The matrix gene segment destabilizes the acid and thermal stability of the hemagglutinin of pandemic live attenuated influenza virus vaccines

Journal of Virology

Volumn 88, Issue 21, 2014, Pages 12374-12384

  O'Donnell, Christopher D ^a,c   Vogel, Leatrice ^a   Matsuoka, Yumiko ^a   Jin, Hong ^b   Subbarao, Kanta ^a  

^a NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

^b MEDIMMUNE   (United States)

^c BAI Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACID; HEMAGGLUTININ; INFLUENZA VACCINE; SIALIDASE; LIVE VACCINE; M1 PROTEIN, INFLUENZA A VIRUS; MATRIX PROTEIN;

2009 H1N1 INFLUENZA; ADULT; ARTICLE; CONTROLLED STUDY; EMBRYO; GENE ACTIVATION; GENETIC REASSORTMENT; HA GENE; HUMAN; HUMAN CELL; INFLUENZA A (H2N2); INFLUENZA A (H5N1); INFLUENZA VIRUS A H1N1; INFLUENZA VIRUS A H2N2; INFLUENZA VIRUS A H5N1; NA GENE; NONHUMAN; PH; TEMPERATURE SENSITIVITY; THERMOSTABILITY; VIRUS GENE; VIRUS REPLICATION; VIRUS STRAIN; VIRUS TRANSMISSION; VIRUS VIRULENCE; CHEMISTRY; DRUG EFFECTS; DRUG STABILITY; GENETICS; INFLUENZA A VIRUS (H1N1); PHYSIOLOGY; PROTEIN STABILITY; RADIATION RESPONSE; TEMPERATURE;

DRUG STABILITY; HEMAGGLUTININS; HUMANS; HYDROGEN-ION CONCENTRATION; INFLUENZA A VIRUS, H1N1 SUBTYPE; INFLUENZA VACCINES; PROTEIN STABILITY; REASSORTANT VIRUSES; TEMPERATURE; VACCINES, ATTENUATED; VIRAL MATRIX PROTEINS; VIRUS REPLICATION;

EID: 84907977986     PISSN: 0022538X     EISSN: 10985514     Source Type: Journal    
DOI: 10.1128/JVI.01107-14     Document Type: Article

References (79)

