title: Differential Impact of LPG-and PG-Deficient Leishmania major Mutants on the Immune Response of Human Dendritic Cells.
abstract: BACKGROUND
  Leishmania major infection induces robust interleukin-12 (IL12) production in human dendritic cells (hDC), ultimately resulting in Th1-mediated immunity and clinical resolution. The surface of Leishmania parasites is covered in a dense glycocalyx consisting of primarily lipophosphoglycan (LPG) and other phosphoglycan-containing molecules (PGs), making these glycoconjugates the likely pathogen-associated molecular patterns (PAMPS) responsible for IL12 induction.
  
  
  RESULTS
  Here we explored the role of parasite glycoconjugates on the hDC IL12 response by generating L. major Friedlin V1 mutants defective in LPG alone, (FV1 lpg1-), or generally deficient for all PGs, (FV1 lpg2-). Infection with metacyclic, infective stage, L. major or purified LPG induced high levels of IL12B subunit gene transcripts in hDCs, which was abrogated with FV1 lpg1- infections. In contrast, hDC infections with FV1 lpg2- displayed increased IL12B expression, suggesting other PG-related/LPG2 dependent molecules may act to dampen the immune response. Global transcriptional profiling comparing WT, FV1 lpg1-, FV1 lpg2- infections revealed that FV1 lpg1- mutants entered hDCs in a silent fashion as indicated by repression of gene expression. Transcription factor binding site analysis suggests that LPG recognition by hDCs induces IL-12 in a signaling cascade resulting in Nuclear Factor κ B (NFκB) and Interferon Regulatory Factor (IRF) mediated transcription.
  
  
  CONCLUSIONS
  These data suggest that L. major LPG is a major PAMP recognized by hDC to induce IL12-mediated protective immunity and that there is a complex interplay between PG-baring Leishmania surface glycoconjugates that result in modulation of host cellular IL12.
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Favila
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Geraci
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Asha
authors.initials: A
authors.lastname: Jayakumar
authors.affiliation: Molecular Microbiology Department, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Hickerson
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Janet
authors.initials: J
authors.lastname: Mostrom
authors.affiliation: Department of Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors.forename: Salvatore J
authors.initials: SJ
authors.lastname: Turco
authors.affiliation: Molecular Microbiology Department, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Beverley
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: McDowell
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology*; D020869:Gene Expression Profiling; D006001:Glycoconjugates / Q000276:immunology*; D006028:Glycosphingolipids / Q000172:deficiency / Q000276:immunology*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis*; D018320:Leishmania major / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism
chemical_list: D006001:Glycoconjugates; D006028:Glycosphingolipids; C500879:IL12B protein, human; D050835:Interferon Regulatory Factors; D053762:Interleukin-12 Subunit p40; D016328:NF-kappa B; C008290:lipophosphonoglycan