1887

Abstract

The nucleoprotein (NP) possesses regions that are highly conserved among influenza A viruses, and has therefore been one of the target viral proteins for development of a universal influenza vaccine. It has been expected that human or humanized antibodies will be made available for the prophylaxis, pre-emptive and acute treatment of viral infection. However, it is still unclear whether anti-NP human antibody can confer protection against influenza virus infection. In this study, we generated transgenic mice expressing anti-NP human mAbs derived from lymphocytes of a patient infected with H5N1 highly pathogenic avian influenza (HPAI) virus, and experimental infections were conducted to examine antiviral effects of the anti-NP antibodies against H5N1 HPAI viral infections with a high fatality rate in mammals. Transgenic mouse lines expressing the anti-NP human mAbs at more than 1 mg ml showed marked resistance to H5N1 virus infections. In addition, resistance to infection with an H1N1 subtype that shows strong pathogenicity to mice was also confirmed. Although the anti-NP mAbs expressed in the transgenic mice did not neutralize the virus, the mAbs could bind to NP located on the surface of infected cells. These results suggested a possibility that the non-neutralizing anti-NP human mAbs could induce indirect antiviral effects, such as antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. Taken together, these results demonstrated that anti-NP human mAbs play an important role in heterosubtypic protection against lethal influenza virus infections .

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000518
2016-09-01
2019-09-22
Loading full text...

Full text loading...

/deliver/fulltext/jgv/97/9/2104.html?itemId=/content/journal/jgv/10.1099/jgv.0.000518&mimeType=html&fmt=ahah

