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Title: Melioidosis in South-East Asia : contribution to a fever cohort, and in vitro studies of MAIT cell function
Author: Chowdhury, Fazle Rabbi
ISNI:       0000 0005 0291 417X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Melioidosis is a neglected tropical disease caused by the Gram-negative bacterium Burkholderia pseudomallei (BP). Diabetes mellitus (DM) is a major risk factor. A mathematical model estimated 1,650,000 melioidosis cases in 2015 worldwide with 16,931 cases in Bangladesh, but the disease is rarely diagnosed in Bangladesh. This thesis set out to determine whether melioidosis is a significant cause of fever in Bangladesh, and to characterise the human mucosal-associated invariant T-cell (MAIT) response to BP and other Gram-negative bacteria. We prospectively determined the aetiology of fever in 201 adult patients in Dhaka, Bangladesh, and found melioidosis to be the joint commonest cause (with E. coli) of bacteraemia. We also noticed high rates of antimicrobial resistance in Gram-negative infections. We tracked the phenotype, activation and function of MAIT cells during acute melioidosis and other Gram-negative infections. MAIT cells responded rapidly to BP, releasing IFN-γ via both MR1 and cytokine-dependent pathways. The frequency and IFN-γ expression by MAIT cells following BP stimulation was significantly reduced in acute melioidosis patients compared to endemic controls, and significantly reduced in acute patients who died compared to survivors. We then examined the effect of DM on the MAIT cell response. In the endemic control population, IFN-γ expression was reduced in DM compared to non-DM. This was not explained by differences in activation or exhaustion markers (PD-1 and TIM-3) between groups. Finally, we found IFN-γ production by MAIT cells was significantly lower in the Gram-negative sepsis patients compared to healthy controls. In conclusion, we have demonstrated that melioidosis is one of the commonest causes of community-acquired bacteraemia in Bangladesh. We have also revealed a potential key role for MAIT cells in survival in acute melioidosis, and their significance in host defence against other Gram-negative bacteria.
Supervisor: Klenerman, Paul ; Dunachie, Susanna Sponsor: Welcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Tropical Immunology ; Clinical Medicine