It is unclear whether RAGE can also interact with ligands from pathogens. If so, this could be part of the explanation for our observation that RAGE involvement during Gram-positive and -negative pneumonia had such opposite eff ects on mortality. In addition, RAGEmediated eff ects on other fi rst-line defense mechanisms, such as chemotaxis, phagocytosis, killing (including respiratory burst), may depend on the pathogen and may contribute to the observed eff ects in Gram-positive and -negative pneumonia models. However, this remains speculative until investigations have been performed to analyze this interesting issue.