title: Role of Interleukin-12 in Protection against Pulmonary Infection with Methicillin-Resistant Staphylococcus aureus.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is a common pathogen associated with nosocomial pneumonia and is an increasing threat for severe community-acquired pneumonia. We have now investigated the role of interleukin-12 (IL-12) in protective immunity against lung infection with MRSA. The importance of IL-12 in protection from pulmonary MRSA infection was demonstrated by the finding that IL-12p35-deficient mice had a lower survival rate, higher bacterial burdens in lung and spleen, and decreased expression of interferon gamma (IFN-γ) in the lung compared to wild-type mice. These effects were completely reversed by replacement intranasal therapy with recombinant IL-12. Furthermore, exogenous IL-12 treatment of wild-type mice 24 h before pulmonary challenge with a lethal dose of MRSA significantly improved bacterial clearance and resulted in protection from death. The IL-12-treated mice had increased numbers of lung natural killer (NK) cells and neutrophils and higher levels of IFN-γ in the lung and serum compared to untreated mice. The major source of IL-12-driven IFN-γ expression in the lung was the NK cell, and the direct target of pulmonary IFN-γ was the lung macrophage, as shown using mice with a macrophage-specific defect in interferon gamma (IFN-γ) signaling (MIIG mice). Importantly, combination therapy with linezolid and IL-12 following intranasal MRSA infection significantly increased survival compared to that of mice receiving linezolid or IL-12 alone. These results indicate that IL-12-based immunotherapy may hold promise for treatment of MRSA pneumonia.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Quang-Tam
authors.initials: QT
authors.lastname: Nguyen
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Furuya
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Roberts
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA metzged@mail.amc.edu.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Metzger
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D000069349:Linezolid / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents; D053765:Interleukin-12 Subunit p35; D007371:Interferon-gamma; D000069349:Linezolid