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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.    Methodology/Principal Findings  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/Significance  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.

Differential Impact of LPG-and PG-Deficient Leishmania major Mutants on the Immune Response of Human Dendritic Cells