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* Department of Microbiology and Immunology and
Center for Vaccine Development, School of Medicine, University of Maryland, Baltimore, MD 21201; and
Laboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Allergenic, and Parasitic Products, Center for Biologics Evaluation and Research/Food and Drug Administration, Bethesda, MD 20852
The macrophage proinflammatory response to Francisella tularensis (Ft) live vaccine strain (LVS) was shown previously to be TLR2 dependent. The observation that intracellular Ft LVS colocalizes with TLR2 and MyD88 inside macrophages suggested that Ft LVS might signal from within the phagosome. Macrophages infected with LVS
iglC, a Ft LVS mutant that fails to escape from the phagosome, displayed greatly increased expression of a subset of TLR2-dependent, proinflammatory genes (e.g., Tnf) but decreased expression of others (e.g., Ifnb1). This latter subset was similarly mitigated in IFN-β–/– macrophages indicating that while Ft LVS-induced TLR2 signaling is necessary, cytosolic sensing of Ft to induce IFN-β is required for full induction of the macrophage proinflammatory response. Although LVSiglC greatly increased IL-1β mRNA in wild-type macrophages, protein secretion was not observed. IL-1β secretion was also diminished in Ft LVS-infected IFN-β–/– macrophages. rIFN-β failed to restore IL-1β secretion in LVSiglC-infected macrophages, suggesting that signals in addition to IFN-β are required for assembly of the inflammasome and activation of caspase-1. IFN-β plays a central role in controlling the macrophage bacterial burden: bacterial recovery was greater in IFN-β–/– than in wild-type macrophages and treatment of Ft LVS-infected macrophages with rIFN-β or 5,6-dimethylxanthenone-4-acetic acid, a potent IFN-β inducer, greatly decreased the intracellular Ft LVS burden. In toto, these observations support the hypothesis that the host inflammatory response to Ft LVS is complex and requires engagement of multiple signaling pathways downstream of TLR2 including production of IFN-β via an unknown cytosolic sensor and activation of the inflammasome.
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1 This work was supported in part by National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) AI-18797 (to S.N.V.), NIAID/NIH Mid-Atlantic Regional Center of Excellence Grant U54 AI-157168 (to A.S.C., E.B., and S.N.V.), and an NIAID/NIH Interagency Agreement (to K.L.E.).
2 Address correspondence and reprint requests to Dr. Stefanie N. Vogel, Department of Microbiology and Immunology, University of Maryland, 660 West Redwood Street, Room 324, Baltimore, MD 21201. E-mail address: svogel{at}som.umaryland.edu
3 Abbreviations used in this paper: Ft, Francisella tularensis; LVS, live vaccine strain; PRR, pattern-recognition receptor; PAMP, pathogen-associated molecular pattern; NLR, Nod-like receptor; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; WT, wild type; MHB, Mueller Hinton broth; MHA, Mueller Hinton agar; km, kanamycin; MOI, multiplicity of infection; IP-10, IFN-
-inducible protein 10; iNOS, inducible NO synthase.
This article has been cited by other articles:
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  K. A. Shirey, L. E. Cole, A. D. Keegan, and S. N. Vogel Francisella tularensis Live Vaccine Strain Induces Macrophage Alternative Activation as a Survival Mechanism J. Immunol., September 15, 2008; 181(6): 4159 - 4167. [Abstract] [Full Text] [PDF]
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