Lung memory T-cell response in mice following intranasal immunization with influenza vector expressing mycobacterial proteins

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Abstract

Improving specific prevention of tuberculosis continues to be a top priority in phthisiology. “Prime-boost” vaccination schemes aim to maintain adequate levels of specific immunity while forming long-term protection. They are based on sequential use of BCG vaccine and new vaccine candidates expressing protective mycobacterial proteins. The development of new tuberculosis prevention approaches requires an understanding of how the anti-tuberculosis immune response forms and which mechanisms provide TB protection. Since tuberculosis is an airborne infection, vaccine effectiveness largely depends on mucosal immunity based on the formation of long-lived, functionally-active memory T-lymphocytes in the respiratory tract. We have previously shown that the influenza vector expressing ESAT-6 and Ag85A mycobacterial proteins (Flu/ESAT-6_Ag85A) in vaccination scheme of intranasal boost immunization resulted in significant increase of BCG's protective effect according to key indicators aggregate data in experimental tuberculosis infection. The aim of this work was to study the effect of intranasal immunization with the Flu/ESAT-6_Ag85A influenza vector on the formation of antigen-specific central and effector memory T cells and the cytokine-producing activity of effector T cells (TEM) in BCG standard and “BCG prime — influenza vector boost” vaccination schemes in mice. Intranasal immunization with the influenza vector has been shown to increase the proportion of antigen-specific CD4+ central memory T cells (TCM) in the pool of activated lymphocytes of lung and spleen reaching significant differences from the BCG group in the percentage of spleen CD4+ TCM (p < 0.01). In contrast to BCG, vaccination with the studied vaccine candidate was accompanied by accumulation of highly differentiated CD8 effector cells in lung, the target organ during tuberculosis infection. Comparative evaluation of the cell-mediated, post-vaccine immune response after immunization with influenzavector-based vaccine candidate (intranasal/mucosal) or BCG vaccine (subcutaneous) showed advantages in the mucosal group: in formation of functionally active subpopulations of effector CD4 and CD8 T lymphocytes (CD44highCD62Llow) in lungs secreting IL-2 as well as polyfunctional cells capable of coproducing two cytokines (IFNγ/TNFα or IFNγ/IL-2) or three cytokines (IFNγ/TNFα/IL-2). Due to their more pronounced effector function, polyfunctional T-lymphocytes can be considered to be potential immunological markers of protective immunity in tuberculosis.

About the authors

A.-P. S. Shurygina

Smorodintsev Research Institute of Influenza Russian Ministry of Health

Email: ann-polin@yandex.ru
ORCID iD: 0000-0003-3685-7068

Schurygina Anna-Polina S., PhD (Medicine), Senior Researcher, Laboratory of Vectored Vaccine

St. Petersburg

Russian Federation

N. V. Zabolotnykh

Saint-Petersburg State Research Institute of Phthisiopulmonology Russian Ministry of Health

Email: zabol-natal@yandex.ru
ORCID iD: 0000-0002-2946-2415

Zabolotnykh Natalia V., PhD, MD (Medicine), Leading Researcher of the “Experimental Tuberculosis and Innovative Technologies” Direction

St. Petersburg

Russian Federation

T. I. Vinogradova

Saint-Petersburg State Research Institute of Phthisiopulmonology Russian Ministry of Health

Email: vinogradova@spbniif.ru
ORCID iD: 0000-0002-5234-349X

Vinogradova Tatiana I., PhD, MD (Medicine), Head Researcher of the “Experimental Tuberculosis and Innovative Technologies” Direction

St. Petersburg

Russian Federation

K. A. Vasilyev

Smorodintsev Research Institute of Influenza Russian Ministry of Health

Email: kirillv5@yandex.ru
ORCID iD: 0000-0002-7750-9652

Vasiliev Kirill А., Researcher, Laboratory of Vectored Vaccine

St. Petersburg

Russian Federation

Zh. V. Buzitskaya

Smorodintsev Research Institute of Influenza Russian Ministry of Health

Email: janna.buzitskaya@influenza.spb.ru
ORCID iD: 0000-0002-8394-102X

Buzitskaya Zhanna V., PhD (Medicine), Senior Researcher, Laboratory of Vectored Vaccine

St. Petersburg

Russian Federation

M. A. Stukova

Smorodintsev Research Institute of Influenza Russian Ministry of Health

Author for correspondence.
Email: marina.stukova@influenza.spb.ru
ORCID iD: 0000-0002-2127-3820

Stukova Marina A., PhD (Medicine), Head of the Laboratory of Vectored Vaccine

197376, St. Petersburg, Prof. Popova str., 15/17

Russian Federation

References

  1. Заболотных Н.В., Шурыгина А.-П.С., Виноградова Т.И., Витовская М.Л., Хайруллин Б.М., Сандыбаев Н.Т., Бузиц кая Ж.В., Стукова М.А. Усиление протективного эффекта вакцины БЦЖ при мукозальной буст-иммунизации гриппозным вектором, экспрессирующим микобактериальные белки ESAT-6 и Ag85A // Биофармацевтический журнал. 2016. Т. 8, № 6. С. 25–31.
  2. Bai C., He J., Niu H., Hu L., Luo Y., Liu X., Peng L., Zhu B. Prolonged intervals during Mycobacterium tuberculosis subunit vaccine boosting contributes to eliciting immunity mediated by central memory-like T cells. Tuberculosis, 2018, vol. 110, pp. 104–111. doi: 10.1016/j.tube.2018.04.006C
  3. Behar S.M. Antigen-specific CD8+ T cells and protective immunity to tuberculosis. Adv. Exp. Med. Biol., 2013, vol. 783, pp. 141– 163. doi: 10.1007/978-1-4614-6111-1_8
  4. Beverley P.C., Sridhar S., Lalvani A., Tchilian E.Z. Harnessing local and systemic immunity for vaccines against tuberculosis. Mucosal Immunol., 2014, vol. 7, no. 1, pp. 20–26. doi: 10.1038/mi.2013.99
  5. Cha S.B., Kim W.S., Kim J.S., Kim H.M., Kwon K.W., Han S.J., Cho S.N., Coler R.N., Reed S.G., Shin S.J. Pulmonary immunity and durable protection induced by the ID93/GLA-SE vaccine candidate against the hyper-virulent Korean Beijing Mycobacterium tuberculosis strain K. Vaccine, 2016, vol. 34, no. 19, pp. 2179–2187. doi: 10.1016/j.vaccine.2016.03.029
  6. Ding Y., Zheng H., Feng C., Wang B., Liu C., Mi K., Cao H., Meng S. Heat-shock protein gp96 enhances T cell responses and protective potential to bacillus Calmette–Guérin vaccine. Scand. J. Immunol. 2016, vol. 84, no. 4, pp. 222–228. doi: 10.1111/sji.12463
  7. Kaveh D.A., Garcia-Pelayo M.C., Hogarth P.J. Persistent BCG bacilli perpetuate CD4 T effector memory and optimal protection against tuberculosis. Vaccine, 2014, vol. 32, pp. 6911–6918. doi: 10.1016/j.vaccine.2014.10.041
  8. Kim W.S., Kim J.S., Kim H.M., Kwon K.W., Eum S.Y., Shin S.J. Comparison of immunogenicity and vaccine efficacy between heat-shock proteins, HSP70 and GrpE, in the DnaK operon of Mycobacterium tuberculosis. Sci. Rep., 2018, vol. 8, no. 1: 14411.
  9. Liang J., Teng X., Yuan X., Zhang Y., Shi C., Yue T., Zhou L., Li J., Fan X. Enhanced and durable protective immune responses induced by a cocktail of recombinant BCG strains expressing antigens of multistage of Mycobacterium tuberculosis. Mol. Immunol., 2015, vol. 66, no. 2, pp. 392–401. doi: 10.1016/j.molimm.2015.04.017
  10. Lindenstrom T., Knudsen N.P., Agger E.M., Andersen P. Control of chronic Mycobacterium tuberculosis infection by CD4 KLRG1-, IL-2-secreting central memory cells. J. Immunol., 2013, vol. 190, pp. 6311–6319. doi: 10.4049/jimmunol.1300248
  11. Ma J., Tian M., Fan X., Yu Q., Jing Y., Wang W., Li L., Zhou Z. Mycobacterium tuberculosis multistage antigens confer comprehensive protection against pre- and post-exposure infections by driving Th1-type T cell immunity. Oncotarget, 2016, vol. 7, no. 39, pp. 63804–63815. doi: 10.18632/oncotarget.11542
  12. Moliva J.I., Turner J., Torrelles J.B. Immune responses to bacillus Calmette–Guérin vaccination: why do they fail to protect against Mycobacterium tuberculosis? Front. Immunol., 2017, vol. 8: 407. doi: 10.3389/fimmu.2017.00407
  13. Nandakumar S., Kannanganat S., Dobos K.M., Lucas M., Spencer J.S., Amara R.R., Plikaytis B.B., Posey J.E., Sable S.B. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis. Sci. Rep., 2016, vol. 6: 25837. doi: 10.1038/srep25837
  14. Perdomo C., Zedler U., Kühl A.A., Lozza L., Saikali P., Sander L.E., Vogelzang A., Kaufmann S.H., Kupz A. Mucosal BCG vaccination induces protective lung-resident memory T cell populations against tuberculosis. MBio, 2016, vol. 7, no. 6: e.01686. doi: 10.1128/mBio.01686-16
  15. Romanova J., Krenn B.M., Wolschek M., Ferko B., Romanovskaja-Romanko E., Morokutti A., Shurygina A.P., Nakowitsch S., Ruthsatz T., Kiefmann B., König U., Bergmann M., Sachet M., Balasingam S., Mann A., Oxford J., Slais M., Kiselev O., Muster T., Egorov A. Preclinical evaluation of a replication-deficient intranasal DeltaNS1 H5N1 influenza vaccine. PLoS One, 2009, vol. 4, no. 6: e.5984. doi: 10.1371/journal.pone.0005984
  16. Ryan A.A., Nambiar J.K., Wozniak T.M., Roediger B., Shklovskaya E., Britton W.J., Fazekas de St Groth B., Triccas J.A. Antigen load governs the differential priming of CD8 T cells in response to the bacille Calmette Guerin vaccine or Mycobacterium tuberculosis infection. J. Immunol., 2009, vol. 182, no. 11, pp. 7172–7177. doi: 10.4049/jimmunol.0801694
  17. Xu Y., Yang E., Wang J., Li R., Li G., Liu G., Song N., Huang Q., Kong C., Wang H. Prime-boost bacillus Calmette-Guérin vaccination with lentivirus-vectored and DNA-based vaccines expressing antigens Ag85B and Rv3425 improves protective efficacy against Mycobacterium tuberculosis in mice. Immunology, 2014, vol. 143, no. 2, pp. 277–286. doi: 10.1111/imm.12308
  18. Zhang M., Dong C., Xiong S. Heterologous boosting with recombinant VSV-846 in BCG-primed mice confers improved protection against Mycobacterium infection. Hum. Vaccin. Immunother., 2017, vol. 13, no. 4, pp. 816–822. doi: 10.1080/21645515.2016.1261229
  19. Заболотных Н.В., Шурыгина А.-П.С., Виноградова Т.И., Витовская М.Л., Хайруллин Б.М., Сандыбаев Н.Т., Бузицкая Ж.В., Стукова М.А.. Усиление протективного эффекта вакцины БЦЖ при мукозальной буст-иммунизации гриппозным вектором, экспрессирующим микобактериальные белки ESAT-6 и Ag85A // Биофармацевтический журнал. – 2016.- Т.8, №:6. – С.25-31.
  20. Bai C., He J., Niu H., Hu L., Luo Y., Liu X., Peng L., Zhu B. Prolonged intervals during Mycobacterium tuberculosis subunit vaccine boosting contributes to eliciting immunity mediated by central memory-like T cells. Tuberculosis, 2018, Vol. 110, pp.104-111.
  21. Behar S. M. Antigen-Specific CD8+ T Cells and Protective Immunity to Tuberculosis. Adv. Exp. Med. Biol. 2013, Vol. 783, pp.141–163.
  22. Beverley P.C., Sridhar S., Lalvani A., Tchilian E.Z.. Harnessing local and systemic immunity for vaccines against tuberculosis. Mucosal Immunol. 2014, Vol. 7, no. 1, pp.20-26.
  23. Cha S.B., Kim W.S., Kim J.S., Kim H.M., Kwon K.W., Han S.J., Cho S.N., Coler R.N., Reed S.G., Shin S.J. Pulmonary immunity and durable protection induced by the ID93/GLA-SE vaccine candidate against the hyper-virulent Korean Beijing Mycobacterium tuberculosis strain K. Vaccine, 2016, Vol. 34, no. 19, pp.2179-2187.
  24. Ding Y., Zheng H., Feng C., Wang B., Liu C., Mi K., Cao H., Meng S. Heat-Shock Protein gp96 Enhances T Cell Responses and Protective Potential to Bacillus Calmette-Guérin Vaccine. Scand. J. Immunol. 2016, Vol. 84, no. 4, pp.222-228.
  25. Kaveh D.A., Garcia-Pelayo M.C., Hogarth P.J. Persistent BCG bacilli perpetuate CD4 T effector memory and optimal protection against tuberculosis. Vaccine, 2014, Vol. 32, pp. 6911-6918.
  26. Kim W.S., Kim J.S., Kim H.M., Kwon K.W., Eum S.Y., Shin SJ. Comparison of immunogenicity and vaccine efficacy between heat-shock proteins, HSP70 and GrpE, in the DnaK operon of Mycobacterium tuberculosis. Sci. Rep., 2018
  27. , Vol. 8, no. 1, p.14411.
  28. Liang J., Teng X., Yuan X., Zhang Y., Shi C., Yue T., Zhou L., Li J., Fan X. Enhanced and durable protective immune responses induced by a cocktail of recombinant BCG strains expressing antigens of multistage of Mycobacterium tuberculosis. Mol. Immunol., 2015, Vol. 66, no. 2, pp.392-401.
  29. Lindenstrom T., Knudsen N. P., Agger E. M. & Andersen P. Control of chronic Mycobacterium tuberculosis infection by CD4 KLRG1- IL-2-secreting central memory cells. J. Immunol. 2013, Vol. 190, pp.6311–6319.
  30. Ma J., Tian M., Fan X., Yu Q., Jing Y., Wang W., Li L., Zhou Z. Mycobacterium tuberculosis multistage antigens confer comprehensive protection against pre- and post-exposure infections by driving Th1-type T cell immunity. Oncotarget., 2016, Vol. 7, no. 39, pp.63804-63815.
  31. Moliva J.I., Turner J., Torrelles J.B. Immune Responses to Bacillus Calmette-Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis? Front. Immunol., 2017, Vol. 8, p. 407.
  32. Nandakumar S., Kannanganat S., Dobos K. M., Lucas M., Spencer J.S., Amara R.R.,Plikaytis B. B., Posey J.E., Sable S. B. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis. Sci. Rep., 2016, Vol. 6, p.25837.
  33. Perdomo C., Zedler U., Kühl A.A., Lozza L., Saikali P., Sander L.E., Vogelzang A., Kaufmann S.H., Kupz A. Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis. MBio., 2016, Vol. 7, no. 6, pp. e.01686.
  34. Romanova J., Krenn B.M., Wolschek M., Ferko B., Romanovskaja-Romanko E., Morokutti A., Shurygina A.P., Nakowitsch S., Ruthsatz T., Kiefmann B., König U., Bergmann M., Sachet M., Balasingam S., Mann A., Oxford J., Slais M., Kiselev O., Muster T., Egorov A. Preclinical evaluation of a replication-deficient intranasal DeltaNS1 H5N1 influenza vaccine. PLoS One, 2009, Vol. 4, no. 6, pp. e.5984.
  35. Ryan AA, Nambiar JK, Wozniak TM, Roediger B, Shklovskaya E, Britton WJ, Fazekas de St Groth B, Triccas JA. Antigen load governs the differential priming of CD8 T cells in response to the bacille Calmette Guerin vaccine or Mycobacterium tuberculosis infection. J. Immunol., 2009, Vol. 182, no. 11, pp. 7172-7177.
  36. Xu Y., Yang E., Wang J., Li R., Li G., Liu G., Song N., Huang Q., Kong C., Wang H. Prime-boost bacillus Calmette-Guérin vaccination with lentivirus-vectored and DNA-based vaccines expressing antigens Ag85B and Rv3425 improves protective efficacy against Mycobacterium tuberculosis in mice. Immunology. 2014, Vol. 143, no. 2, pp. 277-286.
  37. Zhang M., Dong C., Xiong S. Heterologous boosting with recombinant VSV-846 in BCG-primed mice confers improved protection against Mycobacterium infection. Hum. Vaccin. Immunother., 2017, Vol. 13, no. 4, pp. 816–822.
  38. Zabolotnykh N.V., Vinogradova T.I., Shurygina A-P.S., Khairullin B.M., Sandybaev N.T., Buzitskaya Zh.V., Stukova M.A. Mucosal immunization with influenza vector expressing ESAT-6 and Ag85A antigens of M. tuberculosis enhances protective effect of BCG vaccine. Journal of Biopharmaceuticals, 2016, Vol. 8, no. 6, pp. 25-31.
  39. -
  40. -
  41. -
  42. -
  43. -
  44. -
  45. -
  46. -
  47. -
  48. -
  49. -
  50. -
  51. -
  52. -
  53. -
  54. -
  55. -
  56. https://www.sciencedirect.com/science/article/pii/S1472979217304262?via%3Dihub
  57. https://link.springer.com/chapter/10.1007%2F978-1-4614-6111-1_8
  58. https://www.nature.com/articles/mi201399
  59. https://www.sciencedirect.com/science/article/pii/S0264410X16003406?via%3Dihub
  60. https://onlinelibrary.wiley.com/doi/abs/10.1111/sji.12463
  61. https://www.sciencedirect.com/science/article/pii/S0264410X14014315?via%3Dihub
  62. https://www.nature.com/articles/s41598-018-32799-z
  63. https://www.sciencedirect.com/science/article/pii/S0161589015003764?via%3Dihub
  64. http://www.jimmunol.org/content/190/12/6311
  65. http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=11542&path[]=47318
  66. https://www.frontiersin.org/articles/10.3389/fimmu.2017.00407/full
  67. https://www.nature.com/articles/srep25837
  68. https://mbio.asm.org/content/7/6/e01686-16
  69. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005984
  70. http://www.jimmunol.org/content/182/11/7172
  71. https://onlinelibrary.wiley.com/doi/full/10.1111/imm.12308
  72. https://www.tandfonline.com/doi/full/10.1080/21645515.2016.1261229

Copyright (c) 2020 Shurygina A.S., Zabolotnykh N.V., Vinogradova T.I., Vasilyev K.A., Buzitskaya Z.V., Stukova M.A.

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