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The roles of neutrophils in tuberculosis

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Title: The roles of neutrophils in tuberculosis
Authors: Lowe, David
Item Type: Thesis or dissertation
Abstract: This thesis explores the potential roles of neutrophils in the host response to tuberculosis. First, a review of literature identifies the capacity of neutrophils to phagocytose and kill mycobacteria as well as their ability to influence the development of acquired immune responses. The effect of HIV infection on neutrophil function is also explored. Novel assays are presented to assess phagocytosis of mycobacteria (flow cytometry) and restriction of mycobacterial metabolism (bio-luminescence) by human neutrophils. Subsequently neutrophil function is investigated in HIV-infected antiretroviral-naïve patients and control participants from the same community. Results show that HIV-infected patients’ neutrophils restrict mycobacterial metabolism less effectively and undergo more rapid cell death than those of controls. The HIV-infected cohort is followed over 6 months of antiretroviral therapy; during this time all studied functions improve towards the levels of HIV-uninfected participants. In vitro studies on other modifiers of neutrophil antimycobacterial function are inconsistent but there is some evidence for an effect of zinc chloride in arresting neutrophil cell death. Augmentation of human blood with live or dead neutrophils before infection with M.tuberculosis significantly impacts on both mycobacterial control and supernatant cytokine responses. In particular, necrotic neutrophils facilitate more growth of M.tuberculosis and reduce Th1 cytokine responses while increasing IL-10 release. Further investigation into the influence of neutrophils on the development of antimycobacterial immune responses utilises a mouse model to study BCG vaccination. Macrophage Inflammatory Protein-2 (MIP-2)-mediated recruitment of additional neutrophils to the vaccination site significantly increases release of interferon-γ from restimulated splenocytes versus controls three weeks after vaccination, while 1A8 anti-Ly6G antibody-mediated neutrophil depletion pre-vaccination significantly decreases downstream interferon-γ release versus controls. Finally the prognostic significance of neutrophilia in active tuberculosis is investigated. This analysis on 1236 patients finds that neutrophilia, itself predicted by pulmonary disease and white ethnicity, is an independent risk factor for fatality.
Content Version: Open Access
Issue Date: Sep-2013
Date Awarded: Mar-2014
URI: http://hdl.handle.net/10044/1/24828
DOI: https://doi.org/10.25560/24828
Supervisor: Martineau, Adrian
Wilkinson, Robert
Kampmann, Beate
Sponsor/Funder: Wellcome Trust (London, England)
Funder's Grant Number: WT087754
Department: Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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