ABSTRACT

Dextran, the a-1,6-linked glucose polymer widely used in biology and medicine, promises new applications. Linear dextran applied as a blood plasma substitute demonstrates a high rate of biocompatibility. Dextran is present in foods, drugs, and vaccines and in most cases is applied as a biologically inert substance. In this review we analyze dextran's cellular uptake principles, receptor specificity and, therefore, its ability to interfere with pathogen–lectin interactions: a promising basis for new antimicrobial strategies.

Dextran-binding receptors in humans include the DC-SIGN (dendritic cell–specific intercellular adhesion molecule 3-grabbing nonintegrin) family receptors: DC-SIGN (CD209) and L-SIGN (the liver and lymphatic endothelium homologue of DC-SIGN), the mannose receptor (CD206), and langerin. These receptors take part in the uptake of pathogens by dendritic cells and macrophages and may also participate in the modulation of immune responses, mostly shown to be beneficial for pathogens per se rather than host(s). It is logical to predict that owing to receptor-specific interactions, dextran or its derivatives can interfere with these immune responses and improve infection outcome. Recent data support this hypothesis.

We consider dextran a promising molecule for the development of lectin–glycan interaction-blocking molecules (such as DC-SIGN inhibitors) that could be applied in the treatment of diseases including tuberculosis, influenza, hepatitis B and C, human immunodeficiency virus infection and AIDS, etc. Dextran derivatives indeed change the pathology of infections dependent on DC-SIGN and mannose receptors. Complete knowledge of specific dextran–lectin interactions may also be important for development of future dextran applications in biological research and medicine.

INTRODUCTION

Dextran is a glucose polymer with a prevalence of a-1,6-linked units and is usually linear (Figure 1). Dextran is a component of vaccines, cosmetics, foods, and drugs. In addition, it is one of the most widely used blood plasma substitutes. Dextran-based molecules (e.g., fluorescent markers) play an important role in biomedical research. Dextran’s properties provide various advantages including adjustable molecular size and viscosity; chemical stability and simplicity of modification; ability to target certain cell types and cellular compartments; relative biological inertness. We are the first to highlight that dextran shares specific receptors with many pathogens. According to recent studies, this commonality lends dextran the capability to have antimicrobial properties.

 

Figure 1. Types of a-1,6 glucosides. A) Isomaltose (two glucose molecules with a-1-6 linkage). B) Isomaltotriose. C) Linear dextrans. D) Branched dextrans (schematically). e) a-Cyclodextran.

 

Detailed publications on dextran have been written for medical professionals (1), biochemists, pharmacists, and biotechnology specialists (2-4). However complex work is lacking on dextran’s fate at the cellular level. Topics that must be addressed include types of cells that take up dextran, its receptors and interference with infectious processes. Dextran’s biological inertness is implied in many of its applications: it is often used as a nonfunctional biocompatible core molecule conjugated with the functional groups (fluorescent dyes, drugs, charged or hydrophobic groups). However, dextran-binding receptors that belong to the family of C-type lectins, namely mannose receptors (MRs), dendritic cell (DCs)-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing nonintegrin (DC-SIGN), L-SIGN (the liver and lymphatic endothelium homologue of DC-SIGN), and langerin, are involved in the immune recognition and uptake of numerous pathogens such as human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (5).

In HIV infection, DC-SIGN binding to gp120 is considered to be a critical phase in the entry of HIV-1. DC-SIGN antibodies (6), short hairpin RNAs suppressing DC-SIGN gene expression (7) and carbohydrate-binding agents (8) have been touted to inhibit DC-SIGN binding of the HIV-1 envelope complex to DCs and to prevent viral transmission. We have successfully reported inhibition of DC-SIGN and gp120 interaction by screening known inhibitors and carbohydrate-binding agents by devising a novel target-specific high-throughput screening assay (9). We also found that DC-SIGN plays a critical role in infection through human T-lymphotropic virus-1 (HTLV-1) envelope glycoprotein binding and DCs to T-cell transmission (10, 11). Overall, in these studies blocking of DC-SIGN was shown to prevent the binding and transmission of human retroviruses, indicating the suitability of the dextran-binding receptor, DC-SIGN, as an antiretroviral drug target.

Hepatitis B and C viruses, influenza, and various fungi and protozoa are also associated with uptake via C-type lectins, specifically the dextran-binding receptors. These receptors take part in uptake of the pathogens by DCs and macrophages and also participate in the modulation of intracellular signaling and immune responses. In many cases such modulation is beneficial for pathogens (5). Pathogens’ interactions with MR and DC-SIGN suppress T-helper type 1 (Th1) immune responses which are crucial for defense against intracellular pathogens (12). Dextran unlike the surface molecules of pathogens is an inert ligand of mannose receptor and DC-SIGN that does not induce production of cytokines suppressing Th1 response (13). Therefore we suggest that dextran owing to receptor-specific interactions might interfere with an unfavorable immune response and give preference to Th1-inducing pathogen-Toll-like receptor signaling. Moreover dextran could prevent binding and uptake of many viruses via its receptors. To indicate all areas that show potential promise for future applications of dextran as a receptor-specific molecule, we point towards its existing medical and research applications (Figure 2). At last, the paradigm of “biologically inert” dextran can be revised, as this molecule affects the infectious process, most likely owing to the lectin-glycan interaction mechanism.

 

 

Figure 2. Dextran applications.Many dextran applications, especially medical and biological, can benefit from taking into account the receptor specificity of dextran. FITC = fluorescein isothiocyanate.

 

DEXTRAN-BINDING RECEPTORS

 

Mannose receptor: Macrophage mannose receptor (MR, CD206) is a carbohydrate receptor from the superfamily of C-type lectins (14, 15). It is expressed in liver and spleen endothelial cells, in macrophages, and to a lesser extent, in DCs (16). Its main role in mammals is the metabolism of glycoproteins taking place predominantly in the liver (17, 18). MR is also responsible for recognition and phagocytosis of pathogens and allergens, promotion of Th2 immune responses, and antigen presentation (13, 15). Moreover, the uptake of dextran via MR has been proven before (19). A list of all the cell types expressing MR that are able to take up dextran is depicted in Table 1.

 

DC-SIGN family receptors: DC-SIGN is a receptor expressed by monocyte-derived dendritic cells (MDDCs) in vitro and in vivo (20), and by dermal/intestinal/genital mucosae dendritic cells in vivo (21, 22). It is also expressed on activated B cells (23), wound-healing (IL-4-activated) and alternative (M-CSF-activated) monocyte-derived macrophages, tumor-associated macrophages (24), certain tissue macrophages such as in the alveoli and lung (25). This receptor is responsible for the interactions of DCs with T cells (26), vascular and lymphatic endothelial cells (27), including umbilical vein (28) as well as blood-brain barrier endothelial cells (D. Sagar and P. Jain, unpublished results), and also pathogens (12) and allergens (29) (providing their uptake and/or intracellular signaling). Signaling via DC-SIGN limits Th1 responses influencing Toll-like receptor–dependent pathways through Raf1 kinase (30). DC-SIGN is involved in the reception of pathogens of bacterial, viral, fungal, and protozoan origin, as well as those from multicellular parasites. This group of pathogens recognized by DC-SIGN includes mycobacteria, Helicobacter pylori, the worm Schistosoma mansoni, HIV-1, Ebola virus, cytomegalovirus, and Leishmania. Antigenic interaction with DC-SIGN shifts the T helper type1/T helper type 2 balance, causing a chronic infection (12). DC-SIGN receptor in humans has one homologue, L-SIGN (liver/lymph node-specific intercellular adhesion molecule (ICAM)-3-grabbing nonintegrin), expressed mainly in the liver (31); there are eight orthologues in mice, including SIGN-R1 to SIGN-R8 (32). Uptake of dextran via DC-SIGN family receptors (DFRs) DC-SIGN, L-SIGN, SIGN-R1, and SIGN-R3 is proven (33-36). Cells that express these receptors are able to take up dextran (Table 1).

 

Langerin and LSECtin: Langerin is a receptor specific to Langerhans cells of the skin (37) and uptake of dextran via langerin is proven (36). Human and mouse liver and lymph node sinusoidal endothelial C-type lectin receptors (LSECtins) are expressed mainly by liver endothelial sinusoidal cells and lymph endothelium (38). Although these receptors are not proven to bind dextran, it seems probable because of specificity similar to other dextran-binding receptors. Cells expressing these receptors take up dextran (Table 1).