References

  1. Armour K. L., Clark M. R., Hadley A. G., Williamson L. M..( 1999;). Recombinant human IgG molecules lacking Fcgamma receptor I binding and monocyte triggering activities. . Eur J Immunol 29: 2613–2624.[PubMed] [Crossref]
    [Google Scholar]
  2. Bullido R., Gómez-Puertas P., Albo C., Portela A..( 2000;). Several protein regions contribute to determine the nuclear and cytoplasmic localization of the influenza A virus nucleoprotein. . J Gen Virol 81: 135–142. [CrossRef] [PubMed]
    [Google Scholar]
  3. Burton D. R..( 2002;). Antibodies, viruses and vaccines. . Nat Rev Immunol 2: 706–713. [CrossRef] [PubMed]
    [Google Scholar]
  4. Carragher D. M., Kaminski D. A., Moquin A., Hartson L., Randall T. D..( 2008;). A novel role for non-neutralizing antibodies against nucleoprotein in facilitating resistance to influenza virus. . J Immunol 181: 4168–4176.[PubMed] [Crossref]
    [Google Scholar]
  5. Chen W., Antón L. C., Bennink J. R., Yewdell J. W..( 2000;). Dissecting the multifactorial causes of immunodominance in class I-restricted T cell responses to viruses. . Immunity 12: 83–93. [CrossRef] [PubMed]
    [Google Scholar]
  6. Chen Z., Wang J., Bao L., Guo L., Zhang W., Xue Y., Zhou H., Xiao Y., Wang J. et al.( 2015;). Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus. . Nat Commun 6: 10.1038/ncomms7714.
    [Google Scholar]
  7. Doyle T. M., Hashem A. M., Li C., Van Domselaar G., Larocque L., Wang J., Smith D., Cyr T., Farnsworth A. et al.( 2013;). Universal anti-neuraminidase antibody inhibiting all influenza A subtypes. . Antiviral Res 100: 567–574. [CrossRef] [PubMed]
    [Google Scholar]
  8. Epstein S. L., Kong W. P., Misplon J. A., Lo C. Y., Tumpey T. M., Xu L., Nabel G. J..( 2005;). Protection against multiple influenza A subtypes by vaccination with highly conserved nucleoprotein. . Vaccine 23: 5404–5410. [CrossRef] [PubMed]
    [Google Scholar]
  9. Fu T. M., Friedman A., Ulmer J. B., Liu M. A., Donnelly J. J..( 1997;). Protective cellular immunity: cytotoxic T-lymphocyte responses against dominant and recessive epitopes of influenza virus nucleoprotein induced by DNA immunization. . J Virol 71: 2715–2721.[PubMed]
    [Google Scholar]
  10. Fu T. M., Guan L., Friedman A., Schofield T. L., Ulmer J. B., Liu M. A., Donnelly J. J..( 1999;). Dose dependence of CTL precursor frequency induced by a DNA vaccine and correlation with protective immunity against influenza virus challenge. . J Immunol 162: 4163–4170.[PubMed]
    [Google Scholar]
  11. Fu T. M., Freed D. C., Horton M. S., Fan J., Citron M. P., Joyce J. G., Garsky V. M., Casimiro D. R., Zhao Q. et al.( 2009;). Characterizations of four monoclonal antibodies against M2 protein ectodomain of influenza A virus. . Virology 385: 218–226. [CrossRef] [PubMed]
    [Google Scholar]
  12. Fujimoto Y., Ozaki K., Maeda M., Nishijima K., Takakuwa H., Otsuki K., Kida H., Ono E..( 2013;). Resistance to influenza A virus infection in transformed cell lines expressing an anti-PB2 monoclonal antibody. . Vet J 198: 487–493. [CrossRef] [PubMed]
    [Google Scholar]
  13. Gerhard W., Mozdzanowska K., Zharikova D..( 2006;). Prospects for universal influenza virus vaccine. . Emerg Infect Dis 12: 569–574. [CrossRef] [PubMed]
    [Google Scholar]
  14. Grandea A. G., Olsen O. A., Cox T. C., Renshaw M., Hammond P. W., Chan-Hui P. Y., Mitcham J. L., Cieplak W., Stewart S. M., Stewart S. M. et al.( 2010;). Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses. . Proc Natl Acad Sci U S A 107: 12658–12663. [CrossRef] [PubMed]
    [Google Scholar]
  15. Greenberg S. B., Criswell B. S., Six H. R., Couch R. B..( 1977;). Lymphocyte cytotoxicity to influenza virus-infected cells. II. Requirement for antibody and non-T lymphocytes. . J Immunol 119: 2100–2106.[PubMed]
    [Google Scholar]
  16. Greenberg S. B., Criswell B. S., Six H. R., Couch R. B..( 1978;). Lymphocyte cytotoxicity to influenza virus-infected cells: response to vaccination and virus infection. . Infect Immun 20: 640–645.[PubMed]
    [Google Scholar]
  17. Hashimoto G., Wright P. F., Karzon D. T..( 1983a;). Antibody-dependent cell-mediated cytotoxicity against influenza virus-infected cells. . J Infect Dis 148: 785–794.[Crossref]
    [Google Scholar]
  18. Hashimoto G., Wright P. F., Karzon D. T..( 1983b;). Ability of human cord blood lymphocytes to mediate antibody-dependent cellular cytotoxicity against influenza virus-infected cells. . Infect Immun 42: 214–218.
    [Google Scholar]
  19. Heaton N. S., Leyva-Grado V. H., Tan G. S., Eggink D., Hai R., Palese P..( 2013;). In vivo bioluminescent imaging of influenza a virus infection and characterization of novel cross-protective monoclonal antibodies. . J Virol 87: 8272–8281. [CrossRef] [PubMed]
