Characterisation of Zebrafish Haem Oxygenase Function in Mycobacterial Infection

Luo, Kaiming (2021) Characterisation of Zebrafish Haem Oxygenase Function in Mycobacterial Infection. PhD thesis, Victor Chang Cardiac Research Institute & St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney.

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Tuberculosis is one of the top 10 leading causes of death in the world. Infection with pathogenic mycobacteria such as Mycobacterium tuberculosis leads to the formation of granulomas, the hallmark histological feature of tuberculosis. Failure to maintain granuloma integrity results in loss of infection control or reactivation of tuberculosis disease. Hmox1 is a stress-responsive protein that can be upregulated rapidly and confers protection to the host. Haem oxygenase 1 (Hmox1) is a critical regulator of iron homeostasis by degrading haem into carbon monoxide, biliverdin and ferrous iron. The protective role of Hmox1 has been demonstrated in a variety of diseases. However, the role of Hmox1 in mycobacterial infection is equivocal with different results in different host-pathogen pairings. Chemokine production plays a crucial role in the recruitment of leukocytes to the focus of infection, particularly, monocyte chemoattractant protein-1 (MCP1) and its receptor CCR2. Hmox1 has been shown to regulate MCP1 expression in mice in the context of mycobacterial infection but limited information is available in zebrafish. Meanwhile, as a key regulator of iron metabolism, Hmox1 may also control the availability of iron during infection, since iron is essential both the host and pathogen and the restriction of iron is an important host defence against bacteria. Mycobacteria require iron as a redox cofactor for vital enzymes and utilise multiple strategies to acquire iron within the host. In vivo imaging using zebrafish embryos and their natural pathogen Mycobacterium marinum enables us to collect unique insight into the functions of Hmox1 in infection. This thesis describes the first generation of hmox1a mutant zebrafish and the first use of the zebrafish model system to investigate Hmox function in M. marinum infection. It connects mycobacterial infection-induced Hmox to iron restriction and prevention of deleterious ferroptosis during mycobacterial infection. This work provides insight into the role of Hmox in tuberculosis pathogenesis

Item Type: Thesis (PhD )
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 30 Sep 2021 05:11
Last Modified: 30 Sep 2021 05:14

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