1. Luke CJ, Subbarao K. 2006. Vaccines for pandemic influenza. Emerg. Infect. Dis. 12:66-72. http://dx.doi.org/10.3201/eid1201.051147.
2. Kobasa D, Kawaoka Y. 2005. Emerging influenza viruses: past and present. Curr. Mol. Med. 5:791-803. http://dx.doi.org/10.2174/15665 2405774962281.
3. Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M, Yang H, Chen X, Recuenco S, Gomez J, Chen LM, Johnson A, Tao Y, Dreyfus C, Yu W, McBride R, Carney PJ, Gilbert AT, Chang J, Guo Z, Davis CT, Paulson JC, Stevens J, Rupprecht CE, Holmes EC, Wilson IA, Donis RO. 2013. New world bats harbor diverse influenza A viruses. PLoS Pathog. 9:e1003657. http://dx.doi.org/10.1371/journal.ppat.1003657.
4. Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. 1992. Evolution and ecology of influenza A viruses. Microbiol. Rev. 56:152-179.
5. Peiris M, Yuen KY, Leung CW, Chan KH, Ip PL, Lai RW, Orr WK, Shortridge KF. 1999. Human infection with influenza H9N2. Lancet 354: 916-917.
6. Eames KT, Webb C, Thomas K, Smith J, Salmon R, Temple JM. 2010. Assessing the role of contact tracing in a suspected H7N2 influenza A outbreak in humans in Wales. BMC Infect. Dis. 10:141. http://dx.doi.org /10.1186/1471-2334-10-141.
7. Tweed SA, Skowronski DM, David ST, Larder A, Petric M, Lees W, Li Y, Katz J, Krajden M, Tellier R, Halpert C, Hirst M, Astell C, Lawrence D, Mak A. 2004. Human illness from avian influenza H7N3, British Columbia. Emerg. Infect. Dis. 10:2196-2199. http://dx.doi.org/10.3201 /eid1012.040961.
8. Fouchier RA, Schneeberger PM, Rozendaal FW, Broekman JM, Kemink SA, Munster V, Kuiken T, Rimmelzwaan GF, Schutten M, Van Doornum GJ, Koch G, Bosman A, Koopmans M, Osterhaus AD. 2004. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc. Natl. Acad. Sci. U. S. A. 101:1356-1361. http://dx.doi.org/10.1073/pnas.0308352100.
9. Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, Perdue M, Swayne D, Bender C, Huang J, Hemphill M, Rowe T, Shaw M, Xu X, Fukuda K, Cox N. 1998. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279:393-396 http://dx.doi.org/10.1126/science.279.5349.393.
10. Centers for Disease Control and Prevention. 2003. Update: influenza activity-United States and worldwide, 2002-03 season, and composition of the 2003-04 influenza vaccine. MMWR Morb. Mortal. Wkly. Rep. 52: 516-521.
11. 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 GF, Wu G, Wang Y, Yuan Z, Shu Y. 2013. Human infection with a novel avian-origin influenzaA(H7N9) virus. N. Engl. J. Med. 368:1888-1897. http://dx.doi.org/10.1056/NEJMoa1304459.
12. Maassab HF, Bryant ML. 1999. The development of live attenuated cold-adapted influenza virus vaccine for humans. Rev. Med. Virol. 9:237-244 http://dx.doi.org/10.1002/(SICI)1099-1654(199910/12)9:4<237::AI D-RMV252>3.0.CO;2-G.
13. Ambrose CS, Luke C, Coelingh K. 2008. Current status of live attenuated influenza vaccine in the United States for seasonal and pandemic influenza. Influenza Other Respir. Viruses 2:193-202. http://dx.doi.org/10.1111/j.1750-2659.2008.00056.x.
14. Centers for Disease Control and Prevention. 2011. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). 2011. MMWR Morb. Mortal. Wkly. Rep. 60:1128-1132.
15. Murphy BR, Coelingh K. 2002. Principles underlying the development and use of live attenuated cold-adapted influenza A and B virus vaccines. Viral Immunol. 15:295-323. http://dx.doi.org/10.1089/08828240260066242.
16. Luke C, Lakdawala SS, Subbarao K. 2012. Influenza vaccine-live. In Plotkin SA, Orenstein WA, Offit PA (ed), Vaccines: expert consult-online and print, 6th ed. Elsevier/Saunders, Philadelphia, PA.
17. Buonagurio DA, Bechert TM, Yang CF, Shutyak L, D' Arco GA, Kazachkov Y, Wang HP, Rojas EA, O' Neill RE, Spaete RR, Coelingh KL, Zamb TJ, Sidhu MS, Udem SA. 2006. Genetic stability of live, coldadapted influenza virus components of the FluMist/CAIV-T vaccine throughout the manufacturing process. Vaccine 24:2151-2160.