    [Google Scholar]
  20. Heiny A. T., Miotto O., Srinivasan K. N., Khan A. M., Zhang G. L., Brusic V., Tan T. W., August J. T..( 2007;). Evolutionarily conserved protein sequences of influenza a viruses, avian and human, as vaccine targets. . PLoS One 2: e1190. [CrossRef] [PubMed]
    [Google Scholar]
  21. Hoffmann E., Stech J., Guan Y., Webster R. G., Perez D. R..( 2001;). Universal primer set for the full-length amplification of all influenza A viruses. . Arch Virol 146: 2275–2289.[PubMed] [Crossref]
    [Google Scholar]
  22. Idusogie E. E., Wong P. Y., Presta L. G., Gazzano-Santoro H., Totpal K., Ultsch M., Mulkerrin M. G..( 2001;). Engineered antibodies with increased activity to recruit complement. . J Immunol 166: 2571–2575.[PubMed] [Crossref]
    [Google Scholar]
  23. Jegaskanda S., Amarasena T. H., Laurie K. L., Tan H. X., Butler J., Parsons M. S., Alcantara S., Petravic J., Davenport M. P. et al.( 2013a;). Standard trivalent influenza virus protein vaccination does not prime antibody-dependent cellular cytotoxicity in macaques. . J Virol 87: 13706–13718.[Crossref]
    [Google Scholar]
  24. Jegaskanda S., Job E. R., Kramski M., Laurie K., Isitman G., de Rose R., Winnall W. R., Stratov I., Brooks A. G. et al.( 2013b;). Cross-reactive influenza-specific antibody-dependent cellular cytotoxicity antibodies in the absence of neutralizing antibodies. . J Immunol 190: 1837–1848.[Crossref]
    [Google Scholar]
  25. Jegaskanda S., Reading P. C., Kent S. J..( 2014;). Influenza-specific antibody-dependent cellular cytotoxicity: toward a universal influenza vaccine. . J Immunol 193: 469–475. [CrossRef] [PubMed]
    [Google Scholar]
  26. Kashyap A. K., Steel J., Rubrum A., Estelles A., Briante R., Ilyushina N. A., Xu L., Swale R. E., Faynboym A. M. et al.( 2010;). Protection from the 2009 H1N1 pandemic influenza by an antibody from combinatorial survivor-based libraries. . PLoS Pathog 6: e1000990. [CrossRef] [PubMed]
    [Google Scholar]
  27. Kawai S., Takagi Y., Kaneko S., Kurosawa T..( 2011;). Effect of three types of mixed anesthetic agents alternate to ketamine in mice. . Exp Anim 60: 481–487.[PubMed] [Crossref]
    [Google Scholar]
  28. Kobasa D., Wells K., Kawaoka Y..( 2001;). Amino acids responsible for the absolute sialidase activity of the influenza A virus neuraminidase: relationship to growth in the duck intestine. . J Virol 75: 11773–11780. [CrossRef] [PubMed]
    [Google Scholar]
  29. LaMere M. W., Lam H. T., Moquin A., Haynes L., Lund F. E., Randall T. D., Kaminski D. A..( 2011;). Contributions of antinucleoprotein IgG to heterosubtypic immunity against influenza virus. . J Immunol 186: 4331–4339. [CrossRef] [PubMed]
    [Google Scholar]
  30. McElroy M. C., Pittet J. F., Hashimoto S., Allen L., Wiener-Kronish J. P., Dobbs L. G..( 1995;). A type I cell-specific protein is a biochemical marker of epithelial injury in a rat model of pneumonia. . Am J Physiol 268: L181–186.[PubMed] [Crossref]
    [Google Scholar]
  31. Niwa H., Yamamura K., Miyazaki J..( 1991;). Efficient selection for high-expression transfectants with a novel eukaryotic vector. . Gene 108: 193–199.[PubMed] [Crossref]
    [Google Scholar]
  32. O'Brien K. B., Morrison T. E., Dundore D. Y., Heise M. T., Schultz-Cherry S..( 2011;). A protective role for complement C3 protein during pandemic 2009 H1N1 and H5N1 influenza A virus infection. . PLoS One 6: e17377. [CrossRef] [PubMed]
    [Google Scholar]
  33. Ohta R., Torii Y., Imai M., Kimura H., Okada N., Ito Y..( 2011;). Serum concentrations of complement anaphylatoxins and proinflammatory mediators in patients with 2009 H1N1 influenza. . Microbiol Immunol 55: 191–198. [CrossRef] [PubMed]
    [Google Scholar]
  34. Ono E., Tomioka Y., Watanabe Y., Amagai K., Morimatsu M., Shinya K., Cherel P..( 2007;). Comparison of the antiviral potentials among the pseudorabies-resistant transgenes encoding different soluble forms of porcine nectin-1 in transgenic mice. . J Gen Virol 88: 2636–2641. [CrossRef] [PubMed]
    [Google Scholar]
  35. Overdijk M. B., Verploegen S., Ortiz Buijsse A., Vink T., Leusen J. H., Bleeker W. K., Parren P. W..( 2012;). Crosstalk between human IgG isotypes and murine effector cells. . J Immunol 189: 3430–3438. [CrossRef] [PubMed]
    [Google Scholar]
  36. Pan C., Cheung B., Tan S., Li C., Li L., Liu S., Jiang S..( 2010;). Genomic signature and mutation trend analysis of pandemic (H1N1) 2009 influenza A virus. . PLoS One 5: e9549. [CrossRef] [PubMed]
