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Proc Natl Acad Sci USA. Avian influenza virus hemagglutinins H2, H4, H8, and H14 support a highly pathogenic phenotype
[Source: Proc Natl Acad Sci USA, full text: (LINK). Abstract, edited.]
Avian influenza virus hemagglutinins H2, H4, H8, and H14 support a highly pathogenic phenotype
Jutta Veits<SUP>a</SUP><SUP>1</SUP>, Siegfried Weber<SUP>a</SUP><SUP>1</SUP>, Olga Stech<SUP>a</SUP>, Angele Breithaupt<SUP>b</SUP>, Marcus Gr?ber<SUP>a</SUP>, Sandra Gohrbandt<SUP>a</SUP><SUP>2</SUP>, Jessica Bogs<SUP>a</SUP>, Jana Hundt<SUP>a</SUP><SUP>3</SUP>, Jens P. Teifke<SUP>b</SUP>, Thomas C. Mettenleiter<SUP>a</SUP>, and J?rgen Stech<SUP>a</SUP><SUP>4</SUP>
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Author Affiliations: <SUP>a</SUP>Institute of Molecular Biology and <SUP>b</SUP>Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 17493 Greifswald-Insel Riems, Germany
Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved December 30, 2011 (received for review June 10, 2011)
Abstract
High-pathogenic avian influenza viruses (HPAIVs) evolve from low-pathogenic precursors specifying the HA serotypes H5 or H7 by acquisition of a polybasic HA cleavage site. As the reason for this serotype restriction has remained unclear, we aimed to distinguish between compatibility of a polybasic cleavage site with H5/H7 HA only and unique predisposition of these two serotypes for insertion mutations. To this end, we introduced a polybasic cleavage site into the HA of several low-pathogenic avian strains with serotypes H1, H2, H3, H4, H6, H8, H10, H11, H14, or H15, and rescued HA reassortants after cotransfection with the genes from either a low-pathogenic H9N2 or high-pathogenic H5N1 strain. Oculonasal inoculation with those reassortants resulted in varying pathogenicity in chicken. Recombinants containing the engineered H2, H4, H8, or H14 in the HPAIV background were lethal and exhibited i.v. pathogenicity indices of 2.79, 2.37, 2.85, and 2.61, respectively, equivalent to naturally occurring H5 or H7 HPAIV. Moreover, the H2, H4, and H8 reassortants were transmitted to some contact chickens. The H2 reassortant gained two mutations in the M2 proton channel gate region, which is affected in some HPAIVs of various origins. Taken together, in the presence of a polybasic HA cleavage site, non-H5/H7 HA can support a highly pathogenic phenotype in the appropriate viral background, indicating requirement for further adaptation. Therefore, the restriction of natural HPAIV to serotypes H5 and H7 is likely a result of their unique predisposition for acquisition of a polybasic HA cleavage site.
Footnotes
<SUP>1</SUP>J.V. and S.W. contributed equally to this work.
<SUP>2</SUP>Present address: Institute of Immunology, Laboratoire National de Sant?, 11 L-1950 Luxembourg.
<SUP>3</SUP>Present address: Vaccine and Infectious Disease Organization (VIDO)?International Vaccine Centre, Saskatoon, SK, Canada S7N 5E3.
<SUP>4</SUP>To whom correspondence should be addressed. E-mail: juergen.stech@fli.bund.de.
Author contributions: J.V., O.S., A.B., T.C.M., and J.S. designed research; J.V., S.W., O.S., A.B., M.G., S.G., J.B., J.H., and J.S. performed research; J.V., S.W., O.S., A.B., J.P.T., T.C.M., and J.S. analyzed data; and T.C.M. and J.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The sequences reported in this paper have been deposited in the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database (accession nos. EPI317608?EPI317615, EPI341615, EPI341616, and EPI341699?EPI341705).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1109397109/-/DCSupplemental.
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Author Affiliations: <SUP>a</SUP>Institute of Molecular Biology and <SUP>b</SUP>Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 17493 Greifswald-Insel Riems, Germany
Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved December 30, 2011 (received for review June 10, 2011)
Abstract
High-pathogenic avian influenza viruses (HPAIVs) evolve from low-pathogenic precursors specifying the HA serotypes H5 or H7 by acquisition of a polybasic HA cleavage site. As the reason for this serotype restriction has remained unclear, we aimed to distinguish between compatibility of a polybasic cleavage site with H5/H7 HA only and unique predisposition of these two serotypes for insertion mutations. To this end, we introduced a polybasic cleavage site into the HA of several low-pathogenic avian strains with serotypes H1, H2, H3, H4, H6, H8, H10, H11, H14, or H15, and rescued HA reassortants after cotransfection with the genes from either a low-pathogenic H9N2 or high-pathogenic H5N1 strain. Oculonasal inoculation with those reassortants resulted in varying pathogenicity in chicken. Recombinants containing the engineered H2, H4, H8, or H14 in the HPAIV background were lethal and exhibited i.v. pathogenicity indices of 2.79, 2.37, 2.85, and 2.61, respectively, equivalent to naturally occurring H5 or H7 HPAIV. Moreover, the H2, H4, and H8 reassortants were transmitted to some contact chickens. The H2 reassortant gained two mutations in the M2 proton channel gate region, which is affected in some HPAIVs of various origins. Taken together, in the presence of a polybasic HA cleavage site, non-H5/H7 HA can support a highly pathogenic phenotype in the appropriate viral background, indicating requirement for further adaptation. Therefore, the restriction of natural HPAIV to serotypes H5 and H7 is likely a result of their unique predisposition for acquisition of a polybasic HA cleavage site.
Footnotes
<SUP>1</SUP>J.V. and S.W. contributed equally to this work.
<SUP>2</SUP>Present address: Institute of Immunology, Laboratoire National de Sant?, 11 L-1950 Luxembourg.
<SUP>3</SUP>Present address: Vaccine and Infectious Disease Organization (VIDO)?International Vaccine Centre, Saskatoon, SK, Canada S7N 5E3.
<SUP>4</SUP>To whom correspondence should be addressed. E-mail: juergen.stech@fli.bund.de.
Author contributions: J.V., O.S., A.B., T.C.M., and J.S. designed research; J.V., S.W., O.S., A.B., M.G., S.G., J.B., J.H., and J.S. performed research; J.V., S.W., O.S., A.B., J.P.T., T.C.M., and J.S. analyzed data; and T.C.M. and J.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The sequences reported in this paper have been deposited in the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database (accession nos. EPI317608?EPI317615, EPI341615, EPI341616, and EPI341699?EPI341705).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1109397109/-/DCSupplemental.
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