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Eder J, Zijlstra-Willems E, Koen G, Kootstra NA, Wolthers KC, Geijtenbeek TB. Transmission of Zika virus by dendritic cell subsets in skin and vaginal mucosa. Front Immunol 2023; 14:1125565. [PMID: 36949942 PMCID: PMC10025456 DOI: 10.3389/fimmu.2023.1125565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/23/2023] [Indexed: 03/08/2023] Open
Abstract
Zika virus is a member of the Flaviviridae family that has caused recent outbreaks associated with neurological malformations. Transmission of Zika virus occurs primarily via mosquito bite but also via sexual contact. Dendritic cells (DCs) and Langerhans cells (LCs) are important antigen presenting cells in skin and vaginal mucosa and paramount to induce antiviral immunity. To date, little is known about the first cells targeted by Zika virus in these tissues as well as subsequent dissemination of the virus to other target cells. We therefore investigated the role of DCs and LCs in Zika virus infection. Human monocyte derived DCs (moDCs) were isolated from blood and primary immature LCs were obtained from human skin and vaginal explants. Zika virus exposure to moDCs but not skin and vaginal LCs induced Type I Interferon responses. Zika virus efficiently infected moDCs but neither epidermal nor vaginal LCs became infected. Infection of a human full skin model showed that DC-SIGN expressing dermal DCs are preferentially infected over langerin+ LCs. Notably, not only moDCs but also skin and vaginal LCs efficiently transmitted Zika virus to target cells. Transmission by LCs was independent of direct infection of LCs. These data suggest that DCs and LCs are among the first target cells for Zika virus not only in the skin but also the genital tract. The role of vaginal LCs in dissemination of Zika virus from the vaginal mucosa further emphasizes the threat of sexual transmission and supports the investigation of prophylaxes that go beyond mosquito control.
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Affiliation(s)
- Julia Eder
- Department of Experimental Immunology, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands
| | - Esther Zijlstra-Willems
- Department of Experimental Immunology, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands
| | - Gerrit Koen
- Department of Medical Microbiology and Infection Prevention, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands
| | - Neeltje A. Kootstra
- Department of Experimental Immunology, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands
| | - Katja C. Wolthers
- Department of Medical Microbiology and Infection Prevention, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands
| | - Teunis B. Geijtenbeek
- Department of Experimental Immunology, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands
- *Correspondence: Teunis B. Geijtenbeek,
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Xia HB, Wang HJ, Song SS, Zhang JG, He XL, Hu ZM, Zhang CW, Huang DS, Mou XZ. Decreased DC-SIGNR expression in hepatocellular carcinoma predicts poor patient prognosis. Oncol Lett 2020; 19:69-76. [PMID: 31897116 PMCID: PMC6923947 DOI: 10.3892/ol.2019.11074] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 03/07/2019] [Indexed: 12/16/2022] Open
Abstract
Dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin-related protein (DC-SIGNR) is a transmembrane receptor primarily involved in pathogen recognition by the innate immune system, with particular importance for viral recognition. DC-SIGNR may also be associated with tumorigenesis. The aim of the present study was to investigate the association between DC-SIGNR expression, development of hepatocellular carcinoma (HCC), and clinicopathological features. Immunohistochemistry was used to assess DC-SIGNR protein expression in HCC and paired non-cancerous tissue samples. DC-SIGNR expression was lower in HCC tissues compared with adjacent non-tumor tissue samples. The expression of DC-SIGNR was associated with small tumor size, low Edmondson grade and high patient long term survival rates. Bioinformatics analyses were performed on several datasets to assess the potential function of DC-SIGNR and related genes; the data revealed that DC-SIGNR mRNA expression was lower in HCC tissues compared with non-cancerous controls, and analyses of ten-year survival rates indicated patients with low DC-SIGNR expression exhibited shorter average survival times. In conclusion, decreased DC-SIGNR expression in HCC tissues may be a relevant predictive biomarker of clinical prognosis, in addition to being a viable therapeutic target for HCC treatment.
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Affiliation(s)
- Hai-Bing Xia
- Department of Hepatobiliary Surgery, First People's Hospital of Xiaoshan District, Hangzhou, Zhejiang 311200, P.R. China
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Hui-Ju Wang
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Shu-Shu Song
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, Zhejiang 310014, P.R. China
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Jun-Gang Zhang
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
- Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Xiang-Lei He
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Zhi-Ming Hu
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, Zhejiang 310014, P.R. China
| | - Cheng-Wu Zhang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, Zhejiang 310014, P.R. China
| | - Dong-Sheng Huang
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, Zhejiang 310014, P.R. China
- Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Xiao-Zhou Mou
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, Zhejiang 310014, P.R. China
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
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Prado Acosta M, Geoghegan EM, Lepenies B, Ruzal S, Kielian M, Martinez MG. Surface (S) Layer Proteins of Lactobacillus acidophilus Block Virus Infection via DC-SIGN Interaction. Front Microbiol 2019; 10:810. [PMID: 31040840 PMCID: PMC6477042 DOI: 10.3389/fmicb.2019.00810] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 03/29/2019] [Indexed: 01/06/2023] Open
Abstract
Alphaviruses and flaviviruses are important human pathogens that include Chikungunya virus (CHIKV), Dengue virus (DENV), and Zika virus (ZIKV), which can cause diseases in humans ranging from arthralgia to hemorrhagic fevers and microcephaly. It was previously shown that treatment with surface layer (S-layer) protein, present on the bacterial cell-envelope of Lactobacillus acidophilus, is able to inhibit viral and bacterial infections by blocking the pathogen’s interaction with DC-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), a trans-membrane protein that is a C-type calcium-dependent lectin. DC-SIGN is known to act as an attachment factor for several viruses including alphaviruses and flaviviruses. In the present study, we used alphaviruses as a model system to dissect the mechanism of S-layer inhibition. We first evaluated the protective effect of S-layer using 3T3 cells, either wild type or stably expressing DC-SIGN, and infecting with the alphaviruses Semliki Forest virus (SFV) and CHIKV and the flaviviruses ZIKV and DENV. DC-SIGN expression significantly enhanced infection by all four viruses. Treatment of the cells with S-layer prior to infection decreased infectivity of all viruses only in cells expressing DC-SIGN. In vitro ELISA experiments showed a direct interaction between S-layer and DC-SIGN; however, confocal microscopy and flow cytometry demonstrated that S-layer binding to the cells was independent of DC-SIGN expression. S-layer protein prevented SFV binding and internalization in DC-SIGN-expressing cells but had no effect on virus binding to DC-SIGN-negative cells. Inhibition of virus binding occurred in a time-dependent manner, with a significant reduction of infection requiring at least a 30-min pre-incubation of S-layer with DC-SIGN-expressing cells. These results suggest that S-layer has a different mechanism of action compared to mannan, a common DC-SIGN-binding compound that has an immediate effect in blocking viral infection. This difference could reflect slower kinetics of S-layer binding to the DC-SIGN present at the plasma membrane (PM). Alternatively, the S-layer/DC-SIGN interaction may trigger the activation of signaling pathways that are required for the inhibition of viral infection. Together our results add important information relevant to the potential use of L. acidophilus S-layer protein as an antiviral therapy.
