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Infection and Immunity, August 2009, p. 3272-3283, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.01447-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Leishmania major Phosphoglycans Influence the Host Early Immune Response by Modulating Dendritic Cell Functions{triangledown}

Dong Liu,1 Chahnaz Kebaier,2 Nazzy Pakpour,2 Althea A. Capul,3 Stephen M. Beverley,3 Phillip Scott,2 and Jude E. Uzonna1*

Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada,1 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Pennsylvania,2 Department of Molecular Microbiology, Washington University, St. Louis, Missouri 631103

Received 25 November 2008/ Returned for modification 15 January 2009/ Accepted 26 May 2009

The precise role of Leishmania glycoconjugate molecules including phosphoglycans (PGs) and lipophosphoglycan (LPG) on host cellular responses is still poorly defined. Here, we investigated the interaction of Leishmania major LPG2 null mutant (lpg2–), which lacks both PGs and LPG, with dendritic cells (DCs) and the subsequent early immune response in infected mice. Surprisingly, the absence of phosphoglycans did not influence expression pattern of major histocompatibility complex class II (MHC II), CD40, CD80, and CD86 on DCs in vitro and in vivo. However, lpg2– L. major induced significantly higher production of interleukin-12p40 (IL-12p40) by infected bone marrow-derived DCs (BMDCs) than wild-type (WT) parasites in vitro. Furthermore, the production of IL-12p40 by draining lymph node cells from lpg2– mutant-infected mice was higher than those from WT L. major-infected mice. In model antigen presentation experiments, DCs from lpg2– mutant-infected mice induced more gamma interferon (IFN-{gamma}) and IL-2 production by Leishmania-specific T cells than those from WT-infected mice. Lymphocytes isolated from mice infected for 3 days with lpg2– parasites produce similar levels of IFN-{gamma}, but significantly less IL-4 and IL-10 than WT controls. Decreased IL-4 production was also seen in another general PG-deficient mutant lacking the Golgi UDP-galactose transporters (lpg5A– lpg5B–), but not with the lpg1– mutant lacking only LPG, thereby implicating PGs generally in the reduction of IL-4 production. Thus, Leishmania PGs influence host early immune response by modulating DC functions in a way that inhibits antigen presentation and promotes early IL-4 response, and their absence may impact the balance between Th1 and Th2 responses.

* Corresponding author. Mailing address: Parasite Vaccines Development Laboratory, Department of Immunology, University of Manitoba, 730 William Avenue, Winnipeg, Manitoba R3E 0W3, Canada. Phone: 204-977-5659. Fax: 204-789-3921. E-mail: uzonna{at}cc.umanitoba.ca

{triangledown} Published ahead of print on 1 June 2009.

Editor: J. F. Urban, Jr.

Infection and Immunity, August 2009, p. 3272-3283, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.01447-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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