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The Journal of Immunology, 2004, 172: 1186-1190.
Copyright © 2004 by The American Association of Immunologists

The Dendritic Cell Receptor DC-SIGN Discriminates among Species and Life Cycle Forms of Leishmania1

María Colmenares*, Angel L. Corbí*, Salvatore J. Turco{dagger} and Luis Rivas2,*

* Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain; and {dagger} Department of Biochemistry, University of Kentucky Medical Center, Lexington, KY 40536


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Infection of dendritic cells by the human protozoal parasite Leishmania is part of its survival strategy. The dendritic cell receptors for Leishmania have not been established and might differ in their interactions among Leishmania species and infective stages. We present evidence that the surface C-type lectin DC-SIGN (CD 209) is a receptor for promastigote and amastigote infective stages from both visceral (Leishmania infantum) and New World cutaneous (Leishmania pifanoi) Leishmania species, but not for Leishmania major metacyclic promastigotes, an Old World species causing cutaneous leishmaniasis. Leishmania binding to DC-SIGN was found to be independent of lipophosphoglycan, the major glycoconjugate of the promastigote plasma membrane. Our findings emphasize the relevance of DC-SIGN in Leishmania-dendritic cell interactions, an essential link between innate and Leishmania-specific adaptive immune responses, and suggest that DC-SIGN might be a therapeutic target for both visceral and cutaneous leishmaniasis


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The protozoa Leishmania is an intracellular parasite that causes a wide range of pathologies in humans. In its digenetic life cycle, procyclic promastigotes arise when a sand fly vector takes an infective blood meal, attaches to the fly’s midgut epithelial cells, and detaches by differentiating into nonadhering metacyclic promastigotes. Upon inoculation into the vertebrate host, the metacyclic forms eventually enter macrophages and transform into intracellular amastigotes. Interestingly, the immune system of the host is "approached" differently by the various infective Leishmania species and forms (1). As an example, infection with Leishmania infantum usually results in a visceral disease, while infection by Leishmania pifanoi produces a cutaneous pathology. To attain a successful infection, Leishmania needs to subvert the host immune response from the very early steps after its inoculation by the sand fly into the host. In the natural course of infection, these events occur in the dermis, where dendritic cells (DCs)3 may act as a host cell for Leishmania, regardless of the pathological outcome of the infection (2). Therefore, it is likely that differences among Leishmania species in their interaction with phagocytic cells may partially account for the evolution of healing and nonhealing forms of leishmanial disease and their relative ability to activate a Th1 response (2, 3, 4).

Although Leishmania species might differentially subvert dendritic cell effector function (3, 5, 6, 7, 8), the receptors involved in the Leishmania-DC interaction remain largely undefined and could be critical for this process. In contrast, considerable efforts have been made to define macrophage receptors that mediate binding and subsequent uptake of Leishmania parasites. In this regard, two abundantly expressed promastigote surface molecules, lipophosphoglycan (LPG) and the metalloproteinase gp63, bind to complement receptor type 3 (CR3), mannose-fucose, and fibronectin receptors on macrophages (9). Recently, we have described DC-SIGN, a C-type surface lectin, as a high-avidity receptor for L. pifanoi amastigotes in human DCs (10), and subsequent studies reported interactions between Leishmania mexicana LPG and a DC-SIGN-Fc chimeric molecule (11). In this article, we report that DC-SIGN acts as a receptor for the two infective forms of the parasite, promastigote and amastigote, from Leishmania species causing either visceral or cutaneous leishmaniasis (1), and that these interactions are LPG independent.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents

The DC-SIGN-specific mAb (MR-1) has been described previously (12). Soluble mannan from Saccharomyces cerevisiae (M-7504; Sigma-Aldrich, St. Louis, MO) was prepared as a sterile 2-mg/ml stock solution in PBS. Leishmania donovani LPG was purified as described elsewhere (13). The identity and purity of LPG was confirmed by Western blots using the anti-LPG mAb CA7AE and by SDS electrophoresis followed by detection with Stains-all (data not shown) (14, 15).

