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

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. © 2015 favila et al.