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Affiliation(s)
- Mariano Prado Acosta
- Laboratorio de Bacterias Gram Positivas, Departamento de Química Biológica-IQUIBICEN, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.,Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, United States
| | - Eileen M Geoghegan
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, United States
| | - Bernd Lepenies
- Immunology Unit and Research Center for Emerging Infections and Zoonosis, University of Veterinary Medicine Hannover, Hanover, Germany
| | - Sandra Ruzal
- Laboratorio de Bacterias Gram Positivas, Departamento de Química Biológica-IQUIBICEN, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - Margaret Kielian
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, United States
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Bournazos S, Ravetch JV. Diversification of IgG effector functions. Int Immunol 2017; 29:303-310. [PMID: 28472280 PMCID: PMC5890892 DOI: 10.1093/intimm/dxx025] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 04/26/2017] [Indexed: 12/16/2022] Open
Abstract
IgG is the major immunoglobulin class produced during an immune response against foreign antigens and efficiently provides protection through its bifunctional nature. While the Fab domains confer highly specific recognition of the antigen, the Fc domain mediates a wide range of effector functions that modulate several aspects of innate and adaptive immunity. Engagement of the various types of Fcγ receptors (FcγRs) by an IgG Fc domain can activate distinct immunomodulatory pathways with pleiotropic functional consequences for several leukocyte types. Fc effector functions are not limited to phagocytosis and cytotoxicity of IgG-opsonized targets but exhibit remarkable diversity and include modulation of leukocyte activity and survival, cytokine and chemokine expression, maturation of antigen-presenting cells, antigen processing and presentation, B-cell selection and IgG affinity maturation, as well as regulation of IgG production. These functions are initiated upon specific interactions of the Fc domain with the various types of FcγRs-a process that is largely determined by the structural heterogeneity of the IgG Fc domain. Modulation of the Fc-associated glycan structure and composition along with differences in the primary amino acid sequence among the IgG subclasses represent the two main diversification mechanisms of the Fc domain that generate a spectrum of Fc domain phenotypes with distinct affinity for the various FcγR types and differential capacity to activate immunomodulatory pathways.
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Affiliation(s)
- Stylianos Bournazos
- Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Jeffrey V Ravetch
- Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA
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5
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C-type lectin receptors in tuberculosis: what we know. Med Microbiol Immunol 2016; 205:513-535. [DOI: 10.1007/s00430-016-0470-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 07/21/2016] [Indexed: 12/19/2022]
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Shimojima M, Takenouchi A, Shimoda H, Kimura N, Maeda K. Distinct usage of three C-type lectins by Japanese encephalitis virus: DC-SIGN, DC-SIGNR, and LSECtin. Arch Virol 2014; 159:2023-31. [PMID: 24623090 PMCID: PMC7087284 DOI: 10.1007/s00705-014-2042-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Accepted: 02/28/2014] [Indexed: 01/08/2023]
Abstract
Infection with West Nile virus and dengue virus, two mosquito-borne flaviviruses, is enhanced by two calcium-dependent lectins: dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), and its related molecule (DC-SIGNR). The present study examined the relationship between Japanese encephalitis virus (JEV) infection and three lectins: DC-SIGN, DC-SIGNR, and liver sinusoidal endothelial cell lectin (LSECtin). Expression of DC-SIGNR resulted in robust JEV proliferation in a lymphoid cell line, Daudi cells, which was otherwise non-permissive to infection. DC-SIGN expression caused moderate JEV proliferation, with effects that varied according to the cells in which JEV was prepared. LSECtin expression had comparatively minor, but consistent, effects, in all cell types used in JEV preparation. While DC-SIGN/DC-SIGNR-mediated JEV infection was inhibited by yeast mannan, LSECtin-mediated infection was inhibited by N-acetylglucosamine β1-2 mannose. Although involvement of DC-SIGN/DC-SIGNR in infection seems to be a common characteristic, this is the first report on usage of LSECtin in mosquito-borne flavivirus infection.
