Host–Pathogen Interaction Activated Biosynthesis of Natural Products

The way immune cells attack pathogenic microorganisms might trigger pathogens to produce compounds that promote their survival. Based on this idea, we constructed a coculture system of pathogenic fungi and immune cells and isolated fumigatinolactone ( 1 ) as a new natural product by coculture of Aspergillus fumigatus IFM 60237 with RAW264 mouse macrophage-like cells. Fumigatinolactone ( 1 ) was produced via a nonenzymatic coupling reaction between fumigatin ( 4 ) and a new type of intermediate fumarylazlactone ( 5 ). An investigation of the interaction mechanism between the fungi and cells revealed that the survival interaction between pathogen and immune cells played key roles. Surprisingly, fungi showed a response to nitric oxide (NO), which was produced by macrophages, resulting in the production of 4 . In addition, an iron starvation condition triggered the production of 5 . Finally, 1 was obtained by these two mechanisms. Furthermore, compounds 1 – 4, particularly 4, showed inhibition of NO production from RAW264, which might be a defense action for macrophage by fungi. This is the first example of elucidation of interaction mechanisms between pathogen and immune cells for activation of silent genes to produce a new compound. These findings suggest that host–pathogen survival interaction may increase the production of secondary metabolites from fungi.