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

Martinez-Martin, Nadia

Infectious diseases result in millions of deaths each year and therefore identifying new candidate targets for improved therapeutic development remains a pressing health concern. Pathogens have evolved a myriad of elegant and often complex strategies to invade the host and commandeer host immune responses to allow pathogen replication, spread, and persistence in the infected organism. Many cell surface molecules serve as entry receptors for initial host cell invasion, and concerted responses to the pathogenic challenge critically rely on cell functions mediated by receptors and secreted proteins. To allow host colonization, pathogens encode highly optimized protein modulators, in the form of secreted molecules or receptors expressed on the plasma membrane of the infected cells or the surface of the pathogen [11, 12] . Interactions between these proteins and extracellular host molecules form the foundation of communication between a host and a pathogen and play a vital role in the initiation and outcome of the infection [13, 14] . Characterizing host-pathogen ePPI networks is therefore of utmost importance to gain a better understanding of the infection process and to inform the development of novel or improved therapeutic strategies. Excellent studies on mapping hostpathogen interactions, particularly MS-based analysis of viral infection, have provided a wealth of insight into infectious diseases [15] [16] [17] [18] [19] . Nevertheless, similarly to host ePPIs, a significant hurdle to the elucidation of host-pathogen biology has been the shortage of datasets of extracellular interactions between host and pathogen proteins, partly due to the technical challenges that these proteins present. Moreover, an additional consideration when studying pathogen-encoded molecules is that these proteins often lack any recognizable homology with any host molecules, thus precluding prediction of their functions [11, 20] . Robust methodologies that permit unbiased characterization of ePPI in the absence of preexisting hypotheses are thus needed to elucidate the binding partners and molecular functions of most pathogenencoded molecules.