Entomopathogenic fungal-derived metabolites alter innate immunity and gut microbiota in the migratory locust

There are complex temporal and spatial interactions between insects and microbes. Previously, the function of microbial virulence factors has been identified and characterized. However, the roles of disease-related microbial-derived metabolites in regulating host innate immunity and the composition of microbial community are not explored. Entomopathogenic fungi (EPF) are important biological control agents because together with their insect hosts provide an idea model system to analyze the interplay between microbial-derived metabolites and host innate immune activity in relation to gut microbial community composition. Here, we report that the entomopathogenic fungus Metarhizium anisopliae produces a variety of metabolites during growth in the locust hemolymph, and their injection into locusts modifies the expression of a wide range of host genes, which participate in cellular and humoral innate immune processes. However, upon injection of the fungal metabolites, the antimicrobial peptide diptericin is specifically expressed in the locust cuticle and midgut, suppressing the microbiota inhabiting the latter tissue. Also, three commonly identified metabolites (nicotinamide, nicotinate, and choline) can activate the expression of immune-related genes in the locust midgut. Our results further reveal that injection of fungal metabolites into locusts substantially suppresses the locust gut microbial composition. Our findings expose a fungal pathogen infection strategy that involves the release of metabolites for activating insect immune effectors in the cuticle and midgut, which may comprise an important factor to restrain the number of gut-inhabiting bacteria. This study highlights the important functions of entomopathogenic fungal-derived metabolites in manipulating the insect host innate immunity and gut microbiota composition.