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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Safari, Maryam
Languages: English
Types: Doctoral thesis
Subjects: UOW2
Aspergillus fumigatus is a filamentous fungus that colonises the lungs of immunosuppressed patients and causes aspergillosis. Despite recent medical advances, infectious diseases caused by opportunistic pathogens such as A. fumigatus are still one of the main causes of morbidity and mortality among immunosuppressed patients.\ud Gliotoxin is a mycotoxin and a secondary metabolite of A. fumigatus. This toxin possesses immusuppresive activity affecting cells of immune system. This research shows that human adenocarcinoma alveolar epithelial cells (A549) are highly susceptible to gliotoxin- induced cell death. Wild type strains of A. fumigatus cause death in these cells whereas mutant strains (gliotoxin deficient) do not. Gliotoxin induced cell death is mostly via apoptosis programmed cell death rather than necrosis. Long term incubation of A549 cells with gliotoxin-deficient strain causes morphology changes (swelling/partial damage) in these cells. This research proposes that gliotoxin induced death/ inflammation of pneumocytes by programmed apoptosis may contribute to the pathogenesis of aspergillosis, particularly invasive aspergillosis. In addition, other produced metabolites (e.g. proteases or other toxins) also contribute (to a lesser extent) to the lung tissue damage in the absence of gliotoxin.\ud One of the key risk factors in developing aspergillosis is corticosteroid therapy. This is due to the effect of glucocorticoids on suppressing body’s defence mechanism. As hydrocortisone is present during Aspergillus infection, understanding the ability of the fungus to perceive this host-factor enhances the understanding of A. fumigatus interaction with the host within the host environment. Previous reports have shown that physiological and pharmacological concentrations of hydrocortisone enhance the growth-rate of A. fumigatus in vitro. The present work demonstrates the effect of hydrocortisone on cultures of A. fumigatus at both morphological and molecular levels. Hydrocortisone causes an early onset of sporulation and seems to play a role in regulation of haemostasis and stress response in this fungus. Expression of stress-related proteins (hsp70, catalase), proteases (e.g. serine protease, metalloprotease), and carbohydrate metabolism-related proteins increased after supplementation of A..fumigatus cultures with hydrocortisone. Stimulation studies investigating the effect of secondary metabolites of A. fumigatus on A549 cells with and without pre-treatment of the fungal cultures with hydrocortisone indicated subtle increases in the number of dead cells after hydrocortisone pre-treatment. This study shows further that hydrocortisone treatment of the lung alveolar cells enhances the binding of A..fumigatus spores to these cells. The obtained data suggests that presence of hydrocortisone may contribute to the survival of this pathogen within the host environment.\ud This study provides additional knowledge at molecular and cellular level where complications exist as a result of infection by A. fumigatus fungus and during treatment with glucocorticoids.

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