Aspergillus CI was the first described complement inhibitor produced by a fungus which causes human disease. The inhibitor might enhance pathogenicity of Aspergillus in the human host by impairing opsonization and diminishing generation of the chemoattractant for polymorphonuclear neutrophils and monocytes, C5a. Now in press is the demonstration that polar fungal lipids which comigrate during thin layer chromatography with phosphatidylserine/phosphatidylinositol and phosphatidylethanolamine contribute to the inhibitory activity of CI. In addition, the observation has recently been made that properdin, a component of the alternative pathway C3 convertase, is able to completely obliterate CI's activity. During the funding period, inhibitory lipid(s) from preparative TLC will be identified by GC mass spectroscopy, NMR, and gas-liquid chromatography. Binding between (125)I-properdin and polar Aspergillus lipids will be assessed using a combination of TLC and autoradiography. In vivo production of relevant CI lipid(s) will be examined using labeled anti-CI IgG F(ab')2 in a mouse model of invasive aspergillosis , and in available human tissues. Sera of infected mice and of patients with various forms of aspergillosis will be checked for the presence of CI lipid(s) by ELISA. A CI- mutant will be selected following ultraviolet irradiation of CI+ wild-type A. fumigatus. This mutant will allow an assessment of the in vivo significance of CI by comparing LD50s for inhaled inocula of both isolates in the mouse model.
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