The UnSETTLE-NET project aims to bring together 4 international experts to submit a highly competitive proposal at the forthcoming ERC Synergy Grant 2019 (call will close late autumn 2018). The objective of the ERC Synergy Grants is to enable two to four Principal Investigators to work in synergy in order to jointly address ambitious research questions that could not be addressed by the individual Principal Investigators working alone. The UnSETTLE project will bring together partners with unique and complementary expertise to address a key problem in the field of chronic infections: how to train and boost innate immune cells to detect and eliminate stealth pathogens (viruses that establish latency, and intracellular bacteria that establish chronic infection)? Some pathogens have evolved multiple evasion strategies through co-existing evolution with their host to evade both innate and adaptive immunities, and then persist in their host by suppressing immune responses. These so-called stealth pathogens take refuge in a subcellular compartment and maintain undetectable replication levels to continue propagating in their host, all the while suppressing or thwarting host immunity. The aims of our synergy project are 1) to quantify and boost distress signals emitted by latently and chronically infected cells and 2) to understand the dysregulation of the immune system associated with latent and chronic infections. The UnSETTLE project will open up an entirely new and unconventional direction in the field of chronic infections, that will make a break with conventional approaches that seek to boost pathogen replication to trigger its detection, or to train acquired immunity to locate specific antigens. The key to the project is to boost sentinel innate immune cells to distinguish latently or chronically infected cells from self. The project already brings together 3 internationally-recognized Principal Investigators with unique and complementary expertise to address the ambitious project objectives: virology (HIV molecular virology, AIDS pathogenesis, endogenous retroelements, evolutionary virology), microbiology (intracellular bacteria, Coxiella, Brucella), innate immunity (innate signalling, intrinsic immunity, and innate immune cells), high-throughput screening of nuclear translocation events, endogenous peptides with antiviral activity. Our main goal is to include a fourth Principal Investigator expert in immunology and to prepare a solid and competitive version of the UnSETTLE proposal. The aim of the UnSETTLE-NET project will be (i) to identify the 4th PI, (ii) visit two key technical platforms for mass cytometry and animal facility, (iii) organise a workshop with all participants, and (iv) outsource the scientific editing of our proposal.