I started my career with a Medical Degree from the University of Lisbon (Portugal). My graduate work at the European Molecular Biology Laboratory (EMBL, Heidelberg, Germany) has contributed substantially to the study of innate immunity in insects by the identification of a family of complement-like factors in the major vector of human malaria, Anopheles gambiae (Cell. 2001 Mar 9;104(5):709-18) and novel regulators of in vivo phagocytosis showing that this process controls bacterial proliferation (Immunity. 2005 Jul;23(1):65-73). During my post-doctoral work at the Whitehead Institute and Mass. General Hospital (Boston, USA) and in the early years of my lab in Portugal, I made other important contributions, including to the work that identified the long-sought master regulator of CD45 alternative splicing (Science. 2008 Aug 1;321(5889):686-91), the first known modulators of exosome secretion (Nat Cell Biol. 2010 Jan;12(1):19-30) and to the dissection of antigen crosspresentation mechanisms (Immunity. 2009 Apr 17;30(4):544-55 and Cell. 2011 Dec 9;147(6):1355-68). Currently, the overarching goals of my laboratory are to understand how stress responses contribute to organismal homeostasis and how that knowledge can be harnessed for innovative therapeutic applications. In the past 10 years, we have identified the clinical group of anthracyclines as highly protective against sepsis by inducing a DNA Damage Response (Immunity. 2013 Nov 14;39(5):874-84). This work constitutes not only the first demonstration that the mechanisms of disease tolerance can be induced pharmacologically but it is also proof of principle that mild disruption of specific core cellular functions in vertebrates can trigger cytoprotective responses. We have been awarded an international patent for the application of these findings (European patent Nº 2753335, 11.01.2017). A German consortium of leading experts in sepsis clinical trials (where I am an investigator and advisor) has been awarded ~1.5M€ by the Federal German government to conduct a multicenter clinical trial (EPOS-1) in Germany to test the efficacy of epirubicin to treat sepsis patients. The first patient is expected to be enrolled in March 2022. We have identified a second perturbation (mitochondrial ETC inhibition) by the clinically approved group of ribosome-targeting antibiotics as protective in sepsis (and autoimmunity) by inducing disease tolerance, independently from their direct antibacterial activity. These findings were recently published (Immunity. 2021 Jan 12;54(1):53-67 and Immunity. 2021 Jan 12;54(1):68-83) and will serve as the bases for a second Phase III clinical trial in sepsis patients, currently under design and planning. In a separate line of work, we have demonstrated (Proc Natl Acad Sci U S A. 2020 Jun 2;117(22):12281-12287) that the GDF15 hormone correlates with mortality in sepsis patients, causally contributing to its severity, and just participated in the important discovery that this hormone responds to ER stress caused by chemical insults inducing a major HPA axis activation leading to dramatic increases in corticosterone production (Proc Natl Acad Sci U S A. 2021 Jul 6;118(27)). Our lab has been one of the leading groups exploring the idea that disease tolerance, a defense strategy that minimizes the negative impact of an infection on the host without targeting the pathogen directly, is an essential component of a successful immune response (Nat Rev Immunol. 2017 Feb;17(2):83-96). In 2016, we proposed a novel model for an integrated conceptual framework for the initiation of immune responses that depends on the surveillance of homeostasis perturbations to trigger resistance and disease tolerance responses (FEBS J. 2016 Jul;283(13):2448-57). My unconventional hypotheses and proven contributions have been recognized by a Consolidator Grant from the European Research Council (ERC) in 2015.