Despite their inherent limitations, biochemical approaches continue to provide relevant insights into host-pathogen interactions, such as the discovery of the dipeptidyl peptidase 4 (DPP4) as the receptor for the MERS-Co V just within a few months after the emergence of this virus .
In addition, more recently Kabanova and colleagues identified the cell surface receptor for the trimeric entry complex g Hg Lg O encoded by human cytomegalovirus (h CMV) .
Furthermore, given their fundamental functions and their accessibility to systemically delivered drugs, extracellular proteins are particularly suitable targets for therapeutic intervention.
In fact, despite these proteins being encoded by approximately one-fourth of the human genes, at least two-thirds of the existing drugs target either secreted or membrane-bound proteins .
Thus, the elucidation of the e PPI networks on a global scale has become crucial for the biomedical research.
However, in spite of their relevance and abundance, e PPIs are remarkably underrepresented in available large-scale datasets.
Characterizing host-pathogen e PPI 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.
Infectious diseases result in millions of deaths each year and therefore identifying new candidate targets for improved therapeutic development remains a pressing health concern.This discrepancy is due to the low sensitivity and limited compatibility of current high throughput technologies to detect extracellular interactions because of the unusual biochemical nature of the membrane proteins and the intractability of their binding partners [2–4].In particular, transmembrane domain-containing proteins are amphipathic, making it difficult to solubilize them in their native conformation, and often contain posttranslational modifications such as glycans and disulfide bonds, which are not properly added in common heterologous expression systems .Proteins exposed to the extracellular environment, both cell surface-expressed receptors and secreted proteins, are essential targets for initial invasion and play key roles in pathogen recognition and subsequent immunoregulatory processes.The identification of the host and pathogen extracellular molecules and their interaction networks is fundamental to understanding tissue tropism and pathogenesis and to inform the development of therapeutic strategies.SPR requires prior knowledge of the possible interacting partners and is therefore unsuitable for unbiased PPI discovery, whereas immunoprecipitation and MS approaches usually fail to detect weak interactions, which often characterize e PPIs, particularly those that take place on the cell surface.