title: TLR9-dependent induction of intestinal alpha-defensins by Toxoplasma gondii.
abstract: Alpha-defensins (or Cryptdins [Crps]) are a group of antimicrobial peptides produced as a component of Paneth cell (PC) secretory granules in the small intestine. In vivo ligation of TLR9 by synthetic agonists leads to PC degranulation, although the mechanism by which this occurs remains uncertain. In this report, we investigated TLR9-dependent mechanisms, triggered by the parasite Toxoplasma gondii, inducing Crp release in the lumen. Oral challenge of C57BL/6J (B6) wild-type (WT) mice with T. gondii induced TLR9 mRNA upregulation associated with a marked increase of type I IFN mRNA expression. PC secretory granules were released, and Crp-3/-5 mRNA expression by purified epithelial cells was increased following oral challenge of B6 WT mice. Although PCs failed to degranulate in infected B6 TLR9-/- mice, i.p. injection of mouse IFN-beta alone led to Crp-3/-5 mRNA upregulation in B6 WT and TLR9-/- mice. In addition, modulation of Crp mRNA expression in response to T. gondii infection was abrogated in B6 IFNAR-/- mice, which lack a functional type I IFN receptor. Taken together, these data demonstrate that T. gondii induces Crp-3/-5 production and release by PCs via a TLR9-dependent production of type I IFNs. Crps have a limited direct effect against T. gondii but may indirectly affect the early control of T. gondii invasiveness by promoting the initiation of a protective Th1 response against the parasite.
authors.affiliation: Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Foureau
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Mielcarz
authors.forename: Laurence C
authors.initials: LC
authors.lastname: Menard
authors.forename: Julie
authors.initials: J
authors.lastname: Schulthess
authors.forename: Catherine
authors.initials: C
authors.lastname: Werts
authors.forename: Virginie
authors.initials: V
authors.lastname: Vasseur
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Lloyd H
authors.initials: LH
authors.lastname: Kasper
authors.forename: Dominique
authors.initials: D
authors.lastname: Buzoni-Gatel
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000276:immunology; D005260:Female; D015870:Gene Expression; D018928:Immunity, Mucosal / Q000276:immunology; D015151:Immunoblotting; D007421:Intestine, Small / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019879:Paneth Cells / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051217:Toll-Like Receptor 9 / Q000276:immunology*; D014122:Toxoplasma; D014123:Toxoplasmosis / Q000276:immunology* / Q000378:metabolism; D014124:Toxoplasmosis, Animal / Q000276:immunology*; D023084:alpha-Defensins / Q000276:immunology / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D023084:alpha-Defensins