Antagonistic Fungal Enterotoxins Intersect At Multiple Levels With Host Innate Immune Defences

Author summary When a pathogenic fungus invades an animal, it can deploy a bewildering battery of molecular weapons: hundreds of proteins are injected directly into the host's cells to enable the fungus to grow and reproduce. We study a simple animal host, the nematode worm C. elegans and its natural enemy, the fungus Drechmeria coniospora, which has a large repertoire of uncharacterised potential "virulence factors". Here, we focused on just two of these fungal proteins, called enterotoxins. By producing each enterotoxin inside the epidermis of C. elegans, we were able to study their specific effect on the host, and in particular on the way in which they altered the host's immune defences. The two enterotoxins had strikingly different effects. One blocked the worms' ability to make protective antimicrobial peptides, while the other actually stimulated their production. By combining genetics, biochemistry and cell biology, we uncovered the basis of these antagonistic actions. Each of the enterotoxins turned out to act by altering different aspects of the worms' biology, despite both interfering with host protein translation. Our findings provide a first insight into the molecular and cellular basis of enterotoxins in this particular host-pathogen battle.Animals and plants need to defend themselves from pathogen attack. Their defences drive innovation in virulence mechanisms, leading to never-ending cycles of co-evolution in both hosts and pathogens. A full understanding of host immunity therefore requires examination of pathogen virulence strategies. Here, we take advantage of the well-studied innate immune system of Caenorhabditis elegans to dissect the action of two virulence factors from its natural fungal pathogen Drechmeria coniospora. We show that these two enterotoxins have strikingly different effects when expressed individually in the nematode epidermis. One is able to interfere with diverse aspects of host cell biology, altering vesicle trafficking and preventing the key STAT-like transcription factor STA-2 from activating defensive antimicrobial peptide gene expression. The second increases STA-2 levels in the nucleus, modifies the nucleolus, and, potentially as a consequence of a host surveillance mechanism, causes increased defence gene expression. Our results highlight the remarkably complex and potentially antagonistic mechanisms that come into play in the interaction between co-evolved hosts and pathogens.