Scientific Publications by FDA Staff
J Immunol 2008 May 15;180(10):6885-91
Macrophage proinflammatory response to Francisella tularensis live vaccine strain requires coordination of multiple signaling pathways.
Cole LE, Santiago A, Barry E, Kang TJ, Shirey KA, Roberts ZJ, Elkins KL, Cross AS, Vogel SN
Vogel, SN, Univ Maryland, Sch Med, Dept Microbiol & Immunol, 660 W Redwood St,Room 324, Baltimore, MD 21201 USA Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA US FDA, Lab Mycobacterial Dis & Cellular Immunol, Div Bacterial Allergen & Parasit Prod, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA
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 LVSDeltaiglC, 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-beta(-/-) macrophages indicating that while Ft LVS-induced TLR2 signaling is necessary, cytosolic sensing of Ft to induce IFN-beta is required for full induction of the macrophage proinflammatory response. Although LVSDeltaiglC greatly increased IL-1beta mRNA in wild-type macrophages, protein secretion was not observed. IL-1beta secretion was also diminished in Ft LVS-infected IFN-beta(-/-) macrophages. rIFN-beta failed to restore IL-1beta secretion in LVSDeltaiglC-infected macrophages, suggesting that signals in addition to IFN-beta are required for assembly of the inflammasome and activation of caspase-1. IFN-beta plays a central role in controlling the macrophage bacterial burden: bacterial recovery was greater in IFN-beta(-/-) than in wild-type macrophages and treatment of Ft LVS-infected macrophages with rIFN-beta or 5,6-dimethylxanthenone-4-acetic acid, a potent IFN-beta 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-beta via an unknown cytosolic sensor and activation of the inflammasome.
|Category: Journal Article|
|PubMed ID: #18453609|
|Includes FDA Authors from Scientific Area(s): Biologics|
|Entry Created: 2011-10-04||Entry Last Modified: 2012-08-29|