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MESH Headings
- Animals
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/metabolism
- Encephalitis Virus, Japanese/genetics
- Encephalitis Virus, Japanese/physiology
- Encephalitis, Japanese/genetics
- Encephalitis, Japanese/metabolism
- Encephalitis, Japanese/virology
- Humans
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Receptors, Virus/genetics
- Receptors, Virus/metabolism
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Affiliation(s)
- Masayuki Shimojima
- Laboratory of Veterinary Microbiology, Faculty of Agriculture, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8515 Japan
- Present Address: Special Pathogens Laboratory, Department of Virology I, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo 208-0011 Japan
| | - Atsushi Takenouchi
- Laboratory of Veterinary Microbiology, Faculty of Agriculture, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8515 Japan
| | - Hiroshi Shimoda
- Laboratory of Veterinary Microbiology, Faculty of Agriculture, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8515 Japan
| | - Naho Kimura
- Laboratory of Veterinary Microbiology, Faculty of Agriculture, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8515 Japan
| | - Ken Maeda
- Laboratory of Veterinary Microbiology, Faculty of Agriculture, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8515 Japan
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da Silva RC, Segat L, Zanin V, Arraes LC, Crovella S. Polymorphisms in DC-SIGN and L-SIGN genes are associated with HIV-1 vertical transmission in a Northeastern Brazilian population. Hum Immunol 2012; 73:1159-65. [DOI: 10.1016/j.humimm.2012.07.338] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Revised: 07/11/2012] [Accepted: 07/30/2012] [Indexed: 10/28/2022]
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Abstract
In the immune system, C-type lectins and CTLDs have been shown to act both as adhesion and as pathogen recognition receptors. The Dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) and its homologs in human and mouse represent an important C-type lectin family. DC-SIGN contains a lectin domain that recognizes in a Ca2+-dependent manner carbohydrates such as mannose-containing structures present on glycoproteins such as ICAM-2 and ICAM-3. DC-SIGN is a prototype C-type lectin organized in microdomains, which have their role as pathogen recognition receptors in sensing microbes. Although the integrin LFA-1 is a counter-receptor for both ICAM-2 and ICAM-3 on DC, DC-SIGN is the high affinity adhesion receptor for ICAM-2/-3. While cell–cell contact is a primary function of selectins, collectins are specialized in recognition of pathogens. Interestingly, DC-SIGN is a cell adhesion receptor as well as a pathogen recognition receptor. As adhesion receptor, DC-SIGN mediates the contact between dendritic cells (DCs) and T lymphocytes, by binding to ICAM-3, and mediates rolling of DCs on endothelium, by interacting with ICAM-2. As pathogen receptor, DC-SIGN recognizes a variety of microorganisms, including viruses, bacteria, fungi and several parasites (Cambi et al. 2005). The natural ligands of DC-SIGN consist of mannose oligosaccharides or fucose-containing Lewis-type determinants. In this chapter, we shall focus on the structure and functions of DC-SIGN and related CTLDs in the recognition of pathogens, the molecular and structural determinants that regulate the interaction with pathogen-associated molecular patterns. The heterogeneity of carbohydrate residues exposed on cellular proteins and pathogens regulates specific binding of DC-expressed C-type lectins that contribute to the diversity of immune responses created by DCs (van Kooyk et al. 2003a; Cambi et al. 2005).
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Leckband DE, Menon S, Rosenberg K, Graham SA, Taylor ME, Drickamer K. Geometry and adhesion of extracellular domains of DC-SIGNR neck length variants analyzed by force-distance measurements. Biochemistry 2011; 50:6125-32. [PMID: 21650186 PMCID: PMC3140775 DOI: 10.1021/bi2003444] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
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Force–distance measurements have been used to examine differences in the interaction of the dendritic cell glycan-binding receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR (L-SIGN) with membranes bearing glycan ligands. The results demonstrate that upon binding to membrane-anchored ligand, DC-SIGNR undergoes a conformational change similar to that previously observed for DC-SIGN. The results also validate a model for the extracellular domain of DC-SIGNR derived from crystallographic studies. Force measurements were performed with DC-SIGNR variants that differ in the length of the neck that result from genetic polymorphisms, which encode different numbers of the 23-amino acid repeat sequences that constitute the neck. The findings are consistent with an elongated, relatively rigid structure of the neck repeat observed in crystals. In addition, differences in the lengths of DC-SIGN and DC-SIGNR extracellular domains with equivalent numbers of neck repeats support a model in which the different dispositions of the carbohydrate-recognition domains in DC-SIGN and DC-SIGNR result from variations in the sequences of the necks.
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Affiliation(s)
- Deborah E Leckband
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
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Role of DC-SIGN and L-SIGN receptors in HIV-1 vertical transmission. Hum Immunol 2011; 72:305-11. [PMID: 21277928 PMCID: PMC7115691 DOI: 10.1016/j.humimm.2011.01.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Revised: 12/23/2010] [Accepted: 01/13/2011] [Indexed: 12/28/2022]
Abstract
The innate immune system acts in the first line of host defense against pathogens. One of the mechanisms used involves the early recognition and uptake of microbes by host professional phagocytes, through pattern recognition receptors (PRRs). These PRRs bind to conserved microbial ligands expressed by pathogens and initiate both innate and adaptative immune responses. Some PRRs located on the surface of dendritic cells (DCs) and other cells seem to play an important role in human immunodeficiency virus type 1 (HIV-1) transmission. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin, CD209 (DC-SIGN) and its homolog, DC-SIGN-related (DC-SIGNR or L-SIGN) receptors are PPRs able to bind the HIV-1 gp120 envelope protein and, because alterations in their expression patterns also occur, they might play a role in both horizontal and vertical transmission as well as in disseminating the virus within the host. This review aims to explore the involvement of the DC-SIGN and L-SIGN receptors in HIV-1 transmission from mother to child.
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Andreini M, Doknic D, Sutkeviciute I, Reina JJ, Duan J, Chabrol E, Thepaut M, Moroni E, Doro F, Belvisi L, Weiser J, Rojo J, Fieschi F, Bernardi A. Second generation of fucose-based DC-SIGN ligands : affinity improvement and specificity versus Langerin. Org Biomol Chem 2011; 9:5778-86. [DOI: 10.1039/c1ob05573a] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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N-linked glycosylation facilitates sialic acid-independent attachment and entry of influenza A viruses into cells expressing DC-SIGN or L-SIGN. J Virol 2010; 85:2990-3000. [PMID: 21191006 DOI: 10.1128/jvi.01705-10] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
It is widely recognized that sialic acid (SA) can mediate attachment of influenza virus to the cell surface, and yet the specific receptors that mediate virus entry are not known. For many viruses, a definitive demonstration of receptor function has been achieved when nonpermissive cells are rendered susceptible to infection following transfection of the gene encoding a putative receptor. For influenza virus, such approaches have been confounded by the abundance of SA on mammalian cells so that it has been difficult to identify cell lines that are not susceptible to infection. We examined influenza virus infection of Lec2 Chinese hamster ovary (CHO) cells, a mutant cell line deficient in SA. Lec2 CHO cells were resistant to influenza virus infection, and stable cell lines expressing either DC-SIGN or L-SIGN were generated to assess the potential of each molecule to function as SA-independent receptors for influenza A viruses. Virus strain BJx109 (H3N2) bound to Lec2 CHO cells expressing DC-SIGN or L-SIGN in a Ca(2+)-dependent manner, and transfected cells were susceptible to virus infection. Treatment of Lec2-DC-SIGN and Lec2-L-SIGN cells with mannan, but not bacterial neuraminidase, blocked infection, a finding consistent with SA-independent virus attachment and entry. Moreover, virus strain PR8 (H1N1) bears low levels of mannose-rich glycans and was inefficient at infecting Lec2 CHO cells expressing either DC-SIGN or L-SIGN, whereas other glycosylated H1N1 subtype viruses could infect cells efficiently. Together, these data indicate that human C-type lectins (DC-SIGN and L-SIGN) can mediate attachment and entry of influenza viruses independently of cell surface SA.
