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Probing molecular mechanisms of mycobacterium pathogenesis in bone cells
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Milne, Artemis Emily (2023) Probing molecular mechanisms of mycobacterium pathogenesis in bone cells. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3985111
Abstract
Homeostasis of the bone is a tightly regulated process involving bone forming osteoblasts and bone resorptive osteoclasts, which are characterised by their multinucleation and large size. It has been demonstrated that Mycobacterium tuberculosis (Mtb) infection of mature multinuclear osteoclasts can lead to dysregulation of cytokines and chemokines, reprogramming of osteoclast development and disruption of resorption capabilities. However, mechanisms of pathogenesis remain unclear.
In this project, we first characterised the in vitro differentiated osteoclast-like cells (OCLs), followed by the effects of mycobacterial infection on OCLs in two models of infection using M. bovis BCG. Infection of OCLs in vitro show that osteoclast frequency and resorptive activity increased during mycobacterial infection. This was also observed in OCLs obtained from C57BL/6 mice infected intravenously with BCG. To understand the mechanisms involved in mycobacterial infection of OCLs, we conducted transcriptome analysis of infected OCLs from both in vitro and in vivo models.
Our data suggests that host cell death pathways are modulated during BCG infection. To explore further, we investigate apoptosis and pyroptosis using several immunological techniques. We also probe the involvement of the NLRP3 inflammasome during infection.
Our findings refine our understanding of how mycobacteria manipulate the osteoclasts to provide a favourable environment to survive, which may thus inform potential host directed therapy strategies.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology Q Science > QR Microbiology R Medicine > RC Internal medicine |
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Library of Congress Subject Headings (LCSH): | Mycobacterium tuberculosis -- Pathogenesis, Bone cells, Osteoclasts, Cell death, Apoptosis -- Molecular aspects | ||||
Official Date: | 28 February 2023 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Unnikrishnan, Meera ; Singhal, Amit | ||||
Format of File: | |||||
Extent: | 282 pages : illustrations | ||||
Language: | eng |
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