The filamentous fungus Aspergillus fumigatus produces a variety of enzymes and toxins that may
facilitate fungal colonization of tissue and evasion of the host immune response. One such toxin,
fumagillin, was investigated for its ability to inhibit the action of neutrophils, which are a central
component of the innate immune response to microbial infection. Neutrophils exposed to 2 mg
fumagillin ml”1 for 25 min showed a significantly reduced ability to kill yeast cells (P,0.02), to
phagocytose conidia of A. fumigatus (P,0.023) and to consume oxygen (P,0.032). The ability of
neutrophils to generate superoxide is dependent upon the action of a functional NADPH oxidase
complex which is composed of cytosolic (p40phox, p47phox, p67phox, Rac2) and membrane
(gp91phox) proteins. Exposure of neutrophils to fumagillin inhibited the formation of the NADPH
oxidase complex by blocking the translocation of p47phox from the cytosolic to the membrane
fraction (P50.02). In addition to the production of superoxide, neutrophils also undergo
degranulation, which leads to the release of proteolytic enzymes that contribute to the
microbicidal activity of the cell. Fumagillin-treated neutrophils showed reduced degranulation as
evidenced by lower myeloperoxidase activity (P,0.019). Fumagillin-treated cells demonstrated
reduced levels of F-actin, thus indicating that retarding the formation of F-actin may contribute to
the inhibition of the structural rearrangements required in the activated neutrophil. This work
indicates that fumagillin may contribute to reducing the local immune response by altering the
activity of neutrophils and thus facilitate the continued persistence and growth of A. fumigatus in
the host