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Abstract
Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN). DC-SIGN is a C-type lectin receptor that recognizes N-linked high-mannose oligosaccharides and branched fucosylated structures. It is now clear that the biological role of DC-SIGN is two-fold. It is primarily expressed by dendritic cells and mediates important functions necessary for the induction of successful immune responses that are essential for the clearance of microbial infections, such as the capture, destruction, and presentation of microbial pathogens to induce successful immune responses. Yet, on the other hand, pathogens may also exploit DC-SIGN to modulate DC functioning thereby skewing the immune response and promoting their own survival. This chapter presents an overview of the structure of DC-SIGN and its expression pattern among immune cells. The current state of knowledge of DC-SIGN-carbohydrate interactions is discussed and how these interactions influence dendritic cell functioning is examined. The molecular aspects that underlie the selectivity of DC-SIGN for mannose-and fucose-containing carbohydrates are detailed. Furthermore, the chapter discusses the role of DC-SIGN in dendritic cell biology and how certain bacterial pathogens exploit DC-SIGN to escape immune surveillance.
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Lin AF, Xiang LX, Wang QL, Dong WR, Gong YF, Shao JZ. The DC-SIGN of zebrafish: insights into the existence of a CD209 homologue in a lower vertebrate and its involvement in adaptive immunity. THE JOURNAL OF IMMUNOLOGY 2009; 183:7398-410. [PMID: 19890038 DOI: 10.4049/jimmunol.0803955] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN/CD209) has become hot topic in recent studies because of its important roles in immune responses and immune escape. CD209 has been well characterized in humans and several other mammals, but little documentation exists about it in lower vertebrates. This is the first report on the identification and functional characterization of a fish DC-SIGN/CD209 molecule. The zebrafish DC-SIGN/CD209 cDNA translates into 343 aa organized into three domains structurally conserved among vertebrates. An EPN motif essential for interacting with Ca(2+) and for recognizing mannose-containing motifs has been identified. Several conserved motifs crucial for internalization and signal transduction are also present within the cytoplasmic tail. Phylogenetic analysis supports the hypothesis that CD209 family members diverged from a common ancestor. The expression of DC-SIGN/CD209 in immune-related tissues can be significantly up-regulated by exogenous Ags and IL-4. This molecule associates with various APCs, including macrophages, B lymphocytes, and a possible dendritic cell-like (CD83(+)/CD80(+)CD209(+)) population. Functionally, T cell activation, Ab (IgM) production, and bacterial vaccination-elicited immunoprotection can be dramatically inhibited by a CD209 blockade after stimulation with keyhole limpet hemocyanin (KLH) in vivo or challenged with Aeromonas hydrophila, suggesting that DC-SIGN/CD209 in zebrafish is crucial for the initiation and development of adaptive immunity. Phagocytosis analysis showed that DC-SIGN/CD209 does not participate in the uptake of KLH Ag, suggesting that other mechanisms might exist that underlie DC-SIGN/CD209 involvement. We hope that the present study will contribute to a better cross-species understanding of the evolutionary history of the DC-SIGN/CD209 family.
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Affiliation(s)
- Ai-Fu Lin
- College of Life Sciences, Zhejiang University, Hangzhou 310058, Peoples Republic of China
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15
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Abstract
In the last decade, molecular beacons have emerged to become a widely used tool in the multiplex typing of single nucleotide polymorphisms (SNPs). Improvements in detection technologies in instrumentation and chemistries to label these probes have made it possible to use up to six spectrally distinguishable probes per reaction well. With the remarkable advances made in the characterization of human genome diversity, it has been possible to describe empirical patterns of SNPs and haplotype variation in the genome of diverse human populations. These patterns have revealed that the human genome is structured in blocks of strong linkage disequilibrium (LD). Because SNPs tend to be in LD with each other, common haplotypes share common SNPs and thus the majority of the diversity in a region can be characterized by typing a very small number of SNPs; so-called tag SNPs. Herein lies the advantage of the multiplexing ability of molecular beacons, since it becomes possible to use as few as 30 probes to interrogate several haplotypes in a high-throughput approach. Thus, through the combined use of tag SNPs and molecular beacons it becomes possible to type individuals for clinically relevant haplotypes in a high-throughput manner at a cost that is orders of magnitude less than that for high throughput sequencing methods.
