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The role of mucosal-associated invariant T (MAIT) cells in long-term resistance to Mycobacterium tuberculosis (M.tb) infection in healthcare workers with sustained occupational exposure to TB
A small proportion of individuals with sustained tuberculosis (TB) exposure remain persistently uninfected, classified as resisters. Understanding the immune mechanisms underlying this natural resistance is critical for developing TB vaccines and therapeutics. This study characterized the epidemiolo...
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| Format: | Thesis |
| Language: | English English |
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Department of Medicine
2026
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| _version_ | 1869483666398248960 |
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| access_status_str | Open Access |
| author | Balfour, Avuyonke |
| author2 | Shey, Muki |
| author_browse | Balfour, Avuyonke Shey, Muki |
| author_facet | Shey, Muki Balfour, Avuyonke |
| author_sort | Balfour, Avuyonke |
| collection | Thesis |
| description | A small proportion of individuals with sustained tuberculosis (TB) exposure remain persistently uninfected, classified as resisters. Understanding the immune mechanisms underlying this natural resistance is critical for developing TB vaccines and therapeutics. This study characterized the epidemiological, immunological, and transcriptional profiles of resisters among healthcare workers in Cape Town, South Africa. We conducted a cross-sectional study which screened 780 HIV-uninfected healthcare workers from TB facilities in Cape Town, South Africa, who had worked for a minimum of five years in those settings. Participants were classified as resisters, latent TB infection (LTBI), or discordant based on QuantiFERON TB Gold Plus (QFT) and tuberculin skin test results. Resisters were defined as individuals with both a negative QFT (IFN-γ < 0.35 IU/mL) and a negative TST (induration < 10 mm), LTBI participants had a positive QFT (IFN-γ ≥ 0.35 IU/mL) and a positive TST (induration ≥ 10 mm), participants in the Discordant group had a positive QFT (≥ 1 IU/mL) and negative TST (induration = 0 mm). Individuals with a previous TB episode were also included. Blood was collected, and plasma and peripheral blood mononuclear cells (PBMCs) were isolated for downstream analyses. Epidemiologically, resisters and LTBI participants were largely similar, although healthcare workers with 10 to 15 years of TB exposure had lower odds of being resisters, likely reflecting cumulative infection risk. Immunologically, resisters exhibited a distinct T cell profile: MAIT cell frequencies were comparable between groups, but resisters showed higher baseline activation (HLA-DR+, CD27+) yet significantly reduced mycobacteria-specific functional responses (lower frequencies of IFN-γ+ and granzyme B+ cells) and lower proportions of effector memory MAIT cells. Plasma analyses revealed elevated baseline immune mediators in resisters (IFN-α, IL-15, IL-23), while LTBI participants demonstrated stronger T cell responses to M.tb-specific antigens (ESAT-6/CFP-10). Notably, resisters demonstrated greater cytokine secretion following whole mycobacterial stimulation compared to LTBI. Gene expression patterns were largely similar between groups, although resisters showed trends toward upregulated T cell activation genes and downregulated cytotoxic genes following M.tb stimulation. This comprehensive study demonstrates that natural resistance to M.tb is characterized by distinct immune activation patterns rather than altered immune cell frequencies. The contrasting profile of heightened baseline activation coupled with reduced mycobacteria-specific memory responses suggests resisters may clear M.tb through enhanced innate immune readiness before establishing classical adaptive immunity. These findings advance our understanding of protective immunity against M.tb and may inform vaccine strategies targeting early innate activation rather than memory T cell responses alone. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/43382 |
| institution | University of Cape Town (South Africa) |
| language | English eng |
| last_indexed | 2026-07-01T04:02:37.584Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2026 |
| publishDateRange | 2026 |
| publishDateSort | 2026 |
| publisher | Department of Medicine |
| publisherStr | Department of Medicine |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/43382 The role of mucosal-associated invariant T (MAIT) cells in long-term resistance to Mycobacterium tuberculosis (M.tb) infection in healthcare workers with sustained occupational exposure to TB Balfour, Avuyonke Shey, Muki Meintjes , Graeme tuberculosis immune mechanisms A small proportion of individuals with sustained tuberculosis (TB) exposure remain persistently uninfected, classified as resisters. Understanding the immune mechanisms underlying this natural resistance is critical for developing TB vaccines and therapeutics. This study characterized the epidemiological, immunological, and transcriptional profiles of resisters among healthcare workers in Cape Town, South Africa. We conducted a cross-sectional study which screened 780 HIV-uninfected healthcare workers from TB facilities in Cape Town, South Africa, who had worked for a minimum of five years in those settings. Participants were classified as resisters, latent TB infection (LTBI), or discordant based on QuantiFERON TB Gold Plus (QFT) and tuberculin skin test results. Resisters were defined as individuals with both a negative QFT (IFN-γ < 0.35 IU/mL) and a negative TST (induration < 10 mm), LTBI participants had a positive QFT (IFN-γ ≥ 0.35 IU/mL) and a positive TST (induration ≥ 10 mm), participants in the Discordant group had a positive QFT (≥ 1 IU/mL) and negative TST (induration = 0 mm). Individuals with a previous TB episode were also included. Blood was collected, and plasma and peripheral blood mononuclear cells (PBMCs) were isolated for downstream analyses. Epidemiologically, resisters and LTBI participants were largely similar, although healthcare workers with 10 to 15 years of TB exposure had lower odds of being resisters, likely reflecting cumulative infection risk. Immunologically, resisters exhibited a distinct T cell profile: MAIT cell frequencies were comparable between groups, but resisters showed higher baseline activation (HLA-DR+, CD27+) yet significantly reduced mycobacteria-specific functional responses (lower frequencies of IFN-γ+ and granzyme B+ cells) and lower proportions of effector memory MAIT cells. Plasma analyses revealed elevated baseline immune mediators in resisters (IFN-α, IL-15, IL-23), while LTBI participants demonstrated stronger T cell responses to M.tb-specific antigens (ESAT-6/CFP-10). Notably, resisters demonstrated greater cytokine secretion following whole mycobacterial stimulation compared to LTBI. Gene expression patterns were largely similar between groups, although resisters showed trends toward upregulated T cell activation genes and downregulated cytotoxic genes following M.tb stimulation. This comprehensive study demonstrates that natural resistance to M.tb is characterized by distinct immune activation patterns rather than altered immune cell frequencies. The contrasting profile of heightened baseline activation coupled with reduced mycobacteria-specific memory responses suggests resisters may clear M.tb through enhanced innate immune readiness before establishing classical adaptive immunity. These findings advance our understanding of protective immunity against M.tb and may inform vaccine strategies targeting early innate activation rather than memory T cell responses alone. 2026-06-25T09:33:32Z 2026-06-25T09:33:32Z 2026 2026-06-25T09:32:12Z Thesis / Dissertation Doctoral PhD http://hdl.handle.net/11427/43382 en eng application/pdf Department of Medicine Faculty of Health Sciences University of Cape Town |
| spellingShingle | tuberculosis immune mechanisms Balfour, Avuyonke The role of mucosal-associated invariant T (MAIT) cells in long-term resistance to Mycobacterium tuberculosis (M.tb) infection in healthcare workers with sustained occupational exposure to TB |
| thesis_degree_str | Doctoral |
| title | The role of mucosal-associated invariant T (MAIT) cells in long-term resistance to Mycobacterium tuberculosis (M.tb) infection in healthcare workers with sustained occupational exposure to TB |
| title_full | The role of mucosal-associated invariant T (MAIT) cells in long-term resistance to Mycobacterium tuberculosis (M.tb) infection in healthcare workers with sustained occupational exposure to TB |
| title_fullStr | The role of mucosal-associated invariant T (MAIT) cells in long-term resistance to Mycobacterium tuberculosis (M.tb) infection in healthcare workers with sustained occupational exposure to TB |
| title_full_unstemmed | The role of mucosal-associated invariant T (MAIT) cells in long-term resistance to Mycobacterium tuberculosis (M.tb) infection in healthcare workers with sustained occupational exposure to TB |
| title_short | The role of mucosal-associated invariant T (MAIT) cells in long-term resistance to Mycobacterium tuberculosis (M.tb) infection in healthcare workers with sustained occupational exposure to TB |
| title_sort | role of mucosal associated invariant t mait cells in long term resistance to mycobacterium tuberculosis m tb infection in healthcare workers with sustained occupational exposure to tb |
| topic | tuberculosis immune mechanisms |
| url | http://hdl.handle.net/11427/43382 |
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