Importance of Phosphoinositide 3-Kinase γ in the Host Defense against Pneumococcal Infection

Rationale: The pivotal role of phosphoinositide 3-kinase γ (PI3Kγ) in leukocyte recruitment makes it an attractive target for immunomodulatory therapy. However, interfering with PI3Kγ signaling might increase the risk of bacterial infections in humans.Objectives: We hypothesized that deletion or pharmacologic inhibition of PI3Kγ would impair the lung inflammatory response to the prototypic gram-positive bacterial pathogen Streptococcus pneumoniae.Methods: PI3Kγ knockout (KO) and wild-type mice were infected with S. pneumoniae or challenged with the pneumococcal virulence factor pneumolysin (PLY), and inflammatory leukocyte recruitment, bacterial pathogen elimination, and resolution/repair processes were determined.Measurements and Main Results: PI3Kγ KO mice challenged with PLY responded with lung edema and neutrophilic alveolitis, but showed a drop in alveolar macrophages and failed to recruit exudate macrophages when compared with wild-type mice. S. pneumoniae–infected PI3Kγ KO mice and wild-type mice p...