H7N9 Influenza Viruses Are Transmissible in Ferrets by Respiratory Droplet
H7N9 Adaptation
Puzzling and alarming reports of an outbreak in early 2013 of human infections by a low-pathogenicity avian influenza virus has rocked the poultry industry in central eastern China and brought fears of initiating a human pandemic. Over 130 human cases have been reported with 37 deaths until closure of poultry markets accompanied a near-cessation of human case reports. From surveillance sampling of >10,000 isolates obtained during April 2013, Zhang et al. (p. 410, published online 18 July) took 37 isolates of avian origin H7N9 and compared them to human H7N9 isolates. The majority of H7N9 isolates came from live poultry markets, although some originated in pigeons. Sequence analysis indicated that the chicken isolates had retained the avian characteristics at sites on the influenza genes for PB2 and the surface hemagglutinin HA, where adaptive mutations have been observed before. Sequence analysis also showed a higher variability in the internal genes than in HA and neuraminidase NA. By using glycan arrays, it was shown that avian and human isolates bound to human, but also to some extent to avian, receptors. As expected, the virus replicated well in chickens without causing disease, whereas in mice only the human isolates were highly pathogenic. The human virus, but not the avian, transmitted between ferrets through the air.
Abstract
A newly emerged H7N9 virus has caused 132 human infections with 37 deaths in China since 18 February 2013. Control measures in H7N9 virus–positive live poultry markets have reduced the number of infections; however, the character of the virus, including its pandemic potential, remains largely unknown. We systematically analyzed H7N9 viruses isolated from birds and humans. The viruses were genetically closely related and bound to human airway receptors; some also maintained the ability to bind to avian airway receptors. The viruses isolated from birds were nonpathogenic in chickens, ducks, and mice; however, the viruses isolated from humans caused up to 30% body weight loss in mice. Most importantly, one virus isolated from humans was highly transmissible in ferrets by respiratory droplet. Our findings indicate nothing to reduce the concern that these viruses can transmit between humans.
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1
Tong S., Li Y., Rivailler P., Conrardy C., Castillo D. A., Chen L. M., Recuenco S., Ellison J. A., Davis C. T., York I. A., Turmelle A. S., Moran D., Rogers S., Shi M., Tao Y., Weil M. R., Tang K., Rowe L. A., Sammons S., Xu X., Frace M., Lindblade K. A., Cox N. J., Anderson L. J., Rupprecht C. E., Donis R. O., A distinct lineage of influenza A virus from bats. Proc. Natl. Acad. Sci. U.S.A. 109, 4269–4274 (2012).
2
World Health Organisation, Number of confirmed human cases of avian influenza A(H7N9) reported to WHO, www.who.int/influenza/human_animal_interface/influenza_h7n9/08_ReportWebH7N9Number.pdf (May 2013).
3
See supplementary materials on Science Online.
4
Shi J., Deng G. H., Liu P. H., Zhou J. P., Guan L. Z., Li W. H., Li X. Y., Guo J., Wang G. J., Fan J., Wang J. L., Li Y. Y., Jiang Y. P., Liu L. L., Tian G. B., Li C. J., Chen H. L., Isolation and characterization of H7N9 viruses from live poultry markets—Implication of the source of current H7N9 infection in humans. Chin. Sci. Bull. 58, 1857–1863 (2013).
5
Gao R., Cao B., Hu Y., Feng Z., Wang D., Hu W., Chen J., Jie Z., Qiu H., Xu K., Xu X., Lu H., Zhu W., Gao Z., Xiang N., Shen Y., He Z., Gu Y., Zhang Z., Yang Y., Zhao X., Zhou L., Li X., Zou S., Zhang Y., Li X., Yang L., Guo J., Dong J., Li Q., Dong L., Zhu Y., Bai T., Wang S., Hao P., Yang W., Zhang Y., Han J., Yu H., Li D., Gao G. F., Wu G., Wang Y., Yuan Z., Shu Y., Human infection with a novel avian-origin influenza A (H7N9) virus. N. Engl. J. Med. 368, 1888–1897 (2013).
6
Chen Y., Liang W., Yang S., Wu N., Gao H., Sheng J., Yao H., Wo J., Fang Q., Cui D., Li Y., Yao X., Zhang Y., Wu H., Zheng S., Diao H., Xia S., Zhang Y., Chan K. H., Tsoi H. W., Teng J. L., Song W., Wang P., Lau S. Y., Zheng M., Chan J. F., To K. K., Chen H., Li L., Yuen K. Y., Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: Clinical analysis and characterisation of viral genome. Lancet 381, 1916–1925 (2013).
7
Single-letter abbreviations for the amino acid residues are as follows: A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr.
8
Subbarao E. K., London W., Murphy B. R., A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J. Virol. 67, 1761–1764 (1993).
9
Li Z., Chen H., Jiao P., Deng G., Tian G., Li Y., Hoffmann E., Webster R. G., Matsuoka Y., Yu K., Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J. Virol. 79, 12058–12064 (2005).
10
Gao Y., Zhang Y., Shinya K., Deng G., Jiang Y., Li Z., Guan Y., Tian G., Li Y., Shi J., Liu L., Zeng X., Bu Z., Xia X., Kawaoka Y., Chen H., Identification of amino acids in HA and PB2 critical for the transmission of H5N1 avian influenza viruses in a mammalian host. PLoS Pathog. 5, e1000709 (2009).
11
Hatta M., Gao P., Halfmann P., Kawaoka Y., Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293, 1840–1842 (2001).
12
Glaser L., Stevens J., Zamarin D., Wilson I. A., García-Sastre A., Tumpey T. M., Basler C. F., Taubenberger J. K., Palese P., A single amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding specificity. J. Virol. 79, 11533–11536 (2005).
