Technologies for Proteome-Wide Discovery of Extracellular Host-Pathogen Interactions

Martinez-Martin, Nadia

Extracellular PPIs between host-and pathogen-encoded molecules orchestrate an enormous diversity of cellular processes, from initial colonization of the target cell to subsequent immune responses. The elucidation of these extracellular interactomes is integral to understanding the molecular basis of infection and will guide the development of more efficient or innovative therapeutics. Improvements in proteomics and genomics approaches have exponentially increased our understanding of how pathogens, particularly viruses, modulate the intracellular environment of the cell. Concomitantly, we and several other groups have implemented technologies directed towards elucidation of extracellular interactomes [2, 9, 10, 28, 32, 155] , which have begun to reveal fundamental principles of extracellular Journal of Immunology Research 13 host-pathogen interactions. Notably, recent studies have revealed extensive ePPI networks in model organisms such as Drosophila or zebrafish [2, 9] . These undertakings predict that, similarly to intracellular PPIs, extracellular networks will be highly connected, with secreted and plasma membrane-expressed proteins having multiple binding partners. However, as discussed in this review, the identification of the host factors and in many cases the pathogen molecules that mediate ePPIs have largely defied molecular identification, in part due to the technical difficulties inherent to the study of these extracellular proteins. The elucidation of the global principles dictating extracellular pathogen-host PPIs will require a coordinated effort to bring together the areas of biology and technology. There are now considerable opportunities for integrating multiple disciplines for ePPI discovery, particularly proteomics and CRISPR/Cas9 genome-wide screens, which should be powered by commensurable advances in bioinformatics and computation for big data analysis. The integration of orthogonal datasets coming from multiple "omics" approaches will be advantageous for elucidating the intricacies of the host-pathogen extracellular interactomes and will further enhance the rational identification of novel therapeutic targets by uncovering fundamental principles of biology.