title: Human dendritic cells exhibit a pronounced type I IFN signature following Leishmania major infection that is required for IL-12 induction.
abstract: Leishmania major-infected human dendritic cells (DCs) exhibit a marked induction of IL-12, ultimately promoting a robust Th1-mediated response associated with parasite killing and protective immunity. The host cell transcription machinery associated with the specific IL-12 induction observed during L. major infection remains to be thoroughly elucidated. In this study, we used Affymetrix GeneChip (Affymetrix) to globally assess the host cell genes and pathways associated with early L. major infection in human myeloid-derived DCs. Our data revealed 728 genes were significantly differentially expressed and molecular signaling pathway revealed that the type I IFN pathway was significantly enriched. Addition of a neutralizing type I IFN decoy receptor blocked the expression of IRF7 and IL-12p40 during DC infection, indicating the L. major-induced expression of IL-12p40 is dependent upon the type I IFN signaling pathway. In stark contrast, IL-12p40 expression is not elicited by L. donovani, the etiological agent of deadly visceral leishmaniasis. Therefore, we examined the gene expression profile for several IFN response genes in L. major versus L. donovani DC infections. Our data revealed that L. major, but not L. donovani, induces expression of IRF2, IRF7, and IFIT5, implicating the regulation of type I IFN-associated signaling pathways as mediating factors toward the production of IL-12.
authors.affiliation: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556; and.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Favila
authors.affiliation: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556; and.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Geraci
authors.affiliation: Genomics and Bioinformatics Core Facility, University of Notre Dame, Notre Dame, IN 46556.
authors.forename: Erliang
authors.initials: E
authors.lastname: Zeng
authors.affiliation: Genomics and Bioinformatics Core Facility, University of Notre Dame, Notre Dame, IN 46556.
authors.forename: Brent
authors.initials: B
authors.lastname: Harker
authors.affiliation: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556; and.
authors.forename: David
authors.initials: D
authors.lastname: Condon
authors.affiliation: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556; and.
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Cotton
authors.affiliation: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556; and.
authors.forename: Asha
authors.initials: A
authors.lastname: Jayakumar
authors.affiliation: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556; and.
authors.forename: Vinita
authors.initials: V
authors.lastname: Tripathi
authors.affiliation: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556; and mcdowell.11@nd.edu.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: McDowell
mesh_terms: D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D050836:Interferon Regulatory Factor-2 / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000276:immunology*; D007893:Leishmania donovani / Q000276:immunology; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000473:pathology; D007898:Leishmaniasis, Visceral / Q000276:immunology; D008297:Male; D009363:Neoplasm Proteins / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: C110985:IFIT5 protein, human; C500879:IL12B protein, human; C494229:IRF2 protein, human; C494234:IRF7 protein, human; D050836:Interferon Regulatory Factor-2; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D053762:Interleukin-12 Subunit p40; D009363:Neoplasm Proteins