Antigen-presenting cells (APCs) sense the microenvironment through several types of receptors that recognize pathogen-associated molecular patterns. In particular, C-type lectins receptors (CLRs), which are expressed by distinct subsets of dendritic cells (DCs) and macrophages (MØs), recognize and internalize specific carbohydrate antigens in a Ca2+-dependent manner. The targeting of these receptors is becoming an efficient strategy for parasite recognition. However, relatively little is known about how CLRs are involved in both pathogen recognition and the internalization of parasites. The role of CLRs in parasite infections is an area of considerable interest because this research will impact our understanding of the initiation of innate immune responses, which influences the outcome of specific immune responses. This paper attempts to summarize our understanding of the effects of parasites’ interactions with CLRs.
Lectins are a diverse group of mono- and multivalent proteins and glycoproteins of nonimmune origin that have selective affinity for a carbohydrate or a group of carbohydrates [
Summary of structural and functional properties of the lectin family receptors.
Group | Molecules structure | Family members | Ligands | Expression | Function | Reference |
---|---|---|---|---|---|---|
MR | Mannose, fucose, and |
MoPh, retina DCs, LCs, Fbls, and kidney | Pathogen recognition, antigen presentation, clearance of endogenous cytopathic molecules, and regulation of circulating hormones |
[ | ||
DC-SIGN | Mannose, ICAM-3 | Mesangial cells and CMs, MØ, and DCs | Pathogen recognition, antigen presentation, cell migration, and DC-T-cell interactions | |||
C-type | Type-I Type-II |
SIGNR-1 | Zymosan, mannans, and dextran | iDCs spleen MZ, lymph node, and pMØ | Clearance of blood borne antigens | |
Dentin1 |
|
DCs, neutrophils, and splenic T cells | Antifungal host defense, induction of TNF- | |||
Dectin2 |
|
MØ, DCs | Impairment of UV-induced tolerance | |||
mMGL1 | Gal | MØ, DCs | Internalization and antigen presentation, bind to CD45 to inhibit T cells | |||
mMGL2 | Sructure Lex | MØ, DCs | Anti-inflammatory response | |||
L-SIGN | Structure Le(a,b,y) | Liver sinusoidal endothelial cells | Antigen receptor | |||
| ||||||
P-type | Type-I |
CD-MPR |
Man-P-GlcNAc |
Lysosomal hydrolases | Transport Man-6-P containing acid hydrolases from the Golgi to endosomal/lysosomal compartments | [ |
| ||||||
F-type | AAA |
Fucose | Liver and kidney | Modulation of cell functions | [ | |
| ||||||
I-type | Type-I |
Siglec-1 |
Sialic acids with N- and O-linked glycosylations | Myeloid and lymphoid cells | Regulation of cell signaling from leucocytes | [ |
Siglec-3 |
Endocytic receptors |
Abbreviations: Tm: transmenbrane; MØ: macrophages; pMØ: peritoneal macrophages; Dcs: dendritic cells; iDCs: immature dendritic cells; MoPh: mononuclear phagocytes; Fbls: fibroblasts; LCs: langerhans cells; CMs: cardiomyocytes; Lex: Lewis x, a, b, and y structures; Gal: galactose; MR: mannose receptor; DC-SIGN: dendritic cell-specific ICAM-3-grabbing nonintegrin; SIGNR-1: SIGN-related 1; homologe DC-SIGN; mMGL: macrophage galactose type c-lectin; L-SIGN: liver/lymph node-specific ICAM-3 grabbing nonintegrin; CD-MPR: cation-dependent mannose 6-phosphate receptor; CI-MPR: cation-independent mannose 6-phosphate receptor; Man-6-P: mannose 6-phosphate; Man-P-GlcNAc: mannose 6-phisphate N-acetylglucosamine ester; AAA: Anguilla anguilla agglutinin; MsaFBP32: F-lectin present in striped bass (Morone saxatilis).
The CLRs constitute a superfamily of more than 1,000 proteins classified into 17 groups based on their phylogeny and domain organization. Most CLRs possess one or more carbohydrate recognition domains (CRDs) or C-type lectin-like domains (CTLDs). The CTLD is a conserved structural motif containing as two protein loops stabilized by two disulfide bridges at the base of each loop. The second loop is more flexible than the first and generally contains the ligand binding site. Most CLRs are membrane-associated receptors that are involved in antigen capture and presentation [
Structure of members of the C-type lectin (DC-SIGN, MR, Dectin1, and MGL). These receptors contain one or more carbohydrate-recognition domain (CRD), transmembrane domain, and cytoplasmic domain may contains tyrosine-based motif, triad of acidic amino acids, dileucine motif or immunoreceptor tyrosine-based inhibitory motif.
Based on the primary structure of their CRDs, their folding patterns, and their cation requirements, animal lectins can be classified into several families, including C-, F-, P-, and I-type lectins, galectin, pentraxin, and others (Table
The initial recognition of an invading pathogen by antigen-presenting cells APCs, such as macrophages (MØs) or dendritic cells (DCs), is crucial in determining the type of effector T cell that subsequently mediates an immune response [
Protein-carbohydrate interactions have important roles in two distinct aspects of the immune response. These interactions are involved both in pathogen recognition and in the cellular interactions that lead to pathogen neutralization [
In this review, we focus on integral membrane C-type lectins and their participation in the recognition of glycosylated parasite antigens. Despite the presence of a highly conserved domain, C-type lectins are functionally diverse and have been implicated in various processes, including cell adhesion, tissue integration and remodeling, platelet activation, complement activation, pathogen recognition, endocytosis, and phagocytosis [
The importance of C-type lectins is highlighted by the fact that several pathogens and tumor antigens take advantage of these receptors to escape intracellular degradation and to suppress the generation of an efficient immune response [
Several CLRs have been shown to contribute to the loading of endocytosed antigens on MHC class I and class II, thereby facilitating effective antigen-specific CD4+ and CD8+ T-cell responses [
The signaling through MGL is emerging recently, using DCs, has been demonstrated that MGL engagement to anti-MGL antibody or
Moreover, several studies suggest that CLRs may also modulate immune reactions through cross-talk with other receptors, especially TLRs. These results indicate that the outcome of an immune response is determined by the balance between triggering the two receptors families [
C-type lectins in parasitic infection.
Parasite | Receptor | Model |
|
Role | Reference |
---|---|---|---|---|---|
Protozoo | |||||
|
MR | BALB/c mice |
|
Uptake of mannose containing glycoconjugates | [ |
MR | Swiss albino mice |
|
Binding promastigotes | [ | |
MR | hmDMØ |
|
Attachment and ingestion promastigotes | [ | |
|
MR | Skin Fbls |
|
Uptake of mannosylated ligands | [ |
|
MR | BMDMs |
|
Recognizes mannose residues on the surface |
[ |
|
DC-SIGN | MDDCs |
|
Binding and internalization of amastigotes | [ |
|
DC-SIGN | IMDDCs |
|
Receptor for promastigotes and amastigote infective stages from both visceral and cutaneous leishmaniasis | [ |
|
MR | BALB/c mice |
|
Bind to Cz, increasing MR recycling which leads to arginase activity | [ |
Y and DM strains | MR | CM and MØ |
|
Adhesion and uptake of parasites | [ |
|
MGL | C57BL/6 mice |
|
Marker of aaMØ | [ |
Nematodes | |||||
|
MR | C57BL/6 MR-KO mice |
|
Recognized components E/S of parasites | [ |
Trematodes | |||||
|
MGL | Cell lines SW948, |
|
Recognized LDN and LDNF glycans | [ |
MGL | Human DCs |
|
Internalization of glycolipids of SEA | [ | |
DC-SIGN | Human DCs |
|
Adhesion to glycolipids of SEA | [ | |
DC-SIGN | Human DCs |
|
Recognize glycans of SEA | [ | |
L-SIGN | Cell line K562 |
|
Binds to structures Lea,b,y of SEA | [ | |
L-SING | Cell line K562 |
|
Binds and internalization of SEA | [ | |
SIGNR1 | BALB/c WT |
|
Recognize antigens of AWA and SEA | [ | |
Dectin-2 | C57BL/6 |
|
Binds SEA component | [ | |
MR | C57BL/6 WT or |
|
Internalization E/S material by schistosome larvae | [ | |
Cestodes |
MGL |
Human DCs |
|
TcES positively modulated the expression of MGL but negatively modulated DC-SIGN | [ |
Abbreviations: MR: mannose receptor; DC-SIGN: dendritic cell-specific ICAM-3 grabbing nonintegrin; SIGNR-1: SIGN-related 1; homologe DC-SIGN; mMGL: macrophage galactose type c-lectin; L-SIGN: liver/lymph node-specific ICAM-3 grabbing nonintegrin; Fbls: fibroblasts; BMDMs: bone marrow-derived macrophages; MDDCs: monocyte-derived dendritic cells; IMDDCs: immature monocyte-derived DCs; MØ: macrophages; CM: cardiomyocyte; Cz: cruzipaina; E/S: excretory/secretory; LDN: [GalNAc
A number of glycan moieties have been identified in most parasites that potentially bind various CLRs, which act as sensors of the innate immune system.
The trypanosomatid flagellates of the genus
These diseases cause significant morbidity and mortality in the 98 countries or territories, where they are endemic [
Previous studies both
A recent study showed that bone marrow-derived macrophages (BMDMs) infected with
The protozoan parasite
During the process of parasite internalization, the interaction between receptors expressed in the host cell and the parasite is important because these receptors are responsible for recognizing the major antigens of
Furthermore,
Another study found that
The protozoan parasite
Raes et al. report that mMGL1 and mMGL2 are induced in peritoneal MØs during
Several gastrointestinal nematodes have been reported to express ligands for MR on their surface.
Deschoolmeester et al. showed
Parasitic helminths express various carbohydrates containing glycoproteins on their surface and release glycan-rich E/S products that can potentially bind to various CLRs [
Binding assays revealed that MGL recognizes both terminal
In another study using binding assays and blocking antibodies reported that SEA of
Structural characterization of the glycolipids and the study of cellular binding revealed that DC-SIGN binds to the carbohydrate moieties of glycosphingolipids with
L-SIGN, a highly related homolog of DC-SIGN, can bind both schistosome egg antigens (SEAs) and glycosphingolipids and can mediate the internalization of SEAs. However, binding assays showed that L-SIGN recognizes a glycoprotein fraction different from that recognized by DC-SIGN. It has been demonstrated that L-SIGN does not bind to neoglycoconjugates carrying
An
All studies described above demonstrate that CLRs are essential to the recognition of different carbohydrates present on surface or in the excretory/secretory products of different parasites. This recognition can promote the uptake, internalization and processing of parasite antigens that can influence the immune response. However, little is known about the role of CLRs in the immune response to parasitic infections. Future studies are needed to understand the immune mechanisms underlying the interaction of parasite antigens with CLRs.
The authors thank M. S. Imelda Juarez for collecting the items required for this paper. National Council of Science and Technology (CONACYT)-Mexico supported PhD fellowship for A. Vázquez-Mendoza and this review is a requirement to obtain his degree in Biomedical Sciences, UNAM. The author’s research was supported by the Grants ICYT-DF-317-2010, UNAM-DGAPA-PAPIIT-IN212412, PAPCA-23-2012 and by the CONACYT-152224.