18. Talaat KR, Karron RA, Liang PH, McMahon BA, Luke CJ, Thumar B, Chen GL, Min JY, Lamirande EW, Jin H, Coelingh KL, Kemble GW, Subbarao K. 2013. An open-label phase I trial of a live attenuated H2N2 influenza virus vaccine in healthy adults. Influenza Other Respir. Viruses 7:66-73. http://dx.doi.org/10.1111/j.1750-2659.2012.00350.x.
19. Talaat KR, Karron RA, Luke CJ, Thumar B, McMahon BA, Chen GL, Lamirande EW, Jin H, Coelingh KL, Kemble G, Subbarao K. 2011. An open label phase I trial of a live attenuated H6N1 influenza virus vaccine in healthy adults. Vaccine 29:3144-3148.
20. Karron RA, Talaat K, Luke C, Callahan K, Thumar B, Dilorenzo S, McAuliffe J, Schappell E, Suguitan A, Mills K, Chen G, Lamirande E, Coelingh K, Jin H, Murphy BR, Kemble G, Subbarao K. 2009. Evaluation of two live attenuated cold-adapted H5N1 influenza virus vaccines in healthy adults. Vaccine 27:4953-4960.
21. Talaat KR, Karron RA, Callahan KA, Luke CJ, DiLorenzo SC, Chen GL, Lamirande EW, Jin H, Coelingh KL, Murphy BR, Kemble G, Subbarao K. 2009 A live attenuated H7N3 influenza virus vaccine is well tolerated and immunogenic in a phase I trial in healthy adults. Vaccine 27:3744-3753.
22. Karron RA, Callahan K, Luke C, Thumar B, McAuliffe J, Schappell E, Joseph T, Coelingh K, Jin H, Kemble G, Murphy BR, Subbarao K. 2009. A live attenuated H9N2 influenza vaccine is well tolerated and immunogenic in healthy adults. J. Infect. Dis. 199:711-716. http://dx.doi.org/10.1086/596558.
23. Chen Z, Santos C, Aspelund A, Gillim-Ross L, Jin H, Kemble G, Subbarao K. 2009. Evaluation of live attenuated influenza a virus h6 vaccines in mice and ferrets. J. Virol. 83:65-72. http://dx.doi.org/10.1128 /JVI.01775-08.
24. Suguitan AL, Jr, McAuliffe J, Mills KL, Jin H, Duke G, Lu B, Luke CJ, Murphy B, Swayne DE, Kemble G, Subbarao K. 2006. Live, attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets. PLoS Med. 3:e360. http://dx.doi.org/10.1371/journal.pmed.0030360.
25. Chen H, Matsuoka Y, Swayne D, Chen Q, Cox NJ, Murphy BR, Subbarao K. 2003. Generation and characterization of a cold-adapted influenza A H9N2 reassortant as a live pandemic influenza virus vaccine candidate. Vaccine 21:4430-4436.
26. Joseph T, McAuliffe J, Lu B, Vogel L, Swayne D, Jin H, Kemble G, Subbarao K. 2008. A live attenuated cold-adapted influenza A H7N3 virus vaccine provides protection against homologous and heterologous H7 viruses in mice and ferrets. Virology 378:123-132. http://dx.doi.org/10.1016/j.virol.2008.05.021.
27. Chen GL, Lamirande EW, Yang CF, Jin H, Kemble G, Subbarao K. 2010 Evaluation of replication and cross-reactive antibody responses of H2 subtype influenza viruses in mice and ferrets. J. Virol. 84:7695-7702. http://dx.doi.org/10.1128/JVI.00511-10.
28. Min JY, Vogel L, Matsuoka Y, Lu B, Swayne D, Jin H, Kemble G, Subbarao K. 2010. A live attenuated H7N7 candidate vaccine virus induces neutralizing antibody that confers protection from challenge in mice, ferrets, and monkeys. J. Virol. 84:11950-11960. http://dx.doi.org /10.1128/JVI.01305-10.
29. Chen Z, Wang W, Zhou H, Suguitan AL, Jr, Shambaugh C, Kim L, Zhao J, Kemble G, Jin H. 2010. Generation of live attenuated novel influenza virus A/California/7/09 (H1N1) vaccines with high yield in em-bryonated chicken eggs. J. Virol. 84:44-51. http://dx.doi.org/10.1128/JVI.02106-09.
30. Galloway SE, Reed ML, Russell CJ, Steinhauer DA. 2013. Influenza HA subtypes demonstrate divergent phenotypes for cleavage activation and pH of fusion: implications for host range and adaptation. PLoS Pathog. 9:e1003151. http://dx.doi.org/10.1371/journal.ppat.1003151.
31. Zaraket H, Bridges OA, Russell CJ. 2013. The pH of activation of the hemagglutinin protein regulates H5N1 influenza virus replication and pathogenesis in mice. J. Virol. 87:4826-4834. http://dx.doi.org/10.1128 /JVI.03110-12.
32. Zaraket H, Bridges OA, Duan S, Baranovich T, Yoon SW, Reed ML, Salomon R, Webby RJ, Webster RG, Russell CJ. 2013. Increased acid stability of the hemagglutinin protein enhances H5N1 influenza virus growth in the upper respiratory tract but is insufficient for transmission in ferrets. J. Virol. 87:9911-9922. http://dx.doi.org/10.1128/JVI.01175-13.
33. Ilyushina NA, Govorkova EA, Russell CJ, Hoffmann E, Webster RG. 2007 Contribution of H7 haemagglutinin to amantadine resistance and infectivity of influenza virus. J. Gen. Virol. 88:1266-1274. http://dx.doi.org/10.1099/vir.0.82256-0.
34. Keleta L, Ibricevic A, Bovin NV, Brody SL, Brown EG. 2008. Experimental evolution of human influenza virus H3 hemagglutinin in the mouse lung identifies adaptive regions in HA1 and HA2. J. Virol. 82: 11599-11608. http://dx.doi.org/10.1128/JVI.01393-08.
35. Reed ML, Yen HL, DuBois RM, Bridges OA, Salomon R, Webster RG, Russell CJ. 2009. Amino acid residues in the fusion peptide pocket regulate the pH of activation of the H5N1 influenza virus hemagglutinin protein. J. Virol. 83:3568-3580. http://dx.doi.org/10.1128/JVI.02238-08.
36. Reed ML, Bridges OA, Seiler P, Kim JK, Yen HL, Salomon R, Govorkova EA, Webster RG, Russell CJ. 2010. The pH of activation of the hemagglutinin protein regulates H5N1 influenza virus pathogenicity and transmissibility in ducks. J. Virol. 84:1527-1535. http://dx.doi.org/10.1128/JVI.02069-09.
37. DuBois RM, Zaraket H, Reddivari M, Heath RJ, White SW, Russell CJ. 2011 Acid stability of the hemagglutinin protein regulates H5N1 influenza virus pathogenicity. PLoS Pathog. 7:e1002398. http://dx.doi.org/10.1371/journal.ppat.1002398.
38. Koerner I, Matrosovich MN, Haller O, Staeheli P, Kochs G. 2012. Altered receptor specificity and fusion activity of the haemagglutinin contribute to high virulence of a mouse-adapted influenza A virus. J. Gen. Virol. 93:970-979. http://dx.doi.org/10.1099/vir.0.035782-0.
39. Cotter CR, Jin H, Chen Z. 2014. A single amino acid in the stalk region of the H1N1pdm influenza virusHAprotein affects viral fusion, stability and infectivity. PLoS Pathog. 10:e1003831. http://dx.doi.org/10.1371/journal.ppat.1003831.
40. Krenn BM, Egorov A, Romanovskaya-Romanko E, Wolschek M, Nakowitsch S, Ruthsatz T, Kiefmann B, Morokutti A, Humer J, Geiler J, Cinatl J, Michaelis M, Wressnigg N, Sturlan S, Ferko B, Batishchev OV, Indenbom AV, Zhu R, Kastner M, Hinterdorfer P, Kiselev O, Muster T, Romanova J. 2011. Single HA2 mutation increases the infectivity and immunogenicity of a live attenuated H5N1 intranasal influenza vaccine candidate lacking NS1. PLoS One 6:e18577. http://dx.doi.org/10.1371 /journal.pone.0018577.
41. Reed LJ, Muench H. 1938. A simple method of estimating fifty percent endpoints. Am. J. Hyg. (Lond.) 1938:493-497.
42. Hoffmann E, Krauss S, Perez D, Webby R, Webster RG. 2002. Eightplasmid system for rapid generation of influenza virus vaccines. Vaccine 20:3165-3170.
43. Daniels RS, Downie JC, Hay AJ, Knossow M, Skehel JJ, Wang ML, Wiley DC. 1985. Fusion mutants of the influenza virus hemagglutinin glycoprotein. Cell 40:431-439. http://dx.doi.org/10.1016/0092-8674(85)90157-6.
44. Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K, Zhong G, Hanson A, Katsura H, Watanabe S, Li C, Kawakami E, Yamada S, Kiso M, Suzuki Y, Maher EA, Neumann G, Kawaoka Y. 2012. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486:420-428. http://dx.doi.org/10.1038/nature10831.
45. Cross KJ, Burleigh LM, Steinhauer DA. 2001. Mechanisms of cell entry by influenza virus. Expert Rev. Mol. Med. 3:1-18. http://dx.doi.org/10.1017/S1462399401002575.