    [Google Scholar]
  37. Patterson S., Gross J., Oxford J. S..( 1988;). The intracellular distribution of influenza virus matrix protein and nucleoprotein in infected cells and their relationship to haemagglutinin in the plasma membrane. . J Gen Virol 69: 1859–1872. [CrossRef] [PubMed]
    [Google Scholar]
  38. Prokudina E. N., Semenova N. P..( 1991;). Localization of the influenza virus nucleoprotein: cell-associated and extracellular non-virion forms. . J Gen Virol 72: 1699–1702. [CrossRef] [PubMed]
    [Google Scholar]
  39. Quiñones-Parra S., Grant E., Loh L., Nguyen T. H., Campbell K. A., Tong S. Y., Miller A., Doherty P. C., Vijaykrishna D., Vijaykrishna D. et al.( 2014;). Preexisting CD8+ T-cell immunity to the H7N9 influenza A virus varies across ethnicities. . Proc Natl Acad Sci U S A 111: 1049–1054. [CrossRef] [PubMed]
    [Google Scholar]
  40. Rötzschke O., Falk K., Deres K., Schild H., Norda M., Metzger J., Jung G., Rammensee H. G..( 1990;). Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. . Nature 348: 252–254. [CrossRef] [PubMed]
    [Google Scholar]
  41. Shields R. L., Namenuk A. K., Hong K., Meng Y. G., Rae J., Briggs J., Xie D., Lai J., Stadlen A. et al.( 2001;). High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. . J Biol Chem 276: 6591–6604. [CrossRef] [PubMed]
    [Google Scholar]
  42. Shivakoti S., Ito H., Otsuki K., Ito T..( 2010;). Characterization of H5N1 highly pathogenic avian influenza virus isolated from a mountain hawk eagle in Japan. . J Vet Med Sci 72: 459–463.[PubMed] [Crossref]
    [Google Scholar]
  43. Shu L. L., Bean W. J., Webster R. G..( 1993;). Analysis of the evolution and variation of the human influenza A virus nucleoprotein gene from 1933 to 1990. . J Virol 67: 2723–2729.[PubMed]
    [Google Scholar]
  44. Simmons C. P., Bernasconi N. L., Suguitan A. L., Mills K., Ward J. M., Chau N. V., Hien T. T., Sallusto F., Ha do Q. et al.( 2007;). Prophylactic and therapeutic efficacy of human monoclonal antibodies against H5N1 influenza. . PLoS Med 4: e178. [CrossRef] [PubMed]
    [Google Scholar]
  45. Staneková Z., Varečková E..( 2010;). Conserved epitopes of influenza A virus inducing protective immunity and their prospects for universal vaccine development. . Virol J 7: 351. [CrossRef] [PubMed]
    [Google Scholar]
  46. Stitz L., Schmitz C., Binder D., Zinkernagel R., Paoletti E., Becht H..( 1990;). Characterization and immunological properties of influenza A virus nucleoprotein (NP): cell-associated NP isolated from infected cells or viral NP expressed by vaccinia recombinant virus do not confer protection. . J Gen Virol 71: 1169–1179. [CrossRef] [PubMed]
    [Google Scholar]
  47. Sukeno N., Otsuki Y., Konno J., Yamane N., Odagiri T., Arikawa J., Ishida N..( 1979;). Anti-nucleoprotein antibody response in influenza A infection. . Tohoku J Exp Med 128: 241–249.[PubMed] [Crossref]
    [Google Scholar]
  48. Takakuwa H., Yamashiro T., Le M. Q., Phuong L. S., Ozaki H., Tsunekuni R., Usui T., Ito H., Morimatsu M. et al.( 2012;). Molecular epidemiology of avian influenza viruses circulating among healthy poultry flocks in farms in northern Vietnam. . Prev Vet Med 103: 192–200. [CrossRef] [PubMed]
    [Google Scholar]
  49. Tan G. S., Krammer F., Eggink D., Kongchanagul A., Moran T. M., Palese P..( 2012;). A pan-H1 anti-hemagglutinin monoclonal antibody with potent broad-spectrum efficacy in vivo. . J Virol 86: 6179–6188. [CrossRef] [PubMed]
    [Google Scholar]
  50. Ulmer J. B., Donnelly J. J., Parker S. E., Rhodes G. H., Felgner P. L., Dwarki V. J., Gromkowski S. H., Deck R. R., DeWitt C. M. et al.( 1993;). Heterologous protection against influenza by injection of DNA encoding a viral protein. . Science 259: 1745–1749. [CrossRef] [PubMed]
    [Google Scholar]
  51. Virelizier J. L., Allison A. C., Oxford J. S., Schild G. C..( 1977;). Early presence of ribonucleoprotein antigen on surface of influenza virus-infected cells. . Nature 266: 52–54. [CrossRef] [PubMed]
    [Google Scholar]
  52. WHO( 2009;). Clinical features of severe cases of pandemic influenza. Geneva:World Health Organization. . Available on line at http://www.who.int/csr/disease/swineflu/notes/h1n1_clinical_features_20091016/en/.
  53. Yewdell J. W., Frank E., Gerhard W..( 1981;). Expression of influenza A virus internal antigens on the surface of infected P815 cells. . J Immunol 126: 1814–1819.[PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000518
Loading
/content/journal/jgv/10.1099/jgv.0.000518
Loading

Data & Media loading...

Supplementary File 1

PDF

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error