title: Mast cell TLR2 signaling is crucial for effective killing of Francisella tularensis.
abstract: TLR signaling is critical for early host defense against pathogens, but the contributions of mast cell TLR-mediated mechanisms and subsequent effector functions during pulmonary infection are largely unknown. We have previously demonstrated that mast cells, through the production of IL-4, effectively control Francisella tularensis replication. In this study, the highly human virulent strain of F. tularensis SCHU S4 and the live vaccine strain were used to investigate the contribution of mast cell/TLR regulation of Francisella. Mast cells required TLR2 for effective bacterial killing, regulation of the hydrolytic enzyme cathepsin L, and for coordination and trafficking of MHC class II and lysosomal-associated membrane protein 2. Infected TLR2(-/-) mast cells, in contrast to wild-type and TLR4(-/-) cells, lacked detectable IL-4 and displayed increased cell death with a 2-3 log increase of F. tularensis replication, but could be rescued with rIL-4 treatment. Importantly, MHC class II and lysosomal-associated membrane protein 2 localization with labeled F. tularensis in the lungs was greater in wild-type than in TLR2(-/-) mice. These results provide evidence for the important effector contribution of mast cells and TLR2-mediated signaling on early innate processes in the lung following pulmonary F. tularensis infection and provide additional insight into possible mechanisms by which intracellular pathogens modulate respiratory immune defenses.
authors.affiliation: South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, San Antonio, TX 78249, USA.
authors.forename: Annette R
authors.initials: AR
authors.lastname: Rodriguez
authors.forename: Jieh-Juen
authors.initials: JJ
authors.lastname: Yu
authors.forename: M Neal
authors.initials: MN
authors.lastname: Guentzel
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Navara
authors.forename: Karl E
authors.initials: KE
authors.lastname: Klose
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Forsthuber
authors.forename: James P
authors.initials: JP
authors.lastname: Chambers
authors.forename: Michael T
authors.initials: MT
authors.lastname: Berton
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Arulanandam
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D005604:Francisella tularensis / Q000254:growth & development* / Q000276:immunology*; D015847:Interleukin-4 / Q000172:deficiency; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency* / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014406:Tularemia / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control
chemical_list: C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D015847:Interleukin-4