Studies on mycobacterial genes required for growth and virulence

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Pickford, Hayleah (2020). Studies on mycobacterial genes required for growth and virulence. University of Birmingham. Ph.D.

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Abstract

Mycobacterium tuberculosis is the causative agent of tuberculosis, an infectious disease that is the cause of most deaths due to a single infectious pathogen. Approximately one quarter of the world’s population is latently infected with M. tuberculosis, and may serve as a potential reservoir for reactivation and subsequent further infection. There is an increased prevalence in multidrug resistant tuberculosis, and a vulnerability of immunocompromised individuals to M. tuberculosis infection. Therefore, the need for to further knowledge on mycobacterial growth and virulence is imperative in the development of new antitubercular therapies and drugs.

Mycobacteria differ from some other well-studied rod-shaped bacteria, such as E. coli and B. subtilis, in that they incorporate new cell wall material at the cell poles, as opposed to the whole cell length. Additionally, mycobacteria lack homologues of numerous conserved cell division proteins present in laterally elongating rod-shaped bacteria. Research has begun to elucidate the role of these genes that drive and regulate cell elongation and division. In this study numerous deletion strains were constructed, based on sequence and structural homology with known cell growth and division proteins in other microorganisms, with the aim to delineate their potential roles in mycobacterial elongation and division. The deletion of sepIVA, encoding a DivIVA-domain containing protein, and the coiled-coil MSMEG_4306 in M. smegmatis resulted in an elongated phenotype, suggesting a potential role in cell division. The M. smegmatis interacting partners of SepIVA were explored and were found to be involved in a variety of biosynthetic processes, including lipid biosynthesis and cell elongation and division.

This study also aimed to determine the potential immunological differences between wildtype M. tuberculosis and an M. tuberculosis deletion strain, ΔkasB, which demonstrates an altered colony phenotype and mycolic acid profile upon deletion. ΔkasB is also highly attenuated in a mouse infection model. Cytokine production and mRNA expression analysis were utilised to investigate the innate immune response following bone marrow-derived macrophage infection with ΔkasB; IL-1β was produced in significantly greater quantities, yet IL-1β expression was significantly lower when compared to wildtype M. tuberculosis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):