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

¹ Department of Pulmonary Medicine, Laboratory for Experimental Lung Research, Medical School Hannover, Hannover, Germany; ² Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany; ³ Serono Pharmaceutical Research Institute, Serono International, Geneva, Switzerland; ⁴ School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia; ⁵ Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama; ⁶ Department of Internal Medicine, University of Regensburg, Regensburg, Germany; ⁷ Department of Pathology, Justus-Liebig-University, Giessen, Germany; ⁸ Department of Genetics, University of Torino, Turin, Italy; and ⁹ Department of Biochemistry, Justus-Liebig-University, Giessen, Germany

Correspondence and requests for reprints should be addressed to Ulrich A. Maus, Ph.D., Laboratory for Experimental Lung Research, Hannover School of Medicine, Hannover 30625, Germany. E-mail: maus.ulrich{at}mh-hannover.de

Rationale: The pivotal role of phosphoinositide 3-kinase (PI3K) in leukocyte recruitment makes it an attractive target for immunomodulatory therapy. However, interfering with PI3K signaling might increase the risk of bacterial infections in humans.

Objectives: We hypothesized that deletion or pharmacologic inhibition of PI3K would impair the lung inflammatory response to the prototypic gram-positive bacterial pathogen Streptococcus pneumoniae.

Methods: PI3K 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 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 KO 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 gene deletion or pharmacologic inhibition of PI3K 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 signaling to attenuate effector cell recruitment may have implications for innate immune surveillance of remote organ systems.

Key Words: lung • infection • macrophage

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject No data are currently available addressing the role of phosphoinositide 3-kinase (PI3K) deletion or inhibition on the lung host defense to Streptococcus pneumoniae infection. What This Study Adds to the Field Blockade of PI3K activity suppresses effector cell recruitment, reduces lung pneumococcal clearance, and may have implications for the immune surveillance of distant organ systems.

 

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