Dual-species proteomics and targeted intervention of animal-pathogen interactions

Abstract Complexity in host-pathogen interactions drives the need to develop sensitive and accurate biochemical techniques to elucidate host and pathogen protein expressions. Current proteomics techniques reveal information from the point of view of either the host or pathogen, but do not provide data on the corresponding partner. While dual-species transcriptomics is increasingly used to study RNA expression in host and pathogen, it remains challenging to simultaneously study host-pathogen proteomes that reflect the direct competition between host and pathogen. Using Caenorhabditis elegans - Pseudomonas aeruginosa infection model as proof-of-concept, we established a forward+reverse SILAC proteomics approach to simultaneously label and quantify newly-expressed proteins of host and pathogen without physical isolation. We observed iron competition between pathogen iron scavenger and host iron uptake protein, where P. aeruginosa upregulated pyoverdine synthesis protein (PvdA) and secreted pyoverdine, and C. elegans expressed ferritin (FTN-2) respectively. Using Galangin as a novel PvdA inhibitor identified by structure-based virtual-screening, targeted intervention of iron competition eliminated P. aeruginosa infection, and enabled animal survival. Our work provides insights into the mechanisms dictating host-pathogen interactions and offers novel strategies for anti-infective therapy.