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Affiliation(s)
- Anton A. Komar
- Center for Gene Regulation in, Cleveland State University, Euclid Ave. 2121, Cleveland, 44115 U.S.A
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16
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Khoo US, Chan KYK, Chan VSF, Lin CLS. DC-SIGN and L-SIGN: the SIGNs for infection. J Mol Med (Berl) 2008; 86:861-74. [PMID: 18458800 PMCID: PMC7079906 DOI: 10.1007/s00109-008-0350-2] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2007] [Revised: 03/01/2008] [Accepted: 03/05/2008] [Indexed: 12/16/2022]
Abstract
Two closely related trans-membrane C-type lectins dendritic cell-specific intracellular adhesion molecules (ICAM)-3 grabbing non-integrin (DC-SIGN or CD209) and liver/lymph node-specific ICAM-3 grabbing non-integrin (L-SIGN also known as DC-SIGNR, CD209L or CLEC4M) directly recognize a wide range of micro-organisms of major impact on public health. Both genes have long been considered to share similar overall structure and ligand-binding characteristics. This review presents more recent biochemical and structural studies, which show that they have distinct ligand-binding properties and different physiological functions. Of importance in both these genes is the presence of an extra-cellular domain consisting of an extended neck region encoded by tandem repeats that support the carbohydrate-recognition domain, which plays a crucial role in influencing the pathogen-binding properties of these receptors. The notable difference between these two genes is in this extra-cellular domain. Whilst the tandem-neck-repeat region remains relatively constant size for DC-SIGN, there is considerable polymorphism for L-SIGN. Homo-oligomerization of the neck region of L-SIGN has been shown to be important for high-affinity ligand binding, and heterozygous expression of the polymorphic variants of L-SIGN in which neck lengths differ could thus affect ligand-binding affinity. Functional studies on the effect of this tandem-neck-repeat region on pathogen-binding, as well as genetic association studies for various infectious diseases and among different populations, are discussed. Worldwide demographic data of the tandem-neck-repeat region showing distinct differences in the neck-region allele and genotype distribution among different ethnic groups are presented. These findings support the neck region as an excellent candidate acting as a functional target for selective pressures exerted by pathogens.
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Affiliation(s)
- Ui-Soon Khoo
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, University Pathology Building, Hong Kong, SAR, China.
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17
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Barreiro LB, Neyrolles O, Babb CL, van Helden PD, Gicquel B, Hoal EG, Quintana-Murci L. Length variation of DC-SIGN and L-SIGN neck-region has no impact on tuberculosis susceptibility. Hum Immunol 2007; 68:106-12. [PMID: 17321900 PMCID: PMC7132702 DOI: 10.1016/j.humimm.2006.10.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2006] [Revised: 10/12/2006] [Accepted: 10/31/2006] [Indexed: 11/01/2022]
Abstract
The C-type lectins DC-SIGN and L-SIGN are important pathogen-recognition receptors of the human innate immune system. Both lectins have been shown to interact with a vast range of infectious agents, including Mycobacterium tuberculosis, the etiologic agent of tuberculosis in humans. In addition, DC-SIGN and L-SIGN possess a neck region, made up of a variable number of 23 amino acid tandem repeats, which plays a crucial role in the tetramerization of these proteins and support of the carbohydrate recognition domain. The length of the neck region, which shows variable levels of polymorphism, can critically influence the pathogen binding properties of these two receptors. We therefore investigated the impact of the DC-SIGN and L-SIGN neck-region length variation on the outcome of tuberculosis by screening this polymorphism in a large cohort of Coloured South African origin. The analyses of 711 individuals, including 351 tuberculosis patients and 360 healthy controls, revealed that none of the DC-SIGN and L-SIGN neck-region variants or genotypes seems to influence the individual susceptibility to develop tuberculosis.
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Affiliation(s)
- Luis B Barreiro
- CNRS FRE2849, Unit of Human Evolutionary Genetics, Institut Pasteur, Paris, France
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18
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Lozach PY, Burleigh L, Staropoli I, Amara A. The C type lectins DC-SIGN and L-SIGN: receptors for viral glycoproteins. Methods Mol Biol 2007; 379:51-68. [PMID: 17502670 PMCID: PMC7122727 DOI: 10.1007/978-1-59745-393-6_4] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
DC-SIGN and L-SIGN are C-type lectins that recognize carbohydrate structures present on viral glycoproteins and function as attachment factors for several enveloped viruses. DC-SIGN and L-SIGN enhance viral entry and facilitate infection of cells that express the cognate entry receptor (cis-infection). They are also able to capture viruses and transfer viral infections to other target cells (trans-infection). In this chapter, we will give an overview of protocols used to produce soluble viral glycoproteins at high levels and to study the molecular basis of viruses/DC-SIGN and L-SIGN binding and internalization. We will also describe techniques to investigate the molecular mechanisms by which DC-SIGN or L-SIGN spread viral infections.
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Affiliation(s)
- Pierre-Yves Lozach
- Laboratoire de Pathogénie Virale Moléculaire, Institut Pasteur, Paris, France
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19
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Rappocciolo G, Jenkins FJ, Hensler HR, Piazza P, Jais M, Borowski L, Watkins SC, Rinaldo CR. DC-SIGN is a receptor for human herpesvirus 8 on dendritic cells and macrophages. THE JOURNAL OF IMMUNOLOGY 2006; 176:1741-9. [PMID: 16424204 DOI: 10.4049/jimmunol.176.3.1741] [Citation(s) in RCA: 150] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Human herpesvirus 8 (HHV-8) causes Kaposi's sarcoma and pleural effusion lymphoma. In this study, we show that dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN; CD209) is a receptor for HHV-8 infection of myeloid DCs and macrophages. DC-SIGN was required for virus attachment to these cells and DC-SIGN-expressing cell lines. HHV-8 binding and infection were blocked by anti-DC-SIGN mAb and soluble DC-SIGN, and mannan, a natural ligand for DC-SIGN. Infection of DCs and macrophages with HHV-8 led to production of viral proteins, with little production of viral DNA, similar to HHV-8 infection of vascular endothelial cells. Infection of DCs resulted in down-regulation of DC-SIGN, a decrease in endocytic activity, and an inhibition of Ag stimulation of CD8+ T cells. We propose that DC-SIGN serves as a portal for immune dysfunction and oncogenesis caused by HHV-8 infection.
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MESH Headings
- Adult
- Antibodies, Monoclonal/metabolism
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/immunology
- Cell Adhesion Molecules/metabolism
- Cell Line
- Cell Line, Transformed
- Dendritic Cells/metabolism
- Dendritic Cells/virology
- Herpesviridae Infections/immunology
- Herpesvirus 8, Human/metabolism
- Humans
- Integrin alpha3beta1/physiology
- K562 Cells
- Lectins, C-Type/genetics
- Lectins, C-Type/immunology
- Lectins, C-Type/metabolism
- Macrophages/metabolism
- Mannans/metabolism
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/immunology
- Receptors, Cell Surface/metabolism
- Receptors, Virus/genetics
- Receptors, Virus/immunology
- Receptors, Virus/metabolism
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Affiliation(s)
- Giovanna Rappocciolo
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, PA 15261, USA.
