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Immunostimulation with Macrophage-Activating Lipopeptide-2 Increased Survival in Murine Pneumonia

¹ Department of Internal Medicine, Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany; ² Institute of Functional and Applied Anatomy, and ³ Department of Cardiology and Angiology, Medical School of Hannover, Hannover, Germany; and ⁴ Department of Immunology, Max-Planck-Institute for Infection Biology, Berlin, Germany

Correspondence and requests for reprints should be addressed to Martin Witzenrath, Department of Internal Medicine, Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. E-mail: martin.witzenrath{at}charite.de

Community-acquired pneumonia (CAP) is associated with high morbidity and mortality, and Streptococcus pneumoniae is the most prevalent causal pathogen identified in CAP. Impaired pulmonary host defense increases susceptibility to pneumococcal pneumonia. S. pneumoniae may up-regulate Toll-like receptor (TLR)-2 expression and activate TLR-2, contributing to pneumococcus-induced immune responses. In the current study, the course of severe murine pneumococcal pneumonia after pulmonary TLR-2–mediated immunostimulation with synthetic macrophage-activating lipopeptide-2 (MALP-2) was examined. Intratracheal MALP-2 application evoked enhanced proinflammatory cytokine and chemokine release, resulting in recruitment of polymorphonuclear neutrophils (PMN), macrophages, and lymphocytes into the alveolar space in WT, but not in TLR-2–deficient mice. In murine lungs as well as in human alveolar epithelial cells (A549), MALP-2 increased TLR-2 expression at both mRNA and protein level. Blood leukocyte numbers and populations remained unchanged. MALP-2 application 24 hours before intranasal pneumococcal infection resulted in increased levels of CCL5 associated with augmented leukocyte recruitment, and decreased levels of anti-inflammatory IL-10 in bronchoalveolar lavage fluid. Clinically, MALP-2–treated as compared with untreated mice showed increased survival, reduced hypothermia, and increased body weight. MALP-2 also reduced bacteremia and improved bacterial clearance in lung parenchyma, as examined by immunohistochemistry. In conclusion, pulmonary immunostimulation with MALP-2 before infection with S. pneumoniae improved local host defense and increased survival in murine pneumococcal pneumonia.

Key Words: pneumococcal pneumonia • immunostimulation • MALP-2 • TLR-2

CLINICAL RELEVANCE The risk for pneumonia may be increased in specific pathologic situations. Preventive host defense stimulation may provide a future clinical perspective for high-risk patients to improve pneumonia outcome.