The Immunogenicity and Safety of <i>Mycobacterium tuberculosis</i>-<i>mosR</i>-Based Double Deletion Strain in Mice
<i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>) remains a significant global health threat, accounting for ~1.7 million deaths annually. The efficacy of the current vaccine, <i>M. bovis</i> BCG, ranges from 0 to 80% in children and does not prevent adul...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Microorganisms |
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| Online Access: | https://www.mdpi.com/2076-2607/11/8/2105 |
| _version_ | 1797583685524914176 |
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| author | Rachel E. Hildebrand Chungyi Hansen Brock Kingstad-Bakke Chia-Wei Wu Marulasiddappa Suresh Adel Talaat |
| author_facet | Rachel E. Hildebrand Chungyi Hansen Brock Kingstad-Bakke Chia-Wei Wu Marulasiddappa Suresh Adel Talaat |
| author_sort | Rachel E. Hildebrand |
| collection | DOAJ |
| description | <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>) remains a significant global health threat, accounting for ~1.7 million deaths annually. The efficacy of the current vaccine, <i>M. bovis</i> BCG, ranges from 0 to 80% in children and does not prevent adulthood tuberculosis. We explored the immune profile and safety of a live-attenuated <i>M. tuberculosis</i> construct with double deletions of the <i>mosR</i> and <i>echA7</i> genes, where previously, single mutations were protective against an <i>M. tuberculosis</i> aerosol challenge. Over 32 weeks post-vaccination (WPV), immunized mice with <i>M. tuberculosis</i>Δ<i>mosR</i>Δ<i>echA7</i> (double mutant) were sacrificed to evaluate the vaccine persistence, histopathology, and immune responses. Interestingly, despite similar tissue colonization between the vaccine double mutant and wild-type <i>M. tuberculosis</i>, the vaccine construct showed a greater reaction to the ESAT-6, TB.10, and Ag85B antigens with peptide stimulation. Additionally, there was a greater number of antigen-specific CD4 T cells in the vaccine group, accompanied by significant polyfunctional T-cell responses not observed in the other groups. Histologically, mild but widely distributed inflammatory responses were recorded in the livers and lungs of the immunized animals at early timepoints, which turned into organized inflammatory foci via 32WPV, a pathology not observed in BCG-immunized mice. A lower double-mutant dose resulted in significantly less tissue colonization and less tissue inflammation. Overall, the double-mutant vaccine elicited robust immune responses dominated by antigen-specific CD4 T cells, but also triggered tissue damage and vaccine persistence. The findings highlight key features associated with the immunogenicity and safety of the examined vaccine construct that can benefit the future evaluation of other live vaccines. |
| first_indexed | 2024-03-10T23:42:23Z |
| format | Article |
| id | doaj.art-41666e3bce6f47d09a9bb8026211cf45 |
| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-10T23:42:23Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Microorganisms |
| spelling | doaj.art-41666e3bce6f47d09a9bb8026211cf452023-11-19T02:19:20ZengMDPI AGMicroorganisms2076-26072023-08-01118210510.3390/microorganisms11082105The Immunogenicity and Safety of <i>Mycobacterium tuberculosis</i>-<i>mosR</i>-Based Double Deletion Strain in MiceRachel E. Hildebrand0Chungyi Hansen1Brock Kingstad-Bakke2Chia-Wei Wu3Marulasiddappa Suresh4Adel Talaat5Department of Pathobiological Sciences, University of Wisconsin-Madison, 1656 Linden Drive, Madison, WI 53706, USADepartment of Pathobiological Sciences, University of Wisconsin-Madison, 1656 Linden Drive, Madison, WI 53706, USADepartment of Pathobiological Sciences, University of Wisconsin-Madison, 1656 Linden Drive, Madison, WI 53706, USADepartment of Pathobiological Sciences, University of Wisconsin-Madison, 1656 Linden Drive, Madison, WI 53706, USADepartment of Pathobiological Sciences, University of Wisconsin-Madison, 1656 Linden Drive, Madison, WI 53706, USADepartment of Pathobiological Sciences, University of Wisconsin-Madison, 1656 Linden Drive, Madison, WI 53706, USA<i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>) remains a significant global health threat, accounting for ~1.7 million deaths annually. The efficacy of the current vaccine, <i>M. bovis</i> BCG, ranges from 0 to 80% in children and does not prevent adulthood tuberculosis. We explored the immune profile and safety of a live-attenuated <i>M. tuberculosis</i> construct with double deletions of the <i>mosR</i> and <i>echA7</i> genes, where previously, single mutations were protective against an <i>M. tuberculosis</i> aerosol challenge. Over 32 weeks post-vaccination (WPV), immunized mice with <i>M. tuberculosis</i>Δ<i>mosR</i>Δ<i>echA7</i> (double mutant) were sacrificed to evaluate the vaccine persistence, histopathology, and immune responses. Interestingly, despite similar tissue colonization between the vaccine double mutant and wild-type <i>M. tuberculosis</i>, the vaccine construct showed a greater reaction to the ESAT-6, TB.10, and Ag85B antigens with peptide stimulation. Additionally, there was a greater number of antigen-specific CD4 T cells in the vaccine group, accompanied by significant polyfunctional T-cell responses not observed in the other groups. Histologically, mild but widely distributed inflammatory responses were recorded in the livers and lungs of the immunized animals at early timepoints, which turned into organized inflammatory foci via 32WPV, a pathology not observed in BCG-immunized mice. A lower double-mutant dose resulted in significantly less tissue colonization and less tissue inflammation. Overall, the double-mutant vaccine elicited robust immune responses dominated by antigen-specific CD4 T cells, but also triggered tissue damage and vaccine persistence. The findings highlight key features associated with the immunogenicity and safety of the examined vaccine construct that can benefit the future evaluation of other live vaccines.https://www.mdpi.com/2076-2607/11/8/2105tuberculosis vaccinemycobacteriasafetyimmunology |
| spellingShingle | Rachel E. Hildebrand Chungyi Hansen Brock Kingstad-Bakke Chia-Wei Wu Marulasiddappa Suresh Adel Talaat The Immunogenicity and Safety of <i>Mycobacterium tuberculosis</i>-<i>mosR</i>-Based Double Deletion Strain in Mice Microorganisms tuberculosis vaccine mycobacteria safety immunology |
| title | The Immunogenicity and Safety of <i>Mycobacterium tuberculosis</i>-<i>mosR</i>-Based Double Deletion Strain in Mice |
| title_full | The Immunogenicity and Safety of <i>Mycobacterium tuberculosis</i>-<i>mosR</i>-Based Double Deletion Strain in Mice |
| title_fullStr | The Immunogenicity and Safety of <i>Mycobacterium tuberculosis</i>-<i>mosR</i>-Based Double Deletion Strain in Mice |
| title_full_unstemmed | The Immunogenicity and Safety of <i>Mycobacterium tuberculosis</i>-<i>mosR</i>-Based Double Deletion Strain in Mice |
| title_short | The Immunogenicity and Safety of <i>Mycobacterium tuberculosis</i>-<i>mosR</i>-Based Double Deletion Strain in Mice |
| title_sort | immunogenicity and safety of i mycobacterium tuberculosis i i mosr i based double deletion strain in mice |
| topic | tuberculosis vaccine mycobacteria safety immunology |
| url | https://www.mdpi.com/2076-2607/11/8/2105 |
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