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The role of Lymphoblastic leukemia 1 (Lyl1) in Mycobacterium tuberculosis (Mtb) infection
Lymphoblastic leukemia 1 (Lyl1) is a well-studied transcription factor known to exhibit oncogenic potential during various forms of leukemia. Since its discovery in 1989, many reports have been published describing its relationship with cancer as well as demonstrating its function during hematopoies...
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| Format: | Thesis |
| Language: | English |
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Department of Clinical Laboratory Sciences
2021
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| _version_ | 1867613454236385280 |
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| access_status_str | Open Access |
| author | Jones, Shelby-Sara Ann |
| author2 | Brombacher, Frank |
| author_browse | Brombacher, Frank Jones, Shelby-Sara Ann |
| author_facet | Brombacher, Frank Jones, Shelby-Sara Ann |
| author_sort | Jones, Shelby-Sara Ann |
| collection | Thesis |
| description | Lymphoblastic leukemia 1 (Lyl1) is a well-studied transcription factor known to exhibit oncogenic potential during various forms of leukemia. Since its discovery in 1989, many reports have been published describing its relationship with cancer as well as demonstrating its function during hematopoiesis. Lyl1 has been shown to serve a significant role during thymopoiesis by contributing to T-cell development. However, it has been recently reported that irrespective of its significance during T-cell development, mature comparable single positive T-cells are observed in mouse models. The use of murine models has been crucial in identifying potential targets for host-directed therapies (HDT) which has been shown to provide great potential in treating tuberculosis (TB). It is evident that Mycobacterium tuberculosis (Mtb), the causative agent for TB, is capable of developing resistance to various treatments that target the bacterium itself. Therefore, by designing therapies that directly target host factors could assist in circumventing Mtb resistance. By analyzing Mtb-infected bone marrow-derived macrophages (BMDM) that have been subjected to genome-wide transcriptional deep sequencing of total RNA using a single molecule sequencer in conjunction with the cap analysis gene expression (CAGE) technique, various differentially expressed genes were identified, including the oncogenic transcription factor, Lyl1. With the use of murine models, we investigated whether Lyl1 is important for various immunological responses at steady state, the regulation of Lyl1 in response to various immune stimulants including LPS and whether this transcription factor is relevant in bacterial infections including Listeria monocytogenes (Lm) and Mtb. The data in this thesis demonstrate comparable immunological responses, including cellular recruitment by means of flow cytometry and cytokine responses by means of ELISA, between naïve littermate control and Lyl1-deficient mice. Further evaluation of Lyl1 regulation revealed the influence of MAPk and NFκB signaling on Lyl1 expression upon LPS stimulation by significantly downregulating this transcription factor in immune stimulated macrophages. A role for Lyl1 during bacterial infections was observed in Lm-infected mice whereby Lyl1-/- mice succumbed earlier to listeriosis compared to the littermate controls. We further established a functional role for this transcription factor during Mtb infection in vitro and in vivo. The early surrender of Lyl1-deficient mice to Mtb HN878 infection, accompanied by increased bacterial burden during chronic Mtb infection, demonstrated enhanced susceptibility in the absence of Lyl1. We show that Lyl1-deficient host susceptibility is a consequence of enhanced inflammatory responses and increased bacterial growth. This is demonstrated by increased neutrophilic inflammation, pro-inflammatory cytokine and chemokine secretion along with a reduction in anti-inflammatory cytokine release during chronic Mtb infection. Here, we demonstrate the first non-leukemia role for Lyl1 by suggesting a role and requirement for this transcription factor during bacterial infections. Given the significant role during Mtb infection, our studies suggest the use of Lyl1 associated pathways as a potential HDT target for TB. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/33727 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:36:24.280Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | Department of Clinical Laboratory Sciences |