13
Matrosovich M., Tuzikov A., Bovin N., Gambaryan A., Klimov A., Castrucci M. R., Donatelli I., Kawaoka Y., Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. J. Virol. 74, 8502–8512 (2000).
14
Imai M., Watanabe T., Hatta M., Das S. C., Ozawa M., Shinya K., Zhong G., Hanson A., Katsura H., Watanabe S., Li C., Kawakami E., Yamada S., Kiso M., Suzuki Y., Maher E. A., Neumann G., Kawaoka Y., Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486, 420–428 (2012).
15
Herfst S., Schrauwen E. J., Linster M., Chutinimitkul S., de Wit E., Munster V. J., Sorrell E. M., Bestebroer T. M., Burke D. F., Smith D. J., Rimmelzwaan G. F., Osterhaus A. D., Fouchier R. A., Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336, 1534–1541 (2012).
16
Vines A., Wells K., Matrosovich M., Castrucci M. R., Ito T., Kawaoka Y., The role of influenza A virus hemagglutinin residues 226 and 228 in receptor specificity and host range restriction. J. Virol. 72, 7626–7631 (1998).
17
Rogers G. N., Paulson J. C., Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology 127, 361–373 (1983).
18
Zhang Y., Zhang Q., Kong H., Jiang Y., Gao Y., Deng G., Shi J., Tian G., Liu L., Liu J., Guan Y., Bu Z., Chen H., H5N1 hybrid viruses bearing 2009/H1N1 virus genes transmit in guinea pigs by respiratory droplet. Science 340, 1459–1463 (2013).
19
Kageyama T., Fujisaki S., Takashita E., Xu H., Yamada S., Uchida Y., Neumann G., Saito T., Kawaoka Y., Tashiro M., Genetic analysis of novel avian A(H7N9) influenza viruses isolated from patients in China, February to April 2013. Euro Surveill. 18, 20453 (2013).
20
Manual of Diagnostic Tests and Vaccines for Terrestrial Animals (Office International des Epizooties, Paris, 2011).
21
Li Q., Zhou L., Zhou M., Chen Z., Li F., Wu H., Xiang N., Chen E., Tang F., Wang D., Meng L., Hong Z., Tu W., Cao Y., Li L., Ding F., Liu B., Wang M., Xie R., Gao R., Li X., Bai T., Zou S., He J., Hu J., Xu Y., Chai C., Wang S., Gao Y., Jin L., Zhang Y., Luo H., Yu H., Gao L., Pang X., Liu G., Shu Y., Yang W., Uyeki T. M., Wang Y., Wu F., Feng Z., Preliminary report: Epidemiology of the avian influenza A (H7N9) outbreak in China. N. Engl. J. Med. 130424140638006 (2013).
22
Lu X., Tumpey T. M., Morken T., Zaki S. R., Cox N. J., Katz J. M., A mouse model for the evaluation of pathogenesis and immunity to influenza A (H5N1) viruses isolated from humans. J. Virol. 73, 5903–5911 (1999).
23
Li Y., Shi J., Zhong G., Deng G., Tian G., Ge J., Zeng X., Song J., Zhao D., Liu L., Jiang Y., Guan Y., Bu Z., Chen H., Continued evolution of H5N1 influenza viruses in wild birds, domestic poultry, and humans in China from 2004 to 2009. J. Virol. 84, 8389–8397 (2010).
24
Zhang Y., Zhang Q., Gao Y., He X., Kong H., Jiang Y., Guan Y., Xia X., Shu Y., Kawaoka Y., Bu Z., Chen H., Key molecular factors in hemagglutinin and PB2 contribute to efficient transmission of the 2009 H1N1 pandemic influenza virus. J. Virol. 86, 9666–9674 (2012).
25
Lowen A. C., Mubareka S., Tumpey T. M., García-Sastre A., Palese P., The guinea pig as a transmission model for human influenza viruses. Proc. Natl. Acad. Sci. U.S.A. 103, 9988–9992 (2006).
26
Seibert C. W., Kaminski M., Philipp J., Rubbenstroth D., Albrecht R. A., Schwalm F., Stertz S., Medina R. A., Kochs G., García-Sastre A., Staeheli P., Palese P., Oseltamivir-resistant variants of the 2009 pandemic H1N1 influenza A virus are not attenuated in the guinea pig and ferret transmission models. J. Virol. 84, 11219–11226 (2010).
27
Tumpey T. M., Maines T. R., Van Hoeven N., Glaser L., Solórzano A., Pappas C., Cox N. J., Swayne D. E., Palese P., Katz J. M., García-Sastre A., A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science 315, 655–659 (2007).
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Volume 341 | Issue 6144
26 July 2013
26 July 2013
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Copyright © 2013, American Association for the Advancement of Science.
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Received: 15 May 2013
Accepted: 2 July 2013
Published in print: 26 July 2013
Acknowledgments
We thank S. Watson for editing the manuscript, Y. Shu from the China Centers for Disease Control and Prevention for providing the H7N9 viruses isolated from humans, and the Consortium for Functional Glycomics (Scripps Research Institute, Department of Molecular Biology, La Jolla, CA) for providing the glycans. This work was supported by the Ministry of Agriculture (CARS-42-G08) and by the Ministry of Science and Technology (KJYJ-2013-01-01 and 2012ZX10004214). Virus sequence data from this study were deposited in GenBank with the accession numbers CY146905 to CY147200 and in Global Initiative on Sharing Avian Influenza Data with the accession numbers EPI440678 to 440701 and EIP457614 to 457885.
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