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20
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Martens JH, Kzhyshkowska J, Falkowski-Hansen M, Schledzewski K, Gratchev A, Mansmann U, Schmuttermaier C, Dippel E, Koenen W, Riedel F, Sankala M, Tryggvason K, Kobzik L, Moldenhauer G, Arnold B, Goerdt S. Differential expression of a gene signature for scavenger/lectin receptors by endothelial cells and macrophages in human lymph node sinuses, the primary sites of regional metastasis. J Pathol 2006; 208:574-89. [PMID: 16440291 DOI: 10.1002/path.1921] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Sentinel lymph node biopsy for several cancers has shown that metastatic tumour cells are preferentially arrested in the lymph node sinuses. To study the molecular components of this sinusoidal trap, gene profiling of lymph node (sinuses) versus tonsil (no sinuses) was performed. Among other groups of molecules, an intriguing gene signature of scavenger and lectin-like receptors was identified. Nine of the 13 genes were preferentially expressed in sinusoidal cells by immunohistochemistry. Using stabilin-2 and monoclonal antibody 3A5 as exclusive endothelial cell (EC) and macrophage (Mvarphi) markers, respectively, lymph node sinusoidal ECs (stabilin-2+, LYVE-1+, DC-SIGNR+, MARCO+, stabilin-1+, MMR+) and sinusoidal Mvarphi (MMR+, DC-SIGN+, sialoadhesin+, CD163+, stabilin-1+ ) showed distinct, but overlapping expression patterns of the signature molecules by double labelling immunofluorescence. The number of stabilin-1+ sinusoidal Mvarphi, however, varied considerably between samples, indicating turnover/differentiation dynamics in this sinusoidal cell population. In the hepatic sinuses, LYVE-1 and CD36 were strongly up-regulated on both sinusoidal ECs and Mvarphi, while DC-SIGNR and DC-SIGN were strongly down-regulated; in contrast to lymph node sinusoidal ECs, MARCO was confined to Mvarphi (Kupffer cells) in the liver sinuses. As Mvarphi are not present in the wall and lumen of splenic sinuses, splenic sinuses expressed a considerably reduced repertoire of scavenger/lectin receptors lacking sialoadhesin, CD36, CD163, and MARCO; in addition, DC-SIGNR was absent from splenic sinusoidal ECs, while DC-SIGN and thrombomodulin were strongly expressed. Interestingly, most of the signature molecules are known to mediate tumour cell adhesion in addition to their functions as scavenger or pattern recognition receptors. This study establishes a gene and tissue database platform to test the hypothesis that additive expression of the lymph node sinus signature genes in sinusoidal ECs and Mvarphi may contribute to selective tumour cell metastasis in lymph nodes and liver including organ-specific mechanisms, such as intraluminal retention or transmigration, while sparing the spleen.
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Affiliation(s)
- J-H Martens
- Department of Dermatology, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Mannheim, Germany
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21
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Nattermann J, Ahlenstiel G, Berg T, Feldmann G, Nischalke HD, Müller T, Rockstroh J, Woitas R, Sauerbruch T, Spengler U. The tandem-repeat polymorphism of the DC-SIGNR gene in HCV infection. J Viral Hepat 2006; 13:42-6. [PMID: 16364081 DOI: 10.1111/j.1365-2893.2005.00652.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The C-type lectin DC-SIGNR has been shown to bind hepatitis C virus (HCV). Here, we analysed the tandem-repeat polymorphism of the DC-SIGNR gene with respect to intraindividual HCV replication. In a cross-sectional comparison HCV-infected patients (n = 430) and healthy subjects (n = 100) were genotyped for the DC-SIGNR polymorphism using PCR. The distribution of DC-SIGNR alleles did not differ significantly between the two groups. However, HCV-infected patients with 5-, 6-, and 7-repeat alleles had higher HCV-RNA levels when compared with carriers of 4- and 9-repeat alleles (P < 0.05). Thus, the DC-SIGNR polymorphism might affect HCV loads supporting the concept that DC-SIGNR contributes to HCV replication efficacy.
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Affiliation(s)
- J Nattermann
- Department of Internal Medicine I, Rheinische Friedrich Wilhelms Universität Bonn, Bonn, Germany.
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22
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Breburda EE, Dambaeva SV, Slukvin II, Golos TG. Selective distribution and pregnancy-specific expression of DC-SIGN at the maternal–fetal interface in the rhesus macaque: DC-SIGN is a putative marker of the recognition of pregnancy. Placenta 2006; 27:11-21. [PMID: 16310033 DOI: 10.1016/j.placenta.2004.11.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2004] [Revised: 11/03/2004] [Accepted: 11/08/2004] [Indexed: 11/21/2022]
Abstract
We performed immunohistochemical analysis of DC-SIGN expression at the maternal-fetal interface at different stages of pregnancy in the rhesus monkey. Natural killer cells, monocytes and macrophages were observed in the nonpregnant endometrium, particularly in the luteal phase, and were increased in pregnant endometrium. No DC-SIGN+ cells were observed in the nonpregnant uterus. We observed decidual DC-SIGN+ cells within 1 week of implantation, and they increased in number during the first 5 weeks of gestation. DC-SIGN+ cells showed a clear differential distribution in the decidua in the first 2 weeks of pregnancy, being found only adjacent to the implantation site, in marked contrast to the widespread distribution of CD68+ macrophages and CD56+ NK cells throughout the endometrium. DC-SIGN+ cells also showed a more dendritic morphology than the general CD68+ cell population, and analysis of serial sections indicated an overlapping but not identical localization of these markers. Mature dendritic cells could not be detected as judged by total absence of immunostaining for CD83, CD86, DEC-205, or CD1a. DC-SIGN+ cells were defined as MHC class II+ and CD14+ by flow cytometry. We conclude that DC-SIGN expression is an early response by the primate maternal immune system to the implanting embryo. The selectively distributed population of DC-SIGN+ decidual leukocytes may represent a morphologically and phenotypically distinct subpopulation of decidual macrophages of early pregnancy that could contribute to the establishment of maternal-fetal immune tolerance.
