Molecular basis of invasive growth during mould infection of the lung

Abstract

Uju Joy Icheoku; BPharm, MRes PhD Medicine: Molecular basis of invasive growth during mould infection of the lung This study reports a previously unappreciated degree of mechanistic complexity occurring in three sequential phases and involving: contact-mediated perturbation; physical invasion of the epithelial stratum by A. fumigatus germlings, and hyphae and lytic activity of soluble effectors. This study provides evidence that airway epithelial cells respond in a distinctive and dynamic manner to A. fumigatus infection during the early (conidia), intermediate (germlings/immature hyphae) and late (mature hyphae/secreted effector) phases of infection via an immediate and sustained activation of the canonical NF-κB signaling circuit, an intermediate JNK and NF-κB activation in response to swollen conidia and early germlings and a late phase of MAPK JNK, p38 activation in response to hyphae and hyphae-derived secreted soluble effectors . In tandem with activation of host signalling pathways, changes in DNA binding activities of transcription factors occurred in three distinct pattern. Early and intermediate infection increased the transcriptional activity of p65 and p50 with an increase in RelB DNA binding activity during late infection. The events identified from this study as leading to epithelial cell decay appear to be mechanistically due to a combination of factors under the A. fumigatus master regulator PacC . Finally, by using siRNA targeted at NIK, it was found that the non-canonical NF-κB signalling via RelB was a protective epithelial cell response to A. fumigatus induced damage, likely mediated via inflammatory modulation and or upregulation of pro-survival genes.

Date of Award	1 Aug 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	David Denning (Supervisor) & Elaine Bignell (Supervisor)