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.

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.

• Authors: Michelle A Favila, Nicholas S Geraci, Asha Jayakumar, Suzanne Hickerson, Janet Mostrom, Salvatore J Turco, Stephen M Beverley, Mary Ann McDowell
• Journal: PLoS neglected tropical diseases (PLoS Negl Trop Dis) Vol. 9 Issue 12 Pg. e0004238 (Dec 2015) ISSN: 1935-2735 [Electronic] United States
• PMID: 26630499 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glycoconjugates
• Glycosphingolipids
• IL12B protein, human
• Interferon Regulatory Factors
• Interleukin-12 Subunit p40
• NF-kappa B
• lipophosphonoglycan

Topics

• Cells, Cultured
• Dendritic Cells (immunology, parasitology)
• Gene Expression Profiling
• Glycoconjugates (immunology)
• Glycosphingolipids (deficiency, immunology)
• Humans
• Interferon Regulatory Factors (metabolism)
• Interleukin-12 Subunit p40 (biosynthesis)
• Leishmania major (genetics, immunology)
• NF-kappa B (metabolism)