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Affiliation(s)
- E E Breburda
- National Primate Research Center, University of Wisconsin Medical School, University of Wisconsin-Madison, 1223 Capitol Court, Madison, WI 53715-1299, USA
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23
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Barreiro LB, Patin E, Neyrolles O, Cann HM, Gicquel B, Quintana-Murci L. The heritage of pathogen pressures and ancient demography in the human innate-immunity CD209/CD209L region. Am J Hum Genet 2005; 77:869-86. [PMID: 16252244 PMCID: PMC1271393 DOI: 10.1086/497613] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2005] [Accepted: 08/26/2005] [Indexed: 10/26/2022] Open
Abstract
The innate immunity system constitutes the first line of host defense against pathogens. Two closely related innate immunity genes, CD209 and CD209L, are particularly interesting because they directly recognize a plethora of pathogens, including bacteria, viruses, and parasites. Both genes, which result from an ancient duplication, possess a neck region, made up of seven repeats of 23 amino acids each, known to play a major role in the pathogen-binding properties of these proteins. To explore the extent to which pathogens have exerted selective pressures on these innate immunity genes, we resequenced them in a group of samples from sub-Saharan Africa, Europe, and East Asia. Moreover, variation in the number of repeats of the neck region was defined in the entire Human Genome Diversity Panel for both genes. Our results, which are based on diversity levels, neutrality tests, population genetic distances, and neck-region length variation, provide genetic evidence that CD209 has been under a strong selective constraint that prevents accumulation of any amino acid changes, whereas CD209L variability has most likely been shaped by the action of balancing selection in non-African populations. In addition, our data point to the neck region as the functional target of such selective pressures: CD209 presents a constant size in the neck region populationwide, whereas CD209L presents an excess of length variation, particularly in non-African populations. An additional interesting observation came from the coalescent-based CD209 gene tree, whose binary topology and time depth (approximately 2.8 million years ago) are compatible with an ancestral population structure in Africa. Altogether, our study has revealed that even a short segment of the human genome can uncover an extraordinarily complex evolutionary history, including different pathogen pressures on host genes as well as traces of admixture among archaic hominid populations.
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Affiliation(s)
- Luis B Barreiro
- Centre National de la Recherche Scientifique FRE 2849, Unit of Molecular Prevention and Therapy of Human Diseases, Institut Pasteur, 25, 75724 Paris Cedex 15, France
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24
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Nair MPN, Mahajan SD, Schwartz SA, Reynolds J, Whitney R, Bernstein Z, Chawda RP, Sykes D, Hewitt R, Hsiao CB. Cocaine modulates dendritic cell-specific C type intercellular adhesion molecule-3-grabbing nonintegrin expression by dendritic cells in HIV-1 patients. THE JOURNAL OF IMMUNOLOGY 2005; 174:6617-26. [PMID: 15905500 DOI: 10.4049/jimmunol.174.11.6617] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
We report that cocaine may act as cofactor in HIV pathogenesis by increasing dendritic cell-specific C type ICAM-3-grabbing nonintegrin (DC-SIGN) expression on dendritic cells (DC). Our results show that cocaine-using, long-term nonprogressors and normal progressors of HIV infection manifest significantly higher levels of DC-SIGN compared with cocaine-nonusing long-term nonprogressors and normal progressors, respectively. Furthermore, in vitro HIV infection of MDC from normal subjects cultured with cocaine and/or HIV peptides up-regulated DC-SIGN, confirming our in vivo finding. Cocaine, in synergy with HIV peptides, also up-regulates DC-SIGN gene expression by MDC. Furthermore, the cocaine-induced effects were reversed by a D1 receptor antagonist demonstrating the specificity of the reaction. Our results indicate that cocaine exacerbates HIV infection by up-regulating DC-SIGN on DC and these effects are mediated via dysregulation of MAPKs. These data are the first evidence that cocaine up-regulates the expression of DC-SIGN on DC. A better understanding of the role of DC-SIGN in HIV infection may help to design novel therapeutic strategies against the progression of HIV disease in the drug-using population.
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Affiliation(s)
- Madhavan P N Nair
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, State University of New York and Buffalo General Hospital, 14203, USA.
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25
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Nair MPN, Schwartz SA, Mahajan SD, Tsiao C, Chawda RP, Whitney R, Don Sykes BB, Hewitt R. Drug abuse and neuropathogenesis of HIV infection: role of DC-SIGN and IDO. J Neuroimmunol 2004; 157:56-60. [PMID: 15579280 DOI: 10.1016/j.jneuroim.2004.08.040] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2004] [Indexed: 10/26/2022]
Abstract
Dendritic cells are the critical mediators of various immune responses and are the first line of defense against any infection including HIV. They play a major role in harboring HIV and the subsequent infection of T cells and passage of virus through the blood-brain barrier (BBB). The recently discovered DC-specific, CD4-independent HIV attachment receptor, DC-SIGN, and T-cell suppressing factor, indolamine 2,3-dioxygenase (IDO), are known to play a critical role in the immuno-neuropathogenesis of HIV infection. Since brain microvascular cells (BMVEC) express dendritic cell (DC)-specific C type ICAM-3 grabbing nonintegrin (DC-SIGN), it is possible that DC-SIGN may play a critical role in human immunodeficiency virus-type 1 (HIV-1) infection and migration of infected DC across BBB. Matrix metalloproteinases (MMPs) are proteolytic enzymes known to be responsible for maintenance, turnover and integrity of extracellular matrix. Our results show that cocaine upregulates IDO and DC-SIGN expression by DC. Further, cocaine upregulates DC-SIGN and MMPs in BMVEC supporting the hypothesis that cocaine causes membrane permeability facilitating endothelial transmigration of infected DC in to the CNS. Targeting DC-SIGN and IDO with specific monoclonal antibodies, inexpensive synthetic antagonists, antisense oligonucleotides and siRNA may lead to develop novel treatment strategies particularly in high-risk populations such as cocaine users.