46. Yoshimura A, Kuroda K, Kawasaki K, Yamashina S, Maeda T, Ohnishi S. 1982. Infectious cell entry mechanism of influenza virus. J. Virol. 43: 284-293.
47. Scholtissek C. 1985. Stability of infectious influenza A viruses at low pH and at elevated temperature. Vaccine 3:215-218.
48. Carr CM, Chaudhry C, Kim PS. 1997. Influenza hemagglutinin is springloaded by a metastable native conformation. Proc. Natl. Acad. Sci. U. S. A. 94:14306-14313. http://dx.doi.org/10.1073/pnas.94.26.14306.
49. Haywood AM, Boyer BP. 1986. Time and temperature dependence of influenza virus membrane fusion at neutral pH. J. Gen. Virol. 67:2813-2817 http://dx.doi.org/10.1099/0022-1317-67-12-2813.
50. Suguitan AL, Jr, Marino MP, Desai PD, Chen LM, Matsuoka Y, Donis RO, Jin H, Swayne DE, Kemble G, Subbarao K. 2009. The influence of the multi-basic cleavage site of the H5 hemagglutinin on the attenuation, immunogenicity and efficacy of a live attenuated influenza A H5N1 cold-adapted vaccine virus. Virology 395:280-288. http://dx.doi.org/10.1016/j.virol.2009.09.017.
51. Jin H, Lu B, Zhou H, Ma C, Zhao J, Yang CF, Kemble G, Greenberg H. 2003 Multiple amino acid residues confer temperature sensitivity to human influenza virus vaccine strains (FluMist) derived from cold-adapted A/Ann Arbor/6/60. Virology 306:18-24. http://dx.doi.org/10.1016/S0042-6822(02)00035-1.
52. Jin H, Zhou H, Lu B, Kemble G. 2004. Imparting temperature sensitivity and attenuation in ferrets to A/Puerto Rico/8/34 influenza virus by transferring the genetic signature for temperature sensitivity from coldadapted A/Ann Arbor/6/60. J. Virol. 78:995-998. http://dx.doi.org/10.1128/JVI.78.2.995-998.2004.
53. Maassab HF. 1968. Plaque formation of influenza virus at 25°C. Nature 219:645-646. http://dx.doi.org/10.1038/219645a0.
54. Gruber WC. 2002. The role of live influenza vaccines in children. Vaccine 20:S66-S73. http://dx.doi.org/10.1016/S0264-410X(02)00141-X.
55. Skehel JJ, Wiley DC. 2000. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu. Rev. Biochem. 69:531-569 http://dx.doi.org/10.1146/annurev.biochem.69.1.531.
56. Giannecchini S, Campitelli L, Calzoletti L, De Marco MA, Azzi A, Donatelli I. 2006. Comparison of in vitro replication features of H7N3 influenza viruses from wild ducks and turkeys: potential implications for interspecies transmission. J. Gen. Virol. 87:171-175. http://dx.doi.org/10.1099/vir.0.81187-0.
57. Lin YP, Wharton SA, Martin J, Skehel JJ, Wiley DC, Steinhauer DA. 1997 Adaptation of egg-grown and transfectant influenza viruses for growth in mammalian cells: selection of hemagglutinin mutants with elevated pH of membrane fusion. Virology 233:402-410. http://dx.doi.org /10.1006/viro.1997.8626.
58. Doms RW, Gething MJ, Henneberry J, White J, Helenius A. 1986. Variant influenza virus hemagglutinin that induces fusion at elevated pH. J. Virol. 57:603-613.
59. Steinhauer DA, Martin J, Lin YP, Wharton SA, Oldstone MB, Skehel JJ, Wiley DC. 1996. Studies using double mutants of the conformational transitions in influenza hemagglutinin required for its membrane fusion activity. Proc. Natl. Acad. Sci. U. S. A. 93:12873-12878. http://dx.doi.org /10.1073/pnas.93.23.12873.
60. Steinhauer DA, Wharton SA, Skehel JJ, Wiley DC. 1995. Studies of the membrane fusion activities of fusion peptide mutants of influenza virus hemagglutinin. J. Virol. 69:6643-6651.
61. Steinhauer DA, Wharton SA, Skehel JJ, Wiley DC, Hay AJ. 1991. Amantadine selection of a mutant influenza virus containing an acidstable hemagglutinin glycoprotein: evidence for virus-specific regulation of the pH of glycoprotein transport vesicles. Proc. Natl. Acad. Sci. U. S. A. 88:11525-11529. http://dx.doi.org/10.1073/pnas.88.24.11525.
