Primary human bronchial epithelial cells during tuberculosis infection
File(s)
Author(s)
Reuschl, Ann-Kathrin Barbara
Type
Thesis
Abstract
Infection with Mycobacterium tuberculosis (Mtb) is acquired through the lungs after inhalation of aerosolised bacteria. Epidemiological studies have shown that infection can only be detected in 30-50% of individuals after exposure, suggesting that the immune system can mediate clearance of or resistance to infection. Early responses to infection in an Mtb-naïve host are thought to be championed by the innate immune cells in the lungs, such as alveolar macrophages. However, the majority of cells exposed to inhaled air are epithelial, which line the entirety of the respiratory tract. Their function is not well understood in tuberculosis and almost no studies of primary airway epithelial cells have been undertaken. To identify their contribution to the lung immune responses to Mtb infection, human primary bronchial epithelial cells were interrogated in vitro and ex vivo.
Primary bronchial epithelial cells (PBEC) were poor responders to low doses of Mtb in vitro and were markedly less susceptible to infection than macrophages. Large bacterial burden triggered cell death and IL8 release in an NADPH-oxidase dependent manner. Additionally, PBECs were potent responders to myeloid-mediated Mtb-driven inflammation. Myeloid-epithelial cross-talk was, in part, dependent on interleukin 1β and type I interferon-signalling and enhanced the antimicrobial host immune response and neutrophil influx in vitro. Through the assessment of the whole transcriptome and mediator profile of the human airway epithelial lining ex vivo, the in vitro inflammatory epithelial signature could be partially confirmed in patients with suspected pulmonary tuberculosis and Mtb-exposed individuals. Additionally, healthy recently infected Mtb-exposed individuals, showed signs of ongoing low-level immune activation in their nasal and bronchial epithelial mucosa. Taken together, this is the first comprehensive analysis of the human primary airway epithelial response to Mtb-infection and offers new insights into their emerging role in human tuberculosis.
Primary bronchial epithelial cells (PBEC) were poor responders to low doses of Mtb in vitro and were markedly less susceptible to infection than macrophages. Large bacterial burden triggered cell death and IL8 release in an NADPH-oxidase dependent manner. Additionally, PBECs were potent responders to myeloid-mediated Mtb-driven inflammation. Myeloid-epithelial cross-talk was, in part, dependent on interleukin 1β and type I interferon-signalling and enhanced the antimicrobial host immune response and neutrophil influx in vitro. Through the assessment of the whole transcriptome and mediator profile of the human airway epithelial lining ex vivo, the in vitro inflammatory epithelial signature could be partially confirmed in patients with suspected pulmonary tuberculosis and Mtb-exposed individuals. Additionally, healthy recently infected Mtb-exposed individuals, showed signs of ongoing low-level immune activation in their nasal and bronchial epithelial mucosa. Taken together, this is the first comprehensive analysis of the human primary airway epithelial response to Mtb-infection and offers new insights into their emerging role in human tuberculosis.
Version
Open Access
Date Issued
2016-05
Date Awarded
2016-09
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Lalvani, Ajit
Shattock, Robin
Sponsor
NHLI Foundation
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)