Cathepsin G and neutrophil elastase play critical and non-redundant roles in lung protective immunity against S. pneumoniae in mice

Abstract

Neutrophil serine proteases cathepsin G (CtsG), neutrophil elastase (NE) and proteinase-3 (PR3) have recently been shown to contribute to killing of Streptococcus pneumoniae in vitro. However, their relevance in lung protective immunity against different serotypes of S. pneumoniae in vivo has not been determined so far. We here infected CtsG-deficient mice and CtsG/NE deficient mice with two serotypes of S. pneumoniae exhibiting different virulence profiles. Despite similar neutrophil recruitment, both CtsG KO mice and, even more accentuated, CtsG/NE KO mice infected with serotype 19 S. pneumoniae demonstrated a severely impaired bacterial clearance, which was accompanied by lack of CtsG and NE but not PR-3 proteolytic activity in recruited neutrophils, as determined by FRET analysis. Moreover, both CtsG and CtsG/NE KO mice but not wild-type mice responded with increased lung permeability to infection with S. pneumoniae, resulting in severe respiratory distress and progressive mortality. On the other hand, CtsG/NE deficient mice demonstrated a similar mortality after infection with highly invasive serotype 2 S. pneumoniae as compared to wild-type mice. This is the first study to show a differenzial contribution of neutral serine proteases CtsG and NE to regulate lung protective immunity against focal pneumonia-inducing serotype 19 but not sepsis-inducing serotype 2 S. pneumoniae in mice. These data may be important for the development of novel intervention strategies to improve lung protective immune mechanisms in critically ill patients suffering from severe pneumococcal pneumonia.