62. Ciampor F, Bayley PM, Nermut MV, Hirst EM, Sugrue RJ, Hay AJ. 1992 Evidence that the amantadine-induced, M2-mediated conversion of influenza A virus hemagglutinin to the low pH conformation occurs in an acidic trans-Golgi compartment. Virology 188:14-24. http://dx.doi.org /10.1016/0042-6822(92)90730-D.
63. Grambas S, Bennett MS, Hay AJ. 1992. Influence of amantadine resistance mutations on the pH regulatory function of the M2 protein of influenza A viruses. Virology 191:541-549. http://dx.doi.org/10.1016/0042-6822(92)90229-I.
64. Barman S, Ali A, Hui EK, Adhikary L, Nayak DP. 2001. Transport of viral proteins to the apical membranes and interaction of matrix protein with glycoproteins in the assembly of influenza viruses. Virus Res. 77:61-69 http://dx.doi.org/10.1016/S0168-1702(01)00266-0.
65. Scholtissek C, Stech J, Krauss S, Webster RG. 2002. Cooperation between the hemagglutinin of avian viruses and the matrix protein of human influenza A viruses. J. Virol. 76:1781-1786. http://dx.doi.org/10.1128/JVI.76.4.1781-1786.2002.
66. Enami M, Enami K. 1996. Influenza virus hemagglutinin and neuraminidase glycoproteins stimulate the membrane association of the matrix protein. J. Virol. 70:6653-6657.
67. Radyukhin V, Fedorova N, Ksenofontov A, Serebryakova M, Baratova L. 2008. Cold co-extraction of hemagglutinin and matrixM1protein from influenza virus A by a combination of non-ionic detergents allows for visualization of the raft-like nature of the virus envelope. Arch. Virol. 153:1977-1980. http://dx.doi.org/10.1007/s00705-008-0214-7.
68. Betakova T, Ciampor F, Hay AJ. 2005. Influence of residue 44 on the activity of the M2 proton channel of influenza A virus. J. Gen. Virol. 86:181-184. http://dx.doi.org/10.1099/vir.0.80358-0.
69. Murakami S, Horimoto T, Ito M, Takano R, Katsura H, Shimojima M, Kawaoka Y. 2012. Enhanced growth of influenza vaccine seed viruses in Vero cells mediated by broadening the optimal pH range for virus membrane fusion. J. Virol. 86:1405-1410. http://dx.doi.org/10.1128/JVI.06009-11.
70. Cox NJ, Kitame F, Kendal AP, Maassab HF, Naeve C. 1988. Identification of sequence changes in the cold-adapted, live attenuated influenza vaccine strain, A/Ann Arbor/6/60 (H2N2). Virology 167:554-567.
71. Washington N, Steele RJ, Jackson SJ, Bush D, Mason J, Gill DA, Pitt K, Rawlins DA. 2000. Determination of baseline human nasal pH and the effect of intranasally administered buffers. Int. J. Pharm. 198:139-146.
72. Vareille M, Kieninger E, Edwards MR, Regamey N. 2011. The airway epithelium: soldier in the fight against respiratory viruses. Clin. Microbiol. Rev. 24:210-229. http://dx.doi.org/10.1128/CMR.00014-10.
73. Fischer H, Widdicombe JH. 2006. Mechanisms of acid and base secretion by the airway epithelium. J. Membr. Biol. 211:139-150. http://dx.doi.org /10.1007/s00232-006-0861-0.
74. Wine JJ, Joo NS. 2004. Submucosal glands and airway defense. Proc. Am. Thorac. Soc. 1:47-53. http://dx.doi.org/10.1513/pats.2306015.
75. Fischer H, Widdicombe JH, Illek B. 2002. Acid secretion and proton conductance in human airway epithelium. Am. J. Physiol. Cell Physiol. 282:C736-C743. http://dx.doi.org/10.1152/ajpcell.00369.2011.
76. Jacoby DB, Tamaoki J, Borson DB, Nadel JA. 1988. Influenza infection causes airway hyperresponsiveness by decreasing enkephalinase. J. Appl. Physiol. 64:2653-2658.
77. Brown JD, Swayne DE, Cooper RJ, Burns RE, Stallknecht DE. 2007. Persistence of H5 and H7 avian influenza viruses in water. Avian Dis. 51:285-289. http://dx.doi.org/10.1637/7636-042806R.1.
78. Yoshimura A, Ohnishi S. 1984. Uncoating of influenza virus in endosomes. J. Virol. 51:497-504.
79. Thoennes S, Li ZN, Lee BJ, Langley WA, Skehel JJ, Russell RJ, Steinhauer DA. 2008. Analysis of residues near the fusion peptide in the influenza hemagglutinin structure for roles in triggering membrane fusion. Virology 370:403-414. http://dx.doi.org/10.1016/j.virol.2007.08.035.