| publisherStr | Department of Clinical Laboratory Sciences |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/33727 The role of Lymphoblastic leukemia 1 (Lyl1) in Mycobacterium tuberculosis (Mtb) infection Jones, Shelby-Sara Ann Brombacher, Frank Guler Reto clinical laboratory sciences Lymphoblastic leukemia 1 (Lyl1) is a well-studied transcription factor known to exhibit oncogenic potential during various forms of leukemia. Since its discovery in 1989, many reports have been published describing its relationship with cancer as well as demonstrating its function during hematopoiesis. Lyl1 has been shown to serve a significant role during thymopoiesis by contributing to T-cell development. However, it has been recently reported that irrespective of its significance during T-cell development, mature comparable single positive T-cells are observed in mouse models. The use of murine models has been crucial in identifying potential targets for host-directed therapies (HDT) which has been shown to provide great potential in treating tuberculosis (TB). It is evident that Mycobacterium tuberculosis (Mtb), the causative agent for TB, is capable of developing resistance to various treatments that target the bacterium itself. Therefore, by designing therapies that directly target host factors could assist in circumventing Mtb resistance. By analyzing Mtb-infected bone marrow-derived macrophages (BMDM) that have been subjected to genome-wide transcriptional deep sequencing of total RNA using a single molecule sequencer in conjunction with the cap analysis gene expression (CAGE) technique, various differentially expressed genes were identified, including the oncogenic transcription factor, Lyl1. With the use of murine models, we investigated whether Lyl1 is important for various immunological responses at steady state, the regulation of Lyl1 in response to various immune stimulants including LPS and whether this transcription factor is relevant in bacterial infections including Listeria monocytogenes (Lm) and Mtb. The data in this thesis demonstrate comparable immunological responses, including cellular recruitment by means of flow cytometry and cytokine responses by means of ELISA, between naïve littermate control and Lyl1-deficient mice. Further evaluation of Lyl1 regulation revealed the influence of MAPk and NFκB signaling on Lyl1 expression upon LPS stimulation by significantly downregulating this transcription factor in immune stimulated macrophages. A role for Lyl1 during bacterial infections was observed in Lm-infected mice whereby Lyl1-/- mice succumbed earlier to listeriosis compared to the littermate controls. We further established a functional role for this transcription factor during Mtb infection in vitro and in vivo. The early surrender of Lyl1-deficient mice to Mtb HN878 infection, accompanied by increased bacterial burden during chronic Mtb infection, demonstrated enhanced susceptibility in the absence of Lyl1. We show that Lyl1-deficient host susceptibility is a consequence of enhanced inflammatory responses and increased bacterial growth. This is demonstrated by increased neutrophilic inflammation, pro-inflammatory cytokine and chemokine secretion along with a reduction in anti-inflammatory cytokine release during chronic Mtb infection. Here, we demonstrate the first non-leukemia role for Lyl1 by suggesting a role and requirement for this transcription factor during bacterial infections. Given the significant role during Mtb infection, our studies suggest the use of Lyl1 associated pathways as a potential HDT target for TB. 2021-08-06T16:23:36Z 2021-08-06T16:23:36Z 2021 2021-08-06T15:10:22Z Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/33727 eng application/pdf Department of Clinical Laboratory Sciences Faculty of Health Sciences |
| spellingShingle | clinical laboratory sciences Jones, Shelby-Sara Ann The role of Lymphoblastic leukemia 1 (Lyl1) in Mycobacterium tuberculosis (Mtb) infection |
| thesis_degree_str | Doctoral |
| title | The role of Lymphoblastic leukemia 1 (Lyl1) in Mycobacterium tuberculosis (Mtb) infection |
| title_full | The role of Lymphoblastic leukemia 1 (Lyl1) in Mycobacterium tuberculosis (Mtb) infection |
| title_fullStr | The role of Lymphoblastic leukemia 1 (Lyl1) in Mycobacterium tuberculosis (Mtb) infection |
| title_full_unstemmed | The role of Lymphoblastic leukemia 1 (Lyl1) in Mycobacterium tuberculosis (Mtb) infection |
| title_short | The role of Lymphoblastic leukemia 1 (Lyl1) in Mycobacterium tuberculosis (Mtb) infection |
| title_sort | role of lymphoblastic leukemia 1 lyl1 in mycobacterium tuberculosis mtb infection |
| topic | clinical laboratory sciences |
| url | http://hdl.handle.net/11427/33727 |
| work_keys_str_mv | AT jonesshelbysaraann theroleoflymphoblasticleukemia1lyl1inmycobacteriumtuberculosismtbinfection AT jonesshelbysaraann roleoflymphoblasticleukemia1lyl1inmycobacteriumtuberculosismtbinfection |