Stage-specific innate immune recognition of Aspergillus fumigatus and modulation by echinocandin drugs.
The pulmonary innate immune system clears inhaled Aspergillus fumigatus conidia (spores) from terminal airways. Failure to control conidial germination in immune compromised hosts can result in hyphal tissue invasion and fatal disease. Insight into the molecular recognition of A. fumigatus by host leukocytes indicates that the innate immune system exploits obligate changes in fungal cell wall composition that occur at the first stage of germination, conidial swelling. Germinating spores activate at least two host signal transduction pathways. Surface exposure of fungal beta-(1,3) glucan, a polysaccharide constituent of the fungal cell wall, triggers dectin-1 signaling by host phagocytes. Spore germination leads to the induction of Toll-like receptor (TLR) signaling as well. This stage-specific recognition mechanism focuses host antifungal responses on cells with the potential for tissue invasion and may serve to limit potentially deleterious effects of inflammation in space and time. Fungal beta-(1,3) glucan not only activates host innate immune responses but also represents the target of echinocandin drugs. The activity of echinocandin drugs has largely been understood on the basis of pharmacologic growth inhibition of yeast and moulds, resulting in lysis of yeast cells and stunting of dysmorphic hyphae. The recognition that fungal beta-1,3 glucan activates dectin-1 signaling suggests that echinocandin drugs may exert immune modulatory effects by altering innate immune responses to drug-treated fungal cells, a view supported by recent data from studies on C. albicans, A. fumigatus, and non-Aspergillus moulds.
Hohl
Tobias M
TM
Infectious Disease Service, Memorial Sloan-Kettering Cancer Center, New York, USA.
D001228:Aspergillosis / Q000188:drug therapy* / Q000276:immunology* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology*; D054714:Echinocandins / Q000627:therapeutic use*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007155:Immunologic Factors / Q000627:therapeutic use*; D037181:Lectins, C-Type / Q000378:metabolism; D047071:beta-Glucans / Q000378:metabolism; D000099181:Dectin-1
D054714:Echinocandins; D007155:Immunologic Factors; D037181:Lectins, C-Type; D047071:beta-Glucans; C546929:CLEC7A protein, human; D000099181:Dectin-1; C033363:beta-1,3-glucan