The overall objective of our Laboratory is to identify and characterize the evolutionary conserved stress and damage responses that operate in parenchymal tissues to establish disease tolerance to infection. The overall hypothesis tested in our laboratory is that a tight functional interplay between immune-driven mechanisms and these stress and damage responses operates to limit the pathologic outcome of infection. Understanding the mechanisms governing this interplay should be transformative to the current understanding of host-microbe interactions, with a direct impact on the treatment of infectious diseases. The body of work developed by our laboratory was sparked from the discovery, with the late Fritz H. Bach while at Harvard Medical School (1998-2004), that tissue damage control mechanisms operate in transplanted organs to prevent their own rejection. Namely, we found that transplanted cells, tissues or organs induce the expression of heme oxygenase-1 (HO-1), which exerts cytoprotective, anti-proliferative and immunomodulatory effects via the production of carbon monoxide (CO). Collectively, these salutary effects of CO were found to be essential to prevent graft rejection. Subsequently (2001-7) we discovered that CO can be used pharmacologically to exert potent therapeutic effects in a variety of immune-driven inflammatory conditions, preventing graft rejection, arteriosclerosis progression, ischemia/reperfusion injury, autoimmune neuroinflammation or the lethal outcome of major infectious diseases such as malaria. We went on to uncover that the therapeutic effects of CO are exerted via a rather simple mechanism that relies on its tight binding to the iron contained in the heme group of hemoproteins, preventing heme release and the generation of pathogenic labile heme (2007-12). We established that other pathophysiologic mechanisms preventing the deleterious effects of labile heme are also critical to confer protection against major infectious diseases, such as sepsis and malaria. This protective effect was ¿disentangled¿ from the host pathogen load, revealing that labile heme compromises, while heme catabolism promotes, the establishment of disease tolerance to sepsis and malaria. Based on these findings we determined that the protective effect exerted by sickle hemoglobin against malaria relies on the establishment of disease tolerance by CO. More recently (2012-19) our laboratory revealed that ferritin, a master regulator of iron metabolism that neutralizes the iron generated via heme catabolism by HO-1, is also essential to confer tissue damage control and to establish disease tolerance to sepsis and malaria. Unexpectedly this protective effect was found to rely on the control of glucose metabolism, which we found to be essential to the establishment of disease tolerance to sepsis (2015-19). While pursuing these studies on disease tolerance, our team engaged in a parallel line of research that led to the description (2014) of an unknown mechanism via which a glycan expressed by commensal bacteria from the gut microbiota, known as a-gal, induces an antibody response that confers resistance to malaria. This led (2019-21) to the description of another major biologic property of this glycan, whereby loss of a-gal expression during primate evolution enhanced antibody-effector function while shaping the gut microbiota towards an overall reduction of pathogenicity.