An analysis of the interaction of environmental
and clinical isolates of Aspergillus fumigatus
with vertebrate and invertebrate immune
PhD thesis, National University of Ireland Maynooth.
The ubiquitous saprophytic filamentous fungus Aspergillus fumigatus is a
significant pathogen among individuals undergoing chemotherapy, allogenic stem cell
transplantation and in patients with underlying pulmonary conditions or chronic
granulomatous disease patients. Central to the virulence of A. fumigatus is the
production of various secondary metabolites, proteolytic enzymes and iron sequestering
molecules which coupled to the rapidly growing nature of the fungus aid its persistence
in host tissue. Assessment of the virulence of A. fumigatus isolates has previously
centred on the use of murine models of aspergillosis however in recent years there has
been an increasing body of evidence suggesting the use of invertebrates as a viable
The work presented here sought to further develop the use of the Greater wax
moth Galleria mellonella as a novel in vivo tool to assess the pathogenicity of A.
fumigatus isolates as an alternative to murine models of infection. The data presented
here characterises the pathogenicity of clinical and environmental isolates of A.
fumigatus in G. mellonella. Results here suggest that mycotoxins are produced at
varying levels in the A. fumigatus isolates with culture filtrates demonstrating
immunosuppressive properties. In vivo mycotoxin production by A. fumigatus ATCC
26933 in G. mellonella was characterised and demonstrated that high quantities of
fumagillin were produced in the first 24 hours of invasive infection.
A study was performed to assess the effect of fumagillin on human neutrophils
and G. mellonella haemocytes. Fumagillin inhibited phagocytosis and pathogen directed
killing in both cell types and disrupted oxygen consumption through reduced
translocation of p47phox and its insect homologue. Exposure of neutrophils and
haemocytes to fumagillin also disrupted degranulation. Experimental evidence
presented here suggests that the inhibition to cellular processes is mediated by reduced
F-actin assembly. A proteomic analysis of G. mellonella haemolymph revealed
evidence to suggest that fumagillin mediates an oxidative stress in vivo and disrupted
the humoral immune response.
Recent literature has suggested that the immune system of G. mellonella could
be primed to subsequent infection. Larvae primed with specific sub-lethal inocula of
conidia demonstrated improved resistance to subsequent infection through increased
haemocyte density, protein activity, and synthesis of proteins involved in oxygen
transport, pathogen recognition and iron sequesterisation and increased expression of
This project has further developed the G. mellonella model as a model system to
investigate the pathogenicity of A. fumigatus isolates and the immunomodulatory effects
of fungal secondary metabolites due to an immune system which shows a high level of
conservation with the human innate immune system.
||interaction of environmental isolates; clinical isolates; Aspergillus fumigatus; vertebrate and invertebrate immune
||Science & Engineering > Biology
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