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

Authors

Michelle A. Favila, University of Notre Dame
Nicholas S. Geraci, University of Notre Dame
Asha Jayakumar, University of Notre Dame
Suzanne Hickerson, Washington University
Janet Mostrom, University of Notre Dame
Salvatore J. Turco, University of KentuckyFollow
Stephen M. Beverley, Washington University
Mary Ann McDowell, University of Notre Dame

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.

Document Type

Article

Publication Date

12-2-2015

Notes/Citation Information

Published in PLOS Neglected Tropical Diseases, v. 9, no. 12, article e0004238, p. 1-28.

© 2015 Favila et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Digital Object Identifier (DOI)

http://dx.doi.org/10.1371/journal.pntd.0004238

Funding Information

This work was supported by National Institutes of of Allergy and Infectious Diseases grants R01AI056242 (MAM) and NIH RO1AI31078 (SMB, SJT). MAF was a fellow of the Chemistry-Biochemistry-Biology Interface (CBBI) Program at the University of Notre Dame, supported by training grant T32GM075762 from the National Institute of General Medical Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Repository Citation

Favila, Michelle A.; Geraci, Nicholas S.; Jayakumar, Asha; Hickerson, Suzanne; Mostrom, Janet; Turco, Salvatore J.; Beverley, Stephen M.; and McDowell, Mary Ann, "Differential Impact of LPG-and PG-Deficient Leishmania major Mutants on the Immune Response of Human Dendritic Cells" (2015). Molecular and Cellular Biochemistry Faculty Publications. 83.
https://uknowledge.uky.edu/biochem_facpub/83