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The role of cell type-specific tumour necrosis factor in protective immunity against neurotuberculosis
Includes bibliographical references.
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| Main Author: | |
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
Division of Immunology
2014
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| _version_ | 1867614299771371520 |
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| access_status_str | Open Access |
| author | Francisco, Ngiambudulu Mbandu |
| author2 | Jacobs, Muazzam |
| author_browse | Francisco, Ngiambudulu Mbandu Jacobs, Muazzam |
| author_facet | Jacobs, Muazzam Francisco, Ngiambudulu Mbandu |
| author_sort | Francisco, Ngiambudulu Mbandu |
| collection | Thesis |
| description | Includes bibliographical references. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/8706 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:49:50.645Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2014 |
| publishDateRange | 2014 |
| publishDateSort | 2014 |
| publisher | Division of Immunology |
| publisherStr | Division of Immunology |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/8706 The role of cell type-specific tumour necrosis factor in protective immunity against neurotuberculosis Francisco, Ngiambudulu Mbandu Jacobs, Muazzam Includes bibliographical references. Neurotuberculosis is the most severe form of extra-pulmonary tuberculosis, characterised by the formation of rich foci a brain form of granulomas, and tuberculous meningitis. Granulomas contain mycobacteria by recruitment of immune cells that surround the bacteria. The cytokine tumour necrosis factor has been found to be involved in the recruitment of the immune cells and structure maintenance of granulomas. Tumour necrosis factor is a multifunctional proinflammatory cytokine which play a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) infection. This cytokine is synthesised by several cell types of hematopoetic origin, such as microglia/macrophages, neutrophils, dendritic cells and lymphocytes, and non-hematopoetic origin such as astrocytes and neurons. During neurotuberculosis, excess of tumour necrosis factor has been implicated in persisting hyperinflammation, however, deficiency of tumour necrosis factor lead to uncontrolled bacterial growth; both phenomena causing necrotic lysis. Thus, a need exists to investigate the contribution of tumour necrosis factor by specific cell types in the control of cerebral M. tuberculosis infection and its protective immune response. In this study, we investigated the role of tumour necrosis factor derived from neurons, microglia/macrophages, neutrophils, CD4+ and CD8+ T cells in host immunity against M. tuberculosis; using an experimental murine model with cell type-specific gene targeting. We found that mice deficient for tumour necrosis factor in neurons (NsTNF-/-), as well as from microglia/macrophages and neutrophils (M-TNF-/-) are not susceptible to M. tuberculosis infection with a phenotype similar to wild type mice. Interestingly, mice with ablation of tumour necrosis factor in myeloid (microglia/macrophages, neutrophils) and CD4+ and CD8+ T cells (MTTNF-/-) were highly susceptible to M. tuberculosis infection with a phenotype similar to that of complete deficient tumour necrosis factor (TNF-/-) mice, which succumbed by 21 days postinfection. Thus, it seems that the resistance observed in M-TNF-/- mice may be caused by the compensation of T cell-derived TNF whose function appeared as non-redundant. Impaired protective immunity observed in MT-TNF-/- and TNF-/- mice were related to alteration of cytokines and chemokines, and also to reduce antigen response and B cells IgM secretion. Our data suggest that neurons as well as microglia/macrophages and neutrophils derived tumor necrosis factor have a very limited role in protective cerebral immune responses. In MT-TNF-/- mice, TNF mediated protective immunity against cerebral M. tuberculosis infection requires primarily T cell-derived TNF as opposed to macrophage/neutrophil derived TNF. These findings may inform the development of immunomodulatory therapy strategies against neurotuberculosis. 2014-10-21T13:47:44Z 2014-10-21T13:47:44Z 2013 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/8706 eng application/pdf Division of Immunology Faculty of Health Sciences University of Cape Town |
| spellingShingle | Francisco, Ngiambudulu Mbandu The role of cell type-specific tumour necrosis factor in protective immunity against neurotuberculosis |
| thesis_degree_str | Doctoral |
| title | The role of cell type-specific tumour necrosis factor in protective immunity against neurotuberculosis |
| title_full | The role of cell type-specific tumour necrosis factor in protective immunity against neurotuberculosis |
| title_fullStr | The role of cell type-specific tumour necrosis factor in protective immunity against neurotuberculosis |
| title_full_unstemmed | The role of cell type-specific tumour necrosis factor in protective immunity against neurotuberculosis |
| title_short | The role of cell type-specific tumour necrosis factor in protective immunity against neurotuberculosis |
| title_sort | role of cell type specific tumour necrosis factor in protective immunity against neurotuberculosis |
| url | http://hdl.handle.net/11427/8706 |
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