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MESH Headings
- Anesthetics, Local/pharmacology
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/metabolism
- Cells, Cultured
- Cocaine/pharmacology
- Dendritic Cells/drug effects
- Dendritic Cells/metabolism
- Dioxygenases/genetics
- Dioxygenases/metabolism
- Dose-Response Relationship, Drug
- HIV Infections/complications
- HIV Infections/enzymology
- Humans
- Indoleamine-Pyrrole 2,3,-Dioxygenase
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Matrix Metalloproteinases/genetics
- Matrix Metalloproteinases/metabolism
- Matrix Metalloproteinases, Membrane-Associated
- Metalloendopeptidases/genetics
- Metalloendopeptidases/metabolism
- RNA, Messenger/biosynthesis
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Substance-Related Disorders/complications
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Affiliation(s)
- Madhavan P N Nair
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology and State University of New York and Buffalo General Hospital, Kaleida Health System 100 High Street, Buffalo, NY 14203, USA.
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26
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Feinberg H, Guo Y, Mitchell DA, Drickamer K, Weis WI. Extended neck regions stabilize tetramers of the receptors DC-SIGN and DC-SIGNR. J Biol Chem 2004; 280:1327-35. [PMID: 15509576 DOI: 10.1074/jbc.m409925200] [Citation(s) in RCA: 148] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The human cell surface receptors DC-SIGN (dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin) and DC-SIGNR (DC-SIGN-related) bind to oligosaccharide ligands found on human tissues as well as on pathogens including viruses, bacteria, and parasites. The extracellular portion of each receptor contains a membrane-distal carbohydrate-recognition domain (CRD) and forms tetramers stabilized by an extended neck region consisting of 23 amino acid repeats. Cross-linking analysis of full-length receptors expressed in fibroblasts confirms the tetrameric state of the intact receptors. Hydrodynamic studies on truncated receptors demonstrate that the portion of the neck of each protein adjacent to the CRD is sufficient to mediate the formation of dimers, whereas regions near the N terminus are needed to stabilize the tetramers. Some of the intervening repeats are missing from polymorphic forms of DC-SIGNR. Two different crystal forms of truncated DC-SIGNR comprising two neck repeats and the CRD reveal that the CRDs are flexibly linked to the neck, which contains alpha-helical segments interspersed with non-helical regions. Differential scanning calorimetry measurements indicate that the neck and CRDs are independently folded domains. Based on the crystal structures and hydrodynamic data, models for the full extracellular domains of the receptors have been generated. The observed flexibility of the CRDs in the tetramer, combined with previous data on the specificity of these receptors, suggests an important role for oligomerization in the recognition of endogenous glycans, in particular those present on the surfaces of enveloped viruses recognized by these proteins.
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MESH Headings
- Animals
- Calorimetry, Differential Scanning
- Cell Adhesion Molecules/chemistry
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/metabolism
- Crystallography, X-Ray
- Dimerization
- Fibroblasts
- Humans
- Lectins, C-Type/chemistry
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Models, Molecular
- Pliability
- Polymorphism, Genetic/genetics
- Protein Structure, Quaternary
- Rats
- Receptors, Cell Surface/chemistry
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
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Affiliation(s)
- Hadar Feinberg
- Departments of Structural Biology and of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA
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27
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Rinaldo CR, Piazza P. Virus infection of dendritic cells: portal for host invasion and host defense. Trends Microbiol 2004; 12:337-45. [PMID: 15223061 DOI: 10.1016/j.tim.2004.05.003] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Dendritic cells (DCs) act as a portal for virus invasion and as the most potent antigen-presenting cells in antiviral host defense. Human immunodeficiency virus (HIV)-1 has served as the paradigm for virus interaction with DCs. HIV-1 infection of DCs via its primary CD4 receptor and secondary chemokine receptors leads to full virus replication (cis infection), whereas binding to C-type lectin receptors results both in cis replication, as well as transfer and replication of virus in CD4(pos) T cells (trans infection). DCs respond to this invasion by processing viral proteins through MHC class I and II pathways and undergoing a maturation that enhances their presentation of antigen to T cells for induction of adaptive antiviral immunity. HIV-1 and other viruses have evolved mechanisms to subvert this immune function. Engineering of DCs with various forms of viral immunogens and co-treatment with cytokines and chemokines is being used as an immunotherapy for HIV-1 and other viral infections.
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Affiliation(s)
- Charles R Rinaldo
- Department of Infectious Diseases and Microbiology and Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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28
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Abstract
DC-SIGN, a dendritic Cell-specific adhesion receptor and a type II transmembrane mannose-binding C-type lectin, is very important in the function of DC, both in mediating naive T cell interactions through ICAM-3 and as a rolling receptor that mediates the DC-specific ICAM-2-dependent migration processes. It can be used by viral and bacterial pathogens including Human Immunodeficiency Virus (HIV), HCV, Ebola Virus, CMV and Mycobacterium tuberculosis to facilitate infection. Both DC-SIGN and DC-SIGNR can act either in cis, by concentrating virus on target cells, or in trans, by transmission of bound virus to a target cell expressing appropropriate entry receptors. Recent work showed that DC-SIGN are high-affinity binding receptors for HCV. Besides playing a role in entry into DC, HCV E2 interaction with DC-SIGN might also be detrimental for the interaction of DC with T cells during antigen presentation. The clinical strategies that target DC-SIGN may be successful in restricting HCV dissemination and pathogenesis as well as directing the migration of DCs to manipulate appropriate immune responses in autoimmunity and tumorigenic situations.
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Affiliation(s)
- Zhi-Hua Feng
- The Center of Diagnosis and Treatment for Infectious Diseases of PLA, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, Shaanxi Province, China.
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29
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Liu W, Tang L, Zhang G, Wei H, Cui Y, Guo L, Gou Z, Chen X, Jiang D, Zhu Y, Kang G, He F. Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node. J Biol Chem 2004; 279:18748-58. [PMID: 14711836 DOI: 10.1074/jbc.m311227200] [Citation(s) in RCA: 138] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
A new C-type lectin-like gene encodes 293 amino acids and maps to chromosome 19p13.3 adjacent to the previously described C-type lectin genes, CD23, dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), and DC-SIGN-related protein (DC-SIGNR). The four genes form a tight cluster in an insert size of 105 kb and have analogous genomic structures. The new C-type lectin-like molecule, