Importance of phosphoinositide 3-kinase γ in the host defense against pneumococcal infection

Rationale: The pivotal role of phosphoinositide 3-kinase gamma (PI3K gamma) in leukocyte recruitment makes it an attractive target for immunomodulatory therapy. However, interfering with PI3K gamma signaling might increase the risk of bacterial infections in humans. Objectives: We hypothesized that deletion or pharmacologic inhibition of PI3K gamma would impair the lung inflammatory response to the prototypic gram-positive bacterial pathogen Streptococcus pneumoniae. Methods: PI3K gamma 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: PI3K gamma 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 PI3K gamma KID mice and wild-type mice pretreated with the pharmacologic inhibitor AS-605240 recruited similar numbers of neutrophils but substantially fewer exudate macrophages into their lungs than control animals. They also displayed a significantly reduced lung pneumococcal clearance and showed an impaired resolution/repair process, leading to progressive pneumococcal pneumonia. Conclusions: PI3K gamma gene deletion or pharmacologic inhibition of PI3K gamma leads to perturbations of critical innate immune responses of the lung to challenge with S. pneumoniae. These data are of clinical relevance for the treatment of chronic inflammatory diseases where pharmacologic inhibition of PI3K gamma signaling to attenuate effector cell recruitment may have implications for innate immune surveillance of remote organ systems.