , Neus Cardeñosab , Pere Godoyb , Nuria Tornerb , Patricia De Molinaa , Ricard Isantaa , María Teresa Jiménez de Antaa , Tomàs Pumarolaa a
b
Microbiology Laboratory, Hospital Clínic, 08036 Barcelona, Spain Department of Health, Generalitat de Catalunya, 08005 Barcelona, Spain Received 21 January 2010; accepted 2 February 2010
Abstract From 27 April to 16 December 2009, we analyzed the hemagglutinin gene sequence of 2009 pandemic influenza A (H1N1) virus in 189 respiratory specimens. We only found the D225G mutation in 3 severe cases. However, it was not found in samples from other cases with or without clinical criteria of severity. The biologic significance of this mutation remains still unclear. © 2010 Elsevier Inc. All rights reserved. Keywords: Pandemic; Influenza; D225G mutation
The binding of influenza viruses to their target cells is mediated by the viral hemagglutinin (HA), which recognizes cell surface glycoconjugates containing terminal sialic acid (SA) residues. Receptor specificity plays an important role in the viral cell and tissue tropism because human influenza viruses bind preferentially to SAs linked to galactose by an α(2,6) linkage (α2,6 SA), whereas avian and equine strains prefer α(2,3) linkage (α2,3 SA) (Reina 2002). Whereas α2,6 SA expression is abundant in the upper respiratory tract and α2,3 SA is scarce (van Riel et al., 2007), both α2,6 SA and α2,3 SA expression in the distal lung regions is significant (Gagneux et al., 2003; Shinya et al., 2006). Amino acids at positions 190 and 225 (H3 numbering) in the 1918 pandemic influenza A virus HA appear to determine its receptor binding specificity because changes at these positions caused a switch in preference from the α2,6 SA to the α2,3 SA. However, these mutant 1918
☆ This work was partially supported by Fondo de Investigación Sanitaria, grant FIS 08/0118, from Ministry of Health, Spain. ⁎ Corresponding author. E-mail address: [email protected] (A. Antón).
0732-8893/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2010.02.002
pandemic influenza A viruses demonstrated a low transmissibility (Tumpey et al., 2007). A mutation at position 225 of the viral HA protein where aspartic acid (D) is changed to glycine (G) might make a virus with double preference, for both α2,3 SA and α2,6 SA. Severity of the respiratory disease might be due to a deeper infection of the respiratory tract. Otherwise, an influenza virus without this amino acid change could probably replicate deep in the respiratory tract in humans as well, because cells with α2,6 SA are also present in the lower respiratory tract of humans (Tumpey et al., 2007). The mutant D225G 2009 pandemic influenza A (H1N1) virus has been also observed in other countries like Norway, Brazil, China, Japan, Mexico, Ukraine, and the United States. These mutations appear to occur sporadically and spontaneously without spreading (http://www. who.int/csr/disease/swineflu/notes/briefing_20091120/en/ index.html). As the Spanish National Influenza Centre in Barcelona, we monitor HA, NA, M, and PB2 sequences of the circulating 2009 pandemic influenza A (H1N1) viruses in Catalonia. Further than studying weekly some random positive samples for pandemic influenza from our influenza surveillance network in Catalonia (Spain), the study of
208
A. Antón et al. / Diagnostic Microbiology and Infectious Disease 67 (2010) 207–208
additional samples from cases with severe outcomes has special interest. From 27 April to 16 December 2009, a total of 189 samples were analyzed for mutations in HA gene, of which 8 samples corresponded to 7 severe cases. No mutations were found at position 190 in all analyzed samples. However, we found the D225G in viruses from 2 fatal cases of pandemic influenza and 1 patient with severe illness who finally recovered successfully. These 3 cases were the first infected patients by mutant D225G 2009 pandemic influenza A (H1N1) viruses in Spain. There was neither epidemiologic relationship among these strains nor humanto-human transmission (sporadic cases as occurred worldwide). This mutation was not found in any sample from nonsevere cases. Moreover, we also found a different mutation (D225E) at this position in 61 samples, not only from severe cases, but also from patients from the influenza surveillance network. Thus, these data enhance the idea that this mutation does not confer any virologic advantage for the virus.
Although these mutations (D225G and D190E) could affect the virulence of 2009 pandemic influenza A (H1N1) virus, the biologic significance remains still unclear. References Gagneux P, Cheriyan M, Hurtado-Ziola N, van der Linden EC, Anderson D, McClure H, Varki A, Varki NM (2003) Human-specific regulation of alpha 2-6–linked sialic acids. J Biol Chem 278:48245–48250. Reina J (2002) Factors affecting the virulence and pathogenicity of avian and human viral strains (influenza virus type A). Enferm Infecc Microbiol Clin 20:346–353. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y (2006) Avian flu: influenza virus receptors in the human airway. Nature 440:435–436. Tumpey TM, Maines TR, Van Hoeven N, Glaser L, Solórzano A, Pappas C, Cox NJ, Swayne DE, Palese P, Katz JM, García-Sastre A (2007) A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science 315:655–659. van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus AD, Kuiken T (2007) Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals. Am J Pathol 171:1215–1223.