Despite medical progress, the recent outbreaks of viral zoonoses (e.g. MERS-CoV, Ebola virus disease) illustrate the constant threat represented by viruses in a world in motion and globalization. These epidemic events stress the need for an integrative research able to provide tools to anticipate and better understand the interconnections between human and animal health. The goal of this project is to realize a comprehensive mapping of virus-host interactions to understand global perturbations of cellular interactomic networks observed in the course of infection and connect them to pathogenic traits. This project embraces systems biology approaches at a multi-proteome scale to have a better understanding of virus-host interplay. The massively parallel interactomic pipeline that we recently developed is susceptible to link, for the first time, different phenotypes to wide genomic datasets. It will thus be instrumental to exhaustively compare interactomic properties associated with different pathogenic traits that will lead to the development of novel strategies to combat infectious disease in a more global environmental perspective. This systems biology approach aims to improve health through the prevention and anticipation of risks that originate at the interface between humans and their animal environment in a “One Health” perspective.