Francisella tularensis induces aberrant activation of pulmonary dendritic cells.
Francisella tularensis is an obligate intracellular bacterium that induces severe, acute, often fatal disease when acquired by the respiratory route. Despite the seriousness of this pathogen, very little is understood about its interaction with key target cells in the airways and lungs (alveolar macrophages and airway dendritic cells (DC)) after inhalation. In this study we demonstrate replication of F. tularensis in primary DC. Early after infection, F. tularensis induced increased expression of MHC class II and CD86 on DC, but not macrophages. This was followed by depletion of DC from the airways and lungs. Despite logarithmic replication and phenotypic maturation of DC, F. tularensis failed to induce production of several key proinflammatory cytokines, including TNF-alpha and IL-6, from DC. However, F. tularensis infection did elicit production of the potent immunosuppressive cytokine, TGF-beta. Furthermore, F. tularensis actively suppressed the ability of DC to secrete cytokines in response to specific TLR agonists. Finally, we also found that infection of DC and macrophages in the lungs appears to actually increase the severity of pulmonary infection with F. tularensis. For example, depletion of airway DC and alveolar macrophages before infection resulted in significantly prolonged survival times. Together, these data suggest F. tularensis is able to selectively uncouple Ag-presenting functions from proinflammatory cytokine secretion by critical APCs in the lungs, which may serve to create a relatively immunosuppressive environment favorable to replication and dissemination of the organism.
Bosio
Catharine M
CM
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, 80523, USA.
Dow
Steven W
SW
D000818:Animals; D017951:Antigen Presentation; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005260:Female; D005604:Francisella tularensis / Q000276:immunology / Q000472:pathogenicity*; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014406:Tularemia / Q000209:etiology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014774:Virulence
D016207:Cytokines; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha