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Infect. Immun. doi:10.1128/IAI.01528-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The Leishmania pifanoi proteoglycolipid complex P8 induces macrophage cytokine production through TLR4

Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut; Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain

^* To whom correspondence should be addressed. Email: diane.mcmahon-pratt{at}yale.edu.

	Abstract

The P8 proteoglycolipid complex (P8 PGLC) is a glyconjugate expressed by L. mexicana complex parasites. We previously have shown that vaccination with the P8 PGLC provides protection against cutaneous leishmaniasis in susceptible BALB/c mice. However, the biological importance of this complex remains unknown. Herein we show that P8 PGLC localizes to the surface of L. pifanoi amastigotes and upon exposure to macrophages, P8 PGLC binds and induces inflammatory cytokine and chemokine mRNAs such as TNF and RANTES early after stimulation. Our studies indicate that cytokine and chemokine induction is dependent upon TLR4. Interestingly, key inflammatory cytokines and chemokines (such as IL-6,MIP-1, IFN) that can be induced through TLR4 activation, were not induced or only slightly upregulated by P8 PGLC. Activation by P8 PGLC does not occur in the presence of TLR4 alone and requires both CD14 and MD-2 for signaling; this requirement may be responsible for the limited TLR4 response. This is the first characterization of a TLR4 ligand for Leishmania. In vitro experiments indicate that L. pifanoi amastigotes induce lower levels of cytokines in macrophages in the absence of TLR4; however, notably higher IL-10/IFN ratios were found for TLR4 deficient mice than BALB/c mice. Further, increased levels of parasites persist in BALB/c mice deficient in TLR4. Taken together, these results suggest that TLR4 recognition of Leishmania pifanoi amastigotes is important for the control of infection and that this is mediated, in part, through the P8 PGLC.