Bacterial infections present a significant burden on healthcare and cause considerable morbidity and mortality. Emerging resistance against antimicrobial therapy complicates the treatment of these infections. In addition, antibiotic therapy may not be sufficient to prevent mortality in severely ill patients. It is therefore important to expand our knowledge on host defense mechanisms that may help in the development of new treatment strategies.Invasive infection is associated with the release of endogenous molecules, also known as alarmins or damage associated molecular patterns. Alarmins activate innate immune cells and act as endogenous danger signals to initiate and perpetuate inflammation. Uncontrolled release of alarmins however, may lead to an overwhelming inflammatory response and collateral tissue damage. In this thesis we focused on the role of two well-characterized alarmins, High-mobility Group Box 1 and Myeloid-related Protein 8/14 (or calprotectin) in severe infections.