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Protective Role for Macrophages in Respiratory Francisella tularensis Infection
Donald J Steiner1, Yoichi Furuya1, Michael B Jordan2,3
1Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
Abstract:
Francisella tularensis causes lethal pneumonia following infection of the lungs by targeting macrophages for intracellular replication; however, macrophages stimulated with interferon gamma (IFN-γ) can resist infection in vitro We therefore hypothesized that the protective effect of IFN-γ against F. tularensisin vivo requires macrophages receptive to stimulation. We found that the lethality of pulmonary F. tularensis LVS infection was exacerbated under conditions of alveolar macrophage depletion and in mice with a macrophage-specific defect in IFN-γ signaling (termed mice with macrophages insensitive to IFN-γ [MIIG mice]). We previously found that treatment with exogenous interleukin 12 (IL-12) protects against F. tularensis infection; this protection was lost in MIIG mice. MIIG mice also exhibited reduced neutrophil recruitment to the lungs following infection. Systemic neutrophil depletion was found to render wild-type mice highly sensitive to respiratory F. tularensis infection, and depletion beginning at 3 days postinfection led to more pronounced sensitivity than depletion beginning prior to infection. Furthermore, IL-12-mediated protection required NADPH oxidase activity. These results indicate that lung macrophages serve a critical protective role in respiratory F. tularensis LVS infection. Macrophages require IFN-γ signaling to mediate protection, which ultimately results in recruitment of neutrophils to further aid in survival from infection.
Insights
Interferon gamma (IFN-γ) signaling in macrophages is crucial for resisting Francisella tularensis lung infections. Impaired IFN-γ signaling or macrophage depletion worsens pneumonia, highlighting their protective role and the need for neutrophil recruitment.
Area of Science:
- Immunology
- Infectious Diseases
- Pulmonary Medicine
Background:
- Francisella tularensis causes lethal pneumonia by infecting lung macrophages.
- Macrophages stimulated with interferon gamma (IFN-γ) show resistance to F. tularensis in vitro.
- The role of IFN-γ-responsive macrophages in vivo against F. tularensis is not fully understood.
Purpose of the Study:
- To investigate the hypothesis that IFN-γ-mediated protection against F. tularensis in vivo requires receptive macrophages.
- To elucidate the role of macrophages and IFN-γ signaling in pulmonary F. tularensis infection.
Main Methods:
- Utilized mice with macrophage-specific defects in IFN-γ signaling (MIIG mice).
- Investigated the effects of alveolar macrophage depletion and systemic neutrophil depletion.
- Assessed the role of interleukin 12 (IL-12) and NADPH oxidase activity in protection.
Main Results:
- Pulmonary F. tularensis LVS infection lethality was exacerbated in depleted macrophages and MIIG mice.
- IL-12-mediated protection was lost in MIIG mice, which also showed reduced neutrophil recruitment.
- Neutrophil depletion increased sensitivity to F. tularensis, and IL-12 protection depended on NADPH oxidase activity.
Conclusions:
- Lung macrophages play a critical protective role in respiratory F. tularensis LVS infection.
- IFN-γ signaling in macrophages is essential for mediating protection.
- This macrophage-mediated protection involves the subsequent recruitment of neutrophils for enhanced survival.