About
Elaine Bignell – University of Manchester Faculty of Biology, Medecine and Health- UK
Research in my lab seeks a mechanistic understanding of fungal disease with a view to developing novel diagnostics and antifungal therapies. Our approach to studying the host-pathogen interaction transcends multiple experimental scales to address disease outcomes at the molecular, cellular, tissue, organ and whole animal levels. We are currently combining this suite of tools with a systems level approach to define pathogenicity in the major mould pathogen of humans, Aspergillus fumigatus. We are also developing novel pH signalling inhibitors as novel antifungal drugs, and studying secreted fungal proteins as novel vaccine candidates and diagnostic tools. In this talk I will present the data from a new genome-scale study addressing the A. fumigatus regulatory network driving stress adaptation and epithelial damage, and examine how this knowledge might lead to novel therapeutic interventions.
The human lung is continually exposed to spores of the airborne mould Aspergillus fumigatus. Inhaled spores are small enough to bypass mucociliary clearance mechanisms and reach the alveoli of the lung where interaction between host and pathogen cells can lead to fungal clearance, or to development of inflammatory or invasive fungal diseases. A. fumigatus is an accidental pathogen whose encounters with the host, although frequent, are circumstantial in nature. The capacity of this organism to cause human disease is unique amongst a cohort of several hundred related Aspergillus species and relative to closest sequenced relatives there are no large scale genetic events which signify recent evolution of pathogenicity. Clinical relevance of aspergillus species does not correlate with fungal growth rate, but is positively correlated with thermotolerance, and epithelial toxicity.
Fuelled by the results of extensive fungal transcriptome research we have developed, in recent years, a programme of research which seeks the mechanistic basis of lung damage during A. fumigatus infection. In order to find out why A. fumigatus is a pathogen and how infection is cytotoxic to human epithelia we have observed the interaction between host and pathogen in laboratory culture and in mouse disease, and measured epithelial decay, lytic death of host cells, host cell signalling and cytokine degradation in response to fungal challenge. This research has revealed multiple mechanisms involved in eliciting epithelial damage, occurring at different stages of the host-pathogen interaction and involving different fungal morphotypes.
Interestingly, the regulatory network driving stress adaptation in A. fumigatus is largely unlinked to that driving epithelial cytotoxicity. We propose that this reflects the saprotrophic origins of an environmental mould, which is sometimes a human pathogen.
