Abstract
The potential of the filamentous fungus Aspergillus fumigatus to act
as an opportunistic pathogen may be related to its ability to resist
the host defence network. Whilst phagocytic cells are clearly
important in host defences against invading microorganisms their
precise role in the killing of A. fumigatus remains undefined.
The purpose of this study was to examine the basic interactions
between phagocytic cells, from humans and rodents, with spores of
A. fumigatus. In particular the mechanisms whereby phagocytic cells
bind and kill spores of A. fumigatus, when compared with the
relatively non-pathogenic fungus Penicillium ochrochloron were
investigated.
In order to investigate why people with asthma may develop some
hypersensitivity reactions to A. fumigatus, in particular, rather
than to the many other fungi in the atmosphere, the possibility that
there may be a defect in the handling of the fungus by such patients
has been tested. A comparison of the fungal handling by phagocytes
from asthmatic patients, both sensitised and unsensitised to
A. fumigatus with phagocytes from non-asthmatic subjects has been
made.
The principal findings from this study are that spores of
A. fumigatus bind to the surface of the phagocytic cell yet are
relatively resistant to phagocytosis. The spores also fail to
trigger the phagocytic cells into releasing the potentially microbicidal reactive oxygen intermediates. These results may be
related to a further finding which is that spores of A. fumigatus
release a low molecular weight substance (diffusate) which interferes
with various aspects of phagocytic cell activation. Spore
diffusates were shown to inhibit the phagocytosis of radiolabelled
antibody-coated sheep red blood cells and to suppress the spontaneous
release of reactive oxygen intermediates by Corynebacterium parvum
stimulated mouse peritoneal exudate cells. In addition spores
diffusates inhibited the ability of phagocytic cells to spread on
glass and reduce the number of phagocytic cells migrating towards a
known chemoattractant.
Studies on spore killing showed that spores of A. fumigatus opsonised
in autologous serum were more resistant to killing by phagocytic
cells from humans and rodents than similarly opsonised spores of P.
ochrochloron. However, the ability of the phagocytic cells to kill
spores of A. fumigatus was substantially increased when the spores
were opsonised in sera which had been heat-treated for 30 minutes at
56°C. No increased killing was found with P. ochrochloron.
People with asthma sensitised to A. fumigatus showed significant
differences in their handling of A. fumigatus in vitro when compared
with the control group. Monocytes from these sensitised patients
killed significantly fewer spores of A. fumigatus (opsonised in auto¬
logous sera) whilst their polymorphonuclear leucocytes killed
significantly more. No such differences were found for P.
ochrochloron.
The work reported in this Thesis has given us a clearer understanding
of why Aspergillus fumigatus is an important cause of disease in man,
and how the defence mechanisms that it has evolved in its natural
environment the soil, enable it to act as a saprophyte or parasite in
the lungs of humans and animals. The results also suggest a
mechanism whereby heat-labile serum components may be an advantage to
the survival of the fungus, thus perhaps explaining why it may be a
particular problem in the airways of asthmatic patients.