Parasites

The L. pifanoi (MHOM/VE/60/Ltrod) and L. infantum (MCAN/ES/89/IPZ229/1/89) axenic amastigote lines were grown as described previously (16, 17) at 31 and 37°C, respectively. Leishmania major strain WR454 (18), L. pifanoi, and L. infantum promastigotes were grown at 27°C in RPMI 1640 medium containing 20% heat-inactivated FBS. The L. donovani strain (MHOM/SD/00/1S-2D) and its LPG-defective strain R2D2 were grown as described elsewhere (19). Logarithmic promastigotes were harvested after 3 days of an initial culture at 106cells/ml and metacyclic promastigotes were obtained from stationary phase cultures (7–8 days) by natural enrichment (L. pifanoi (20) and L. infantum (21)) or by negative selection with peanut agglutinin (22).

Mammalian cells

Immature monocyte-derived DCs (IMDDCs) were prepared from peripheral blood monocytes using IL-4 (1000 U/ml) and GM-CSF (1000 U/ml) (12). K562 cells transfected with DC-SIGN (K562-DC-SIGN) were cultured in complete medium: (RPMI 1640 plus 10% heat-inactivated FBS, 2 mM glutamine, and 10 µg/ml gentamicin) supplemented with G418 (300 µg/ml) (12).

Leishmania-DC-SIGN binding assay

Binding assays were performed as described previously (10). Briefly, mammalian cells (105 cells/assay) were incubated with CFSE-labeled parasites at a 5:1 parasites/cell ratio for 1 h at 35°C. Subsequently, mammalian cells with or without attached parasites were resolved by flow cytometry in two peaks of low (B) and high (C) fluorescence intensity, after gating on IMDDCs or K562 on a Coulter EPICS-CS (Fullerton, CA). For blocking assays, mammalian cells were washed with PBS/1 mM EDTA and preincubated for 10 min at 25°C with the corresponding blocking agent in complete medium before CFSE-labeled parasite addition. For displacement experiments, mammalian cells were first incubated with CFSE-labeled parasites and, after 2 min, a 4-fold excess of unlabeled L. pifanoi amastigotes was added. Parasite opsonization was achieved by a 20-min incubation of L. infantum axenic amastigotes with a pool of human serum from patients with visceral leishmaniasis from Spain (kindly provided by Dr. C. Cañavate, Centro Nacional de Microbiología, ISCIII, Madrid, Spain) and Ab opsonization was confirmed by fluorescence microscopy using anti-human Ig-rhodamine conjugate.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Promastigotes and amastigotes of L. infantum and L. pifanoi bind to dendritic cells (DCs) in a DC-SIGN dependent-manner

We have previously demonstrated that L. pifanoi amastigote binding to IMDDCs is mainly mediated by DC-SIGN (10). To identify other infective forms of the parasite recognized by DC-SIGN, we analyzed the capacity of IMDDCs to bind metacyclic-enriched stationary growth cultures of promastigotes and amastigotes of L. pifanoi and L. infantum. As shown in Fig. 1, both species were able to attach to DCs regardless of the developmental infectious stage (54.1 and 65.0% for amastigotes of L. pifanoi and L. infantum, respectively). In all cases, parasite binding was significantly reduced by preincubation with the anti-DC-SIGN blocking mAb MR-1 (64% reduction for both L. pifanoi forms and 55% reduction for L. infantum forms). The percentage of IMDDCs with bound parasites was always lower for promastigotes (37.4 and 30.6% for L. pifanoi and L. infantum, respectively), which suggests a reduced avidity of the flagellated form for DC-SIGN. These results indicate that DC-SIGN binds stationary phase metacyclic promastigotes and amastigotes from Leishmania species responsible for both cutaneous (L. pifanoi) and visceral (L. infantum) leishmaniasis.



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  		FIGURE 1. Leishmania binding to IMDDCs. IMDDCs were pretreated (10 min, 25°C) or not with the blocking anti-DC-SIGN mAb MR-1 (1.2 µg/ml) and incubated with CFSE-labeled parasites at a 1:5 ratio for 1 h at 35°C. Afterward, the percentage of cells with bound parasites was quantified by flow cytometry.

 
To gain further insight into the role of DC-SIGN in Leishmania-DC interactions, binding experiments were done with K562 transfected with DC-SIGN cells and extended to L. major, a species responsible for cutaneous pathology in the Old World. As for IMDDCs, the percentage of cells with bound metacyclic promastigotes (58.9 and 34.1% for L. pifanoi and L. infantum, respectively) were lower than for amastigotes from both species (75.2 and 54.8% for L. pifanoi and L. infantum, respectively; Table I). These results confirmed the differences in relative binding between promastigotes and amastigotes. Surprisingly, L. major metacyclic promastigotes bound poorly to K562 cells expressing DC-SIGN (17.2% cells with bound parasites) and the mAb against DC-SIGN reduced this value by 42.5% (Table I). When the parasite/cell ratio was increased to 20:1, 39.6% of the cells have L. major metacyclic promastigotes attached (68.7% inhibition by anti-DC-SIGN), while for the same conditions 84.0% had L. pifanoi amastigotes bound (83.6% inhibition by anti-DC-SIGN), confirming that L. major binds DC-SIGN albeit with lower affinity than other Leishmania species.


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  		Table I. Leishmania binding to K562 cells transfected with DC-SIGNa

 
Altogether, these results support the notion that the avidity of DC-SIGN varies for the various Leishmania species and infectious stages. The differences between the infective forms of L. pifanoi were further confirmed in displacement assays using an excess of unlabeled amastigotes: the addition of L. pifanoi amastigotes reduced binding of logarithmic (30%) and stationary phase promastigotes (32%), but scarcely displaced amastigotes previously bound to DC-SIGN (6.2% reduction).

Opsonization of amastigotes reduces binding to DCs

The attachment and uptake of Leishmania parasites by phagocytic cells is mediated by several receptors (9). Among them, the role of C3 and Fc receptors in the parasite infection has been extensively studied in macrophages, but not in DCs. The relative contribution of DC-SIGN, CR3, and FcR in L. infantum attachment to human DCs was analyzed in binding experiments using axenic amastigotes opsonized in vitro with serum from patients with L. infantum visceral leishmaniasis. As shown in Fig. 2, opsonized amastigotes exhibited a lower capacity to bind to IMDDCs than nonopsonized parasites (25.9 and 52.9%, respectively). Moreover, the attachment of opsonized parasites was reduced by only 19.7% in the presence of a blocking anti-DC-SIGN mAb, whereas the DC-SIGN-dependent binding to IMDDCs was 75.8% for nonopsonized amastigotes (Fig. 2). Therefore, parasite opsonization appears to interfere in the interaction of DC-SIGN with its Leishmania ligand(s).



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  		FIGURE 2. Ab-opsonized L. infantum amastigote binding to K562 cells expressing DC-SIGN. DC-SIGN-transfected K562 cells (K562-DC-SIGN) were left untreated (control) or pretreated with a mAb (MR-1) against DC-SIGN and then incubated at 35°C with CFSE-labeled parasites at a 1:5 cell:parasite ratio for 1 h, either nonopsonized or previously in vitro opsonized as described in Materials and Methods. The percentage of cells with bound parasites was quantified by flow cytometry.

 
Leishmania binding to DC-SIGN is not mediated by LPG

Leishmania LPG, a membrane glycolipid abundantly present on promastigotes but down-regulated in amastigotes (23, 24, 25), has been recently proposed as a Leishmania ligand for DC-SIGN (11). Since amastigotes bind to DC-SIGN, we sought to clarify the implication of LPG in Leishmania-DC-SIGN interactions. To this end, the attachment of promastigotes and amastigotes from L. pifanoi and L. infantum to K562-DC-SIGN cells was assayed in the presence of LPG. Since LPG content in L. donovani promastigotes has been estimated to be 0.15 µg/106 cells (26), the experiments were performed with an LPG amount (0.75 or 7.5 µg) which roughly corresponds to 10 and 100 times the number of CSFE-labeled parasites used in the assay. As shown in Fig. 3, preincubation with an excess of LPG had no influence on Leishmania binding to DC-SIGN, whereas the DC-SIGN Ab almost completely prevented the interaction.



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  		FIGURE 3. LPG effect on Leishmania binding to DC-SIGN. K562-DC-SIGN cells were pretreated with either a blocking mAb against DC-SIGN (MR-1), LPG, or left untreated and then incubated at 35°C with CFSE-labeled parasites at a 1:5 cell:parasite ratio for 1 h. The proportion of cells with bound parasites was quantified by flow cytometry.

 
To further confirm that LPG is not essential for promastigote binding to DC-SIGN, we evaluated the attachment to DG-SIGN-transfected K562 cells of L. donovani promastigotes from either wild-type or the LPG-deficient strain R2D2 (27). The percentage of K562-DC-SIGN cells with bound R2D2 parasites (76.5%) was significantly higher than with wild-type promastigotes (57.7%; Fig. 4). Furthermore, LPG had no effect on the binding of both types of promastigotes to DC-SIGN (Fig. 4). Collectively, these results confirm that promastigote binding to DC-SIGN is LPG independent and suggest that LPG may mask other DC-SIGN ligands on the promastigote membrane. In fact, this hindrance effect of LPG has been previously described for other membrane components (27, 28, 29). The actual ligand for DC-SIGN remains to be elucidated.



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  		FIGURE 4. Wild-type and LPG-mutant L. donovani stationary phase promastigotes binding to DC-SIGN. K562 (untransfected) or K562-DC-SIGN cells were pretreated or not with a mAb against DC-SIGN (MR-1) or LPG and then incubated at 35°C with CFSE-labeled wild-type or an LPG mutant strain (R2D2) L. donovani promastigotes at a 1:5 cell:parasite ratio for 1 h. The proportion of cells with bound parasites was quantified by flow cytometry.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
All infective stages and species of Leishmania dwell inside tissue macrophages and DCs (2). This accuracy in the choice of the host cell is mediated by specific interactions between parasite ligands and cell surface receptors. Both types of myeloid cells are endowed with a wide variety of receptors involved in pathogen recognition and engulfment. Macrophage recognition of Leishmania promastigotes and amastigotes is mainly mediated by CR3, FcRs, and mannose-specific lectins (9), whose expression has also been detected on DCs (30). In the present report, we demonstrate that DC-SIGN is a receptor for both infective stages of the parasite in human DCs.

Leishmania parasites cause a diversity of pathologies that depend on the species implicated. L. pifanoi is responsible for cutaneous leishmaniasis, characterized by a localized infection at the site of inoculation by the vector, while L. infantum causes visceral leishmaniasis due to parasite dissemination into internal organs. Since infection of immature dermal DCs is a common step shared by all Leishmania species, independent of their pathological outcome, our results underscore the relevance of the DC-SIGN-Leishmania interaction in both visceral (L. infantum) and cutaneous (L. pifanoi) leishmaniasis. However, although L. pifanoi (New World L. mexicana complex) and L. major (Old World Leishmania tropica complex) both cause cutaneous leishmaniasis, they significantly differ in their manipulation of the host immune system (1). In this regard, our results indicate that DC-SIGN is an important DC receptor for L. pifanoi but not for L. major, suggesting that their diverse host immune responses include differences in their initial interactions with these professional phagocytes.

Th lymphocytes can be divided into two distinct subsets of effector cells (Th1/Th2) based on their functional capabilities and the profile of cytokines they produce. Unlike L. major-infected mice, in which a polarized differentiation of Th1 and Th2 CD4+ T cells can be detected in resistant and susceptible mice, respectively, susceptible L. mexicana-infected mice do not uniformly show an enhanced Th2 response (31, 32). Because different factors influence DC priming, a process of crucial importance in Ag presentation to T lymphocytes, hence for the selective differentiation of either Th1/Th2 subset (33), it is tempting to speculate that differences observed in Leishmania-DC interaction via DC-SIGN may be involved in the different pathological outcome between these two species causing cutaneous leishmaniasis.

In the mammalian host, Leishmania infection is sustained and progresses by macrophage uptake of amastigotes. In this step, parasites are opsonized by serum components, such as Ab and complement factors, that may facilitate the interaction with macrophages that abundantly expresses receptors for Fc and C3, but do not express DC-SIGN (34). We have shown that amastigote opsonization reduced parasite interaction with DC-SIGN. These results emphasize the important role of DCs, an abundant cell type in the site where Leishmania inoculation takes place.

Since the membrane composition of the parasite changes throughout its life cycle (35, 36), the implication of DC-SIGN as receptor for the three main life cycle forms of the parasite (logarithmic and stationary promastigotes along with amastigotes) was also analyzed. Amastigotes showed the strongest interaction, whereas the avidity for DC-SIGN increased from noninfective to infective promastigotes (i.e., procyclic and metacyclic promastigotes, respectively). Hence, avidity of the different forms of the parasite is linked to their virulence inside the vertebrate host.

LPG is one of the most abundant glycoconjugates exposed on the cell surface of promastigotes, but very scarcely expressed on amastigotes (23, 24, 25), and plays a pleiotropic role through the life cycle of Leishmania (25, 37, 38, 39). This molecule is characterized by a high mannose content that might mediate promastigote interaction with host DCs via DC-SIGN (11). However, our results indicate that LPG is not an important Leishmania ligand for DC-SIGN as: 1) LPG is strongly down-regulated in amastigotes (23, 24, 25), which otherwise exhibit the highest DC-SIGN-binding ability; 2) LPG was unable to block Leishmania binding to DC-SIGN for all species and parasite developmental stages assayed; and 3) the LPG-defective L. donovani (R2D2) promastigotes bound to DC-SIGN-expressing cells. Furthermore, since LPG-defective promastigotes bound DC-SIGN with higher avidity than their wild-type counterparts (Fig. 3), LPG might in fact mask other membrane promastigote ligands with affinity for DC-SIGN.

Taken together, the present work demonstrates that DC-SIGN is a broad Leishmania receptor that exhibits variable affinity for the distinct infective forms and species of the parasite. Because DCs play a key role in the link between innate and adaptive immune responses, a deeper knowledge of the Leishmania-DC-SIGN interaction, as well as its subsequent immune consequences, may pave the way for the design of new therapeutic approaches against leishmaniasis.


   Footnotes
 
1 This work was supported in part by: Programa General de Grupos Estratégicos, BIO2003-09056CO2O2 and 08.3/0026/2000.1 (Comunidad Autónoma de Madrid, to L.R.), Grants SAF2002-04615-C02-01 (Ministerio de Educación y Ciencia), and 01/0063-01 (Fondo de Investigaciones Sanitarias, to A.L.C.), and National Institutes of Health Grant AI20941 (to S.T.). Centro de Investigaciones Biologicas is a recipient center for the Grant FIS CO3/14. M.C. was successively supported by a postdoctoral fellowship (Comunidad de Madrid) and an I3P contract from Consejo Superior de Investigaciones Cientificas. Back

2 Address correspondence and reprint requests to Dr. Luis Rivas, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, 28040 Madrid, Spain. E-mail address: luis_rivas{at}cib.csic.es Back

3 Abbreviations used in this paper: DC, dendritic cell; LPG, lipophosphoglycan; CR3, complement receptor type 3; IMDDC, immature monocyte-derived DC. Back

Received for publication July 24, 2003. Accepted for publication November 4, 2003.


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 Introduction
 Materials and Methods
 Results
 Discussion
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