Targeting the C-type Lectins-Mediated Host-Pathogen Interactions with Dextran

Abstract

Dextran, the α-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.

Short Communication: Inhibition of DC-SIGN-Mediated HIV-1 Infection by Complementary Actions of Dendritic Cell Receptor Antagonists and Env-Targeting Virus Inactivators

“…Many potential DC-SIGN inhibitors are in various stages of research, [13][14][15] and approaches for the high-throughput screening of potential inhibitors are being developed. 37 Our earlier studies on human macrophages 38 demonstrate that dextrans are also inhibitors of the interaction of HIV with another C-type lectin MR (CD206). This latter receptor binds HIV on the surface of macrophages, also allowing them to transinfect the T cells, 39 and mediates the HIV infection of brain macrophages.…”

“…In addition, it has not been demonstrated that oligosaccharides with the linear dextran structure (a-1,6-linked glucose units) bind DC-SIGN. 17 Hence, we proposed to utilize the dextran molecule, as it is part of several injectable drug formulations that have a proven safety record, as an inhibitor of pathogen interaction with a set of C-type lectins including DC-SIGN (CD209) and mannose receptor (CD206). 17 In addition, we tested whether peptide triazoles could inhibit DC-SIGN-mediated HIV infection.…”

“…17 Hence, we proposed to utilize the dextran molecule, as it is part of several injectable drug formulations that have a proven safety record, as an inhibitor of pathogen interaction with a set of C-type lectins including DC-SIGN (CD209) and mannose receptor (CD206). 17 In addition, we tested whether peptide triazoles could inhibit DC-SIGN-mediated HIV infection. These compounds have proven to be effective inhibitors of HIV infection mediated by CD4 and coreceptors CCR5/CXCR4 18 due to gp120 shedding and, in the case of test compound KR13, by additional lytic release of the viral capsid protein p24.…”

“…15 While the fact that Raji/DC-SIGN cells are not permissive for HIV is well proven, 15 another work more convincingly shows most of HIV gp120 is internalized in Raji/DC-SIGN cells while a smaller share stays bound on the cell surface and the ratio conforms to our data. 16 The increase of virus-per-cell number between 2 and 24 h may be explained mainly by upregulation of DC-SIGN expression by HIV, 17 but not its replication. D66 decreased DC-SIGN-dependent HIV infection even when B-THP-1/DC-SIGN cells were treated at 20 h postinfection.…”

“…Possibly we are increasing our understanding of the microbiota-independent, lectin-dependent mechanisms of their immunomodulatory effects. 34 We identified currently used drug dextran and food supplement isomaltooligosaccharides as DC-SIGN inhibitors and now they may find new applications in therapy for numerous infections 17 including HIV. Several-fold infection inhibition provided by dextrans (and many other DC-SIGN inhibitors that bind the carbohydrate recognition domain) might be therapeutically challenging.…”