Inhibition of neutrophil function following exposure to the Aspergillus fumigatus toxin, fumagillin
Author:
Fallon JP, Reeves EP, Kavanagh KA
Date: 14 April 2010
Abstract:
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 μg fumagillin ml!!-1!! for 25 minutes 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 (p40!!phox!!, p47!!phox!!, p67!!phox!!, rac2) and membrane (gp91!!phox!!) proteins. Exposure of neutrophils to fumagillin inhibits the formation of the NADPH oxidase complex by blocking the translocation of p47!!phox!! from the cytosolic to the membrane faction (p = 0.02). 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.
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