IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

Intranasal Immunization With Nanoparticles Containing an Orientia tsutsugamushi Protein Vaccine Candidate and a Polysorbitol Transporter Adjuvant Enhances Both Humoral and Cellular Immune Responses

  • Cheol Gyun Kim (Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences) ;
  • Won Kyong Kim (Division of Zoonotic and Vector Borne Disease Research, Center for Infectious Disease Research, National Institute of Health) ;
  • Narae Kim (Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences) ;
  • Young Jin Pyung (Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences) ;
  • Da-Jeong Park (Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences) ;
  • Jeong-Cheol Lee (Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences) ;
  • Chong-Su Cho (Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences) ;
  • Hyuk Chu (Division of Zoonotic and Vector Borne Disease Research, Center for Infectious Disease Research, National Institute of Health) ;
  • Cheol-Heui Yun (Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences)
  • Received : 2023.01.01
  • Accepted : 2023.12.10
  • Published : 2023.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Scrub typhus, a mite-borne infectious disease, is caused by Orientia tsutsugamushi. Despite many attempts to develop a protective strategy, an effective preventive vaccine has not been developed. The identification of appropriate Ags that cover diverse antigenic strains and provide long-lasting immunity is a fundamental challenge in the development of a scrub typhus vaccine. We investigated whether this limitation could be overcome by harnessing the nanoparticle-forming polysorbitol transporter (PST) for an O. tsutsugamushi vaccine strategy. Two target proteins, 56-kDa type-specific Ag (TSA56) and surface cell Ag A (ScaA) were used as vaccine candidates. PST formed stable nano-size complexes with TSA56 (TSA56-PST) and ScaA (ScaA-PST); neither exhibited cytotoxicity. The formation of Ag-specific IgG2a, IgG2b, and IgA in mice was enhanced by intranasal vaccination with TSA56-PST or ScaA-PST. The vaccines containing PST induced Ag-specific proliferation of CD8+ and CD4+ T cells. Furthermore, the vaccines containing PST improved the mouse survival against O. tsutsugamushi infection. Collectively, the present study indicated that PST could enhance both Ag-specific humoral immunity and T cell response, which are essential to effectively confer protective immunity against O. tsutsugamushi infection. These findings suggest that PST has potential for use in an intranasal vaccination strategy.

Keywords

Acknowledgement

This research was supported by the Korea Initiative for Fostering University Research and Innovation Program of the National Research Foundation (NRF), funded by the Korean government (MSIT) (No. NRF-2020M3H1A1073304) and a National Institutes of Health research project (2021-NI-013-00). This work also received partial support from the Ministry of Health & Welfare (HV22C0183), Republic of Korea. The study was also partially supported by the BK21 FOUR Program of the Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea.

References

  1. Xu G, Walker DH, Jupiter D, Melby PC, Arcari CM. A review of the global epidemiology of scrub typhus. PLoS Negl Trop Dis 2017;11:e0006062.
  2. Luce-Fedrow A, Lehman ML, Kelly DJ, Mullins K, Maina AN, Stewart RL, Ge H, John HS, Jiang J, Richards AL. A review of scrub typhus (Orientia tsutsugamushi and related organisms): then, now, and tomorrow. Trop Med Infect Dis 2018;3:8.
  3. Kala D, Gupta S, Nagraik R, Verma V, Thakur A, Kaushal A. Diagnosis of scrub typhus: recent advancements and challenges. 3 Biotech 2020;10:396.
  4. Banerjee A, Kulkarni S. Orientia tsutsugamushi: the dangerous yet neglected foe from the East. Int J Med Microbiol 2021;311:151467.
  5. Valbuena G, Walker DH. Approaches to vaccines against Orientia tsutsugamushi. Front Cell Infect Microbiol 2013;2:170.
  6. Park SM, Gu MJ, Ju YJ, Cheon IS, Hwang KJ, Gill B, Shim BS, Jeong HJ, Son YM, Choi S, et al. Intranasal vaccination with outer-membrane protein of Orientia tsutsugamushi induces protective immunity against scrub typhus. Immune Netw 2020;21:e14.
  7. Basharat Z, Akhtar U, Khan K, Alotaibi G, Jalal K, Abbas MN, Hayat A, Ahmad D, Hassan SS. Differential analysis of Orientia tsutsugamushi genomes for therapeutic target identification and possible intervention through natural product inhibitor screening. Comput Biol Med 2022;141:105165.
  8. Ha NY, Sharma P, Kim G, Kim Y, Min CK, Choi MS, Kim IS, Cho NH. Immunization with an autotransporter protein of Orientia tsutsugamushi provides protective immunity against scrub typhus. PLoS Negl Trop Dis 2015;9:e0003585.
  9. Ha NY, Shin HM, Sharma P, Cho HA, Min CK, Kim HI, Yen NT, Kang JS, Kim IS, Choi MS, et al. Generation of protective immunity against Orientia tsutsugamushi infection by immunization with a zinc oxide nanoparticle combined with ScaA antigen. J Nanobiotechnology 2016;14:76.
  10. Kim HI, Ha NY, Kim G, Min CK, Kim Y, Yen NT, Choi MS, Cho NH. Immunization with a recombinant antigen composed of conserved blocks from TSA56 provides broad genotype protection against scrub typhus. Emerg Microbes Infect 2019;8:946-958. https://doi.org/10.1080/22221751.2019.1632676
  11. Chattopadhyay S, Richards AL. Scrub typhus vaccines: past history and recent developments. Hum Vaccin 2007;3:73-80. https://doi.org/10.4161/hv.3.3.4009
  12. Koralur MC, Ramaiah A, Dasch GA. Detection and distribution of Sca autotransporter protein antigens in diverse isolates of Orientia tsutsugamushi. PLoS Negl Trop Dis 2018;12:e0006784.
  13. Cho BA, Cho NH, Seong SY, Choi MS, Kim IS. Intracellular invasion by Orientia tsutsugamushi is mediated by integrin signaling and actin cytoskeleton rearrangements. Infect Immun 2010;78:1915-1923. https://doi.org/10.1128/IAI.01316-09
  14. Lee JH, Cho NH, Kim SY, Bang SY, Chu H, Choi MS, Kim IS. Fibronectin facilitates the invasion of Orientia tsutsugamushi into host cells through interaction with a 56-kDa type-specific antigen. J Infect Dis 2008;198:250-257. https://doi.org/10.1086/589284
  15. Cai T, Liu H, Zhang S, Hu J, Zhang L. Delivery of nanovaccine towards lymphoid organs: recent strategies in enhancing cancer immunotherapy. J Nanobiotechnology 2021;19:389.
  16. Zhang Y, Lin S, Wang XY, Zhu G. Nanovaccines for cancer immunotherapy. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2019;11:e1559.
  17. Jiang H, Wang Q, Sun X. Lymph node targeting strategies to improve vaccination efficacy. J Control Release 2017;267:47-56. https://doi.org/10.1016/j.jconrel.2017.08.009
  18. Kim CG, Kye YC, Yun CH. The role of nanovaccine in cross-presentation of antigen-presenting cells for the activation of CD8+ T cell responses. Pharmaceutics 2019;11:612.
  19. Firdous J, Islam MA, Park SM, Cheon IS, Shim BS, Yoon HS, Song M, Chang J, Choi YJ, Park YM, et al. Induction of long-term immunity against respiratory syncytial virus glycoprotein by an osmotic polymeric nanocarrier. Acta Biomater 2014;10:4606-4617. https://doi.org/10.1016/j.actbio.2014.07.034
  20. Kye YC, Park SM, Shim BS, Firdous J, Kim G, Kim HW, Ju YJ, Kim CG, Cho CS, Kim DW, et al. Intranasal immunization with pneumococcal surface protein A in the presence of nanoparticle forming polysorbitol transporter adjuvant induces protective immunity against the Streptococcus pneumoniae infection. Acta Biomater 2019;90:362-372. https://doi.org/10.1016/j.actbio.2019.03.049
  21. Paramithiotis E, Sugden S, Papp E, Bonhomme M, Chermak T, Crawford SY, Demetriades SZ, Galdos G, Lambert BL, Mattison J, et al. Cellular immunity is critical for assessing COVID-19 vaccine effectiveness in immunocompromised individuals. Front Immunol 2022;13:880784.
  22. Griffiths KL, Khader SA. Novel vaccine approaches for protection against intracellular pathogens. Curr Opin Immunol 2014;28:58-63. https://doi.org/10.1016/j.coi.2014.02.003
  23. Hauptmann M, Kolbaum J, Lilla S, Wozniak D, Gharaibeh M, Fleischer B, Keller CA. Protective and pathogenic roles of CD8+ T lymphocytes in murine Orientia tsutsugamushi infection. PLoS Negl Trop Dis 2016;10:e0004991.
  24. Xu G, Mendell NL, Liang Y, Shelite TR, Goez-Rivillas Y, Soong L, Bouyer DH, Walker DH. CD8+ T cells provide immune protection against murine disseminated endotheliotropic Orientia tsutsugamushi infection. PLoS Negl Trop Dis 2017;11:e0005763.
  25. Kim HW, Ju DB, Kye YC, Ju YJ, Kim CG, Lee IK, Park SM, Choi IS, Cho KK, Lee SH, et al. Galectin-9 induced by dietary probiotic mixture regulates immune balance to reduce atopic dermatitis symptoms in mice. Front Immunol 2020;10:3063.
  26. Chu H, Park SM, Cheon IS, Park MY, Shim BS, Gil BC, Jeung WH, Hwang KJ, Song KD, Hong KJ, et al. Orientia tsutsugamushi infection induces CD4+ T cell activation via human dendritic cell activity. J Microbiol Biotechnol 2013;23:1159-1166. https://doi.org/10.4014/jmb.1303.03019
  27. Tamura A, Urakami H. Easy method for infectivity titration of Rickettsia tsutsugamushi by infected cell counting. Nippon Saikingaku Zasshi 1981;36:783-785. https://doi.org/10.3412/jsb.36.783
  28. Min CK, Kim HI, Ha NY, Kim Y, Kwon EK, Yen NT, Youn JI, Jeon YK, Inn KS, Choi MS, et al. A type i interferon and IL-10 induced by Orientia tsutsugamushi infection suppresses antigen-specific T cells and their memory responses. Front Immunol 2018;9:2022.
  29. Bhat P, Leggatt G, Waterhouse N, Frazer IH. Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. Cell Death Dis 2017;8:e2836.
  30. Sumonwiriya M, Paris DH, Sunyakumthorn P, Anantatat T, Jenjaroen K, Chumseng S, Im-Erbsin R, Tanganuchitcharnchai A, Jintaworn S, Blacksell SD, et al. Strong interferon-gamma mediated cellular immunity to scrub typhus demonstrated using a novel whole cell antigen ELISpot assay in rhesus macaques and humans. PLoS Negl Trop Dis 2017;11:e0005846.
  31. Seong SY, Choi MS, Kim IS. Orientia tsutsugamushi infection: overview and immune responses. Microbes Infect 2001;3:11-21. https://doi.org/10.1016/S1286-4579(00)01352-6
  32. Farber DL, Yudanin NA, Restifo NP. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol 2014;14:24-35. https://doi.org/10.1038/nri3567
  33. Sasaki K, Moussawy MA, Abou-Daya KI, Macedo C, Hosni-Ahmed A, Liu S, Juya M, Zahorchak AF, Metes DM, Thomson AW, et al. Activated-memory T cells influence naive T cell fate: a noncytotoxic function of human CD8 T cells. Commun Biol 2022;5:634.
  34. Tarke A, Coelho CH, Zhang Z, Dan JM, Yu ED, Methot N, Bloom NI, Goodwin B, Phillips E, Mallal S, et al. SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron. Cell 2022;185:847-859.e11. https://doi.org/10.1016/j.cell.2022.01.015
  35. Hemmi T, Ainai A, Hashiguchi T, Tobiume M, Kanno T, Iwata-Yoshikawa N, Iida S, Sato Y, Miyamoto S, Ueno A, et al. Intranasal vaccination induced cross-protective secretory IgA antibodies against SARS-CoV-2 variants with reducing the potential risk of lung eosinophilic immunopathology. Vaccine 2022;40:5892-5903. https://doi.org/10.1016/j.vaccine.2022.08.049
  36. Li L, Wang M, Hao J, Han J, Fu T, Bai J, Tian M, Jin N, Zhu G, Li C. Mucosal IgA response elicited by intranasal immunization of Lactobacillus plantarum expressing surface-displayed RBD protein of SARSCoV-2. Int J Biol Macromol 2021;190:409-416. https://doi.org/10.1016/j.ijbiomac.2021.08.232
  37. Shelite TR, Saito TB, Mendell NL, Gong B, Xu G, Soong L, Valbuena G, Bouyer DH, Walker DH. Hematogenously disseminated Orientia tsutsugamushi-infected murine model of scrub typhus [corrected]. PLoS Negl Trop Dis 2014;8:e2966.
  38. Trent B, Fisher J, Soong L. Scrub Typhus Pathogenesis: Innate Immune Response and Lung Injury During Orientia tsutsugamushi Infection. Front Microbiol 2019;10:2065.
  39. Trent B, Liang Y, Xing Y, Esqueda M, Wei Y, Cho NH, Kim HI, Kim YS, Shelite TR, Cai J, et al. Polarized lung inflammation and Tie2/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection. PLoS Negl Trop Dis 2020;14:e0007675.
  40. Atwal S, Wongsantichon J, Giengkam S, Saharat K, Pittayasathornthun YJ, Chuenklin S, Wang LC, Chung T, Huh H, Lee SH, et al. The obligate intracellular bacterium Orientia tsutsugamushi differentiates into a developmentally distinct extracellular state. Nat Commun 2022;13:3603.
  41. Liu J, Chandrashekar A, Sellers D, Barrett J, Jacob-Dolan C, Lifton M, McMahan K, Sciacca M, VanWyk H, Wu C, et al. Vaccines elicit highly conserved cellular immunity to SARS-CoV-2 Omicron. Nature 2022;603:493-496. https://doi.org/10.1038/s41586-022-04465-y
  42. Farhood B, Najafi M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol 2019;234:8509-8521. https://doi.org/10.1002/jcp.27782
  43. Kuznetsova M, Lopatnikova J, Shevchenko J, Silkov A, Maksyutov A, Sennikov S. Cytotoxic activity and memory T cell subset distribution of in vitro-stimulated CD8+ T cells specific for HER2/neu epitopes. Front Immunol 2019;10:1017.
  44. Hillaire ML, Lawrence P, Lagrange B. IFN-γ: a crucial player in the fight against HBV infection? Immune Netw 2023;23:e30.
  45. Kiniry BE, Hunt PW, Hecht FM, Somsouk M, Deeks SG, Shacklett BL. Differential expression of CD8+ T cell cytotoxic effector molecules in blood and gastrointestinal mucosa in HIV-1 infection. J Immunol 2018;200:1876-1888. https://doi.org/10.4049/jimmunol.1701532
  46. Zophel D, Angenendt A, Kaschek L, Ravichandran K, Hof C, Janku S, Hoth M, Lis A. Faster cytotoxicity with age: Increased perforin and granzyme levels in cytotoxic CD8+ T cells boost cancer cell elimination. Aging Cell 2022;21:e13668.
  47. Aktas E, Kucuksezer UC, Bilgic S, Erten G, Deniz G. Relationship between CD107a expression and cytotoxic activity. Cell Immunol 2009;254:149-154. https://doi.org/10.1016/j.cellimm.2008.08.007
  48. Green AM, Difazio R, Flynn JL. IFN-γ from CD4 T cells is essential for host survival and enhances CD8 T cell function during Mycobacterium tuberculosis infection. J Immunol 2013;190:270-277. https://doi.org/10.4049/jimmunol.1200061
  49. Topchyan P, Lin S, Cui W. The role of CD4 T cell help in CD8 T cell differentiation and function during chronic infection and cancer. Immune Netw 2023;23:e41.
  50. Bousso P. T-cell activation by dendritic cells in the lymph node: lessons from the movies. Nat Rev Immunol 2008;8:675-684. https://doi.org/10.1038/nri2379
  51. Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S. Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 2002;20:621-667. https://doi.org/10.1146/annurev.immunol.20.100301.064828
  52. Pooley JL, Heath WR, Shortman K. Cutting edge: intravenous soluble antigen is presented to CD4 T cells by CD8- dendritic cells, but cross-presented to CD8 T cells by CD8+ dendritic cells. J Immunol 2001;166:5327-5330. https://doi.org/10.4049/jimmunol.166.9.5327
  53. Gerner MY, Casey KA, Mescher MF. Defective MHC class II presentation by dendritic cells limits CD4 T cell help for antitumor CD8 T cell responses. J Immunol 2008;181:155-164. https://doi.org/10.4049/jimmunol.181.1.155
  54. Joffre OP, Segura E, Savina A, Amigorena S. Cross-presentation by dendritic cells. Nat Rev Immunol 2012;12:557-569. https://doi.org/10.1038/nri3254
  55. Alloatti A, Kotsias F, Magalhaes JG, Amigorena S. Dendritic cell maturation and cross-presentation: timing matters! Immunol Rev 2016;272:97-108. https://doi.org/10.1111/imr.12432
  56. Embgenbroich M, Burgdorf S. Current concepts of antigen cross-presentation. Front Immunol 2018;9:1643.
  57. Gros M, Amigorena S. Regulation of antigen export to the cytosol during cross-presentation. Front Immunol 2019;10:41.