Putative virulence factors of Aspergillus fumigatus

Watanabe A., Toyotome T., Sato A., Ochiai E., Nagayoshi M., Kamei K.

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The number of patients with invasive fungal infection (TFT) has dramatically increased in last 3 decades. Aspergillus fumigatus, the most common species recovered from aspergillosis, is one of the most important pathogen of IFT. Although our antifungal armamentarium has been expanded recently, mortality from aspergillosis is still high. Early initiation of therapy seems to improve the survival rate. Study of virulence factors of the fungus may lead to the development of novel diagnostic tools or advancements in therapy. A. fumigatus is known to produce various immunomodulatory substances. Although many Candidates of the fungal virulence factors have been studied, non of these substances has been confirmed as being tied to the pathogenesis of the fungus. We previously examined the influence of fungal secondary metabolites such as gliotoxin and other low molecular substances on the virulence. Gliotoxin possesses potent immunosuppressive activity on various mammalian cells, but was known to be produced very slowly in a conventional environment. Recently it was learned that, in well-aerated condition, gliotoxin is produced much faster than previously believed. The primary target of infection by A. fumigatus is lung, which is well-aerated organ with high oxygen content, and this fact is believed to contribute to gliotoxin production in vivo. Recently, gliotoxin was found to be detectable in the sera of aspergillosis mice and of aspergillosis patients. Moreover, the δ GliP mutant strains (GliP: the gene encodes a nonribosomal peptide synthase that catalyzes the first step in gliotoxin biosynthesis) showed partially attenuated virulence in immunosuppressive mice. These findings indicate that gliotoxin is, at least partly, showed to contribute the pathogenesis of aspergillosis. Some other virulence factors are expected to playa synergistic role with gliotoxin, and we showed that A. fumigatus produces potent cytotoxic substances other than gliotoxin. Studies are in progress to clarify the significance of the unknown substances.

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17th International Society for Human and Animal Mycology
    • ISHAM 17th (2009)