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.