In addition to its potential to cause pandemics, seasonal infl uenza A virus infection causes over 200,000 hospitalizations and approximately 41,000 deaths in the United States annually, being the 7 th leading cause of mortality. We demonstrated that RAGE defi ciency resulted in a better outcome from pulmonary infl uenza A virus infection as indicated by a relative protection from infl uenza A virus-induced lethality in mice [40] . Th is was accompanied by improved viral clearance and enhanced cellular T cell response and activation of neutrophils, suggesting that endogenous RAGE impairs the cellular immunity against respiratory tract infection with infl uenza A virus. RAGE ligand, HMGB1, as well as sRAGE were upregulated in BAL fl uid during infl uenza A virus pneumonia. Hence, similar to pneumonia induced by the Gram-positive bacterium S. pneumoniae, RAGE is detrimental during pneumonia caused by infl uenza A virus. Th is is of particular interest, since it has been suggested that the greatest proportion of the mortality associated with infl uenza A virus infection is due to secondary bacterial pneumonia, with S. pneumoniae as the most frequent pathogen of the superinfection. Th erefore, RAGE is a potential treatment target in postinfl uenza pneumococcal pneumonia and further research is warranted to investigate this.