An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis
Lengthy tuberculosis (TB) treatment is required to overcome the ability of a subpopulation of persistent Mycobacterium tuberculosis (Mtb) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the RelMtb-mediated stringent response. We...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.972266/full |
| _version_ | 1828230946800795648 |
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| author | Styliani Karanika Styliani Karanika James T. Gordy Pranita Neupane Pranita Neupane Theodoros Karantanos Jennie Ruelas Castillo Jennie Ruelas Castillo Darla Quijada Darla Quijada Kaitlyn Comstock Avinaash K. Sandhu Aakanksha R. Kapoor Aakanksha R. Kapoor Yinan Hui Samuel K. Ayeh Samuel K. Ayeh Rokeya Tasneen Rokeya Tasneen Stefanie Krug Stefanie Krug Carina Danchik Carina Danchik Tianyin Wang Courtney Schill Richard B. Markham Petros C. Karakousis Petros C. Karakousis |
| author_facet | Styliani Karanika Styliani Karanika James T. Gordy Pranita Neupane Pranita Neupane Theodoros Karantanos Jennie Ruelas Castillo Jennie Ruelas Castillo Darla Quijada Darla Quijada Kaitlyn Comstock Avinaash K. Sandhu Aakanksha R. Kapoor Aakanksha R. Kapoor Yinan Hui Samuel K. Ayeh Samuel K. Ayeh Rokeya Tasneen Rokeya Tasneen Stefanie Krug Stefanie Krug Carina Danchik Carina Danchik Tianyin Wang Courtney Schill Richard B. Markham Petros C. Karakousis Petros C. Karakousis |
| author_sort | Styliani Karanika |
| collection | DOAJ |
| description | Lengthy tuberculosis (TB) treatment is required to overcome the ability of a subpopulation of persistent Mycobacterium tuberculosis (Mtb) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the RelMtb-mediated stringent response. We developed a novel therapeutic DNA vaccine containing a fusion of the relMtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3α/CCL20. To augment mucosal immune responses, intranasal delivery was also evaluated. We found that intramuscular delivery of the MIP-3α/relMtb (fusion) vaccine or intranasal delivery of the relMtb (non-fusion) vaccine potentiate isoniazid activity more than intramuscular delivery of the DNA vaccine expressing relMtb alone in a chronic TB mouse model (absolute reduction of Mtb burden: 0.63 log10 and 0.5 log10 colony-forming units, respectively; P=0.0002 and P=0.0052), inducing pronounced Mtb-protective immune signatures. The combined approach involving intranasal delivery of the DNA MIP-3α/relMtb fusion vaccine demonstrated the greatest mycobactericidal activity together with isoniazid when compared to each approach alone (absolute reduction of Mtb burden: 1.13 log10, when compared to the intramuscular vaccine targeting relMtb alone; P<0.0001), as well as robust systemic and local Th1 and Th17 responses. This DNA vaccination strategy may be a promising adjunctive approach combined with standard therapy to shorten curative TB treatment, and also serves as proof of concept for treating other chronic bacterial infections. |
| first_indexed | 2024-04-12T18:55:55Z |
| format | Article |
| id | doaj.art-9e6a0ab5a6a54babb18f999d3a442d6d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T18:55:55Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-9e6a0ab5a6a54babb18f999d3a442d6d2022-12-22T03:20:20ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.972266972266An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosisStyliani Karanika0Styliani Karanika1James T. Gordy2Pranita Neupane3Pranita Neupane4Theodoros Karantanos5Jennie Ruelas Castillo6Jennie Ruelas Castillo7Darla Quijada8Darla Quijada9Kaitlyn Comstock10Avinaash K. Sandhu11Aakanksha R. Kapoor12Aakanksha R. Kapoor13Yinan Hui14Samuel K. Ayeh15Samuel K. Ayeh16Rokeya Tasneen17Rokeya Tasneen18Stefanie Krug19Stefanie Krug20Carina Danchik21Carina Danchik22Tianyin Wang23Courtney Schill24Richard B. Markham25Petros C. Karakousis26Petros C. Karakousis27Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United StatesW. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDivision of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United StatesW. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesDivision of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, MD, United StatesDivision of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United StatesW. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesDivision of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United StatesW. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDivision of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United StatesCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDivision of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United StatesW. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesDivision of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United StatesW. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesDivision of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United StatesW. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesDivision of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United StatesW. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDivision of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United StatesW. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesLengthy tuberculosis (TB) treatment is required to overcome the ability of a subpopulation of persistent Mycobacterium tuberculosis (Mtb) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the RelMtb-mediated stringent response. We developed a novel therapeutic DNA vaccine containing a fusion of the relMtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3α/CCL20. To augment mucosal immune responses, intranasal delivery was also evaluated. We found that intramuscular delivery of the MIP-3α/relMtb (fusion) vaccine or intranasal delivery of the relMtb (non-fusion) vaccine potentiate isoniazid activity more than intramuscular delivery of the DNA vaccine expressing relMtb alone in a chronic TB mouse model (absolute reduction of Mtb burden: 0.63 log10 and 0.5 log10 colony-forming units, respectively; P=0.0002 and P=0.0052), inducing pronounced Mtb-protective immune signatures. The combined approach involving intranasal delivery of the DNA MIP-3α/relMtb fusion vaccine demonstrated the greatest mycobactericidal activity together with isoniazid when compared to each approach alone (absolute reduction of Mtb burden: 1.13 log10, when compared to the intramuscular vaccine targeting relMtb alone; P<0.0001), as well as robust systemic and local Th1 and Th17 responses. This DNA vaccination strategy may be a promising adjunctive approach combined with standard therapy to shorten curative TB treatment, and also serves as proof of concept for treating other chronic bacterial infections.https://www.frontiersin.org/articles/10.3389/fimmu.2022.972266/fullMycobacterium tuberculosistuberculosis DNA vaccinespersistencestringent responseimmunotherapyintranasal route |
| spellingShingle | Styliani Karanika Styliani Karanika James T. Gordy Pranita Neupane Pranita Neupane Theodoros Karantanos Jennie Ruelas Castillo Jennie Ruelas Castillo Darla Quijada Darla Quijada Kaitlyn Comstock Avinaash K. Sandhu Aakanksha R. Kapoor Aakanksha R. Kapoor Yinan Hui Samuel K. Ayeh Samuel K. Ayeh Rokeya Tasneen Rokeya Tasneen Stefanie Krug Stefanie Krug Carina Danchik Carina Danchik Tianyin Wang Courtney Schill Richard B. Markham Petros C. Karakousis Petros C. Karakousis An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis Frontiers in Immunology Mycobacterium tuberculosis tuberculosis DNA vaccines persistence stringent response immunotherapy intranasal route |
| title | An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis |
| title_full | An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis |
| title_fullStr | An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis |
| title_full_unstemmed | An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis |
| title_short | An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis |
| title_sort | intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis |
| topic | Mycobacterium tuberculosis tuberculosis DNA vaccines persistence stringent response immunotherapy intranasal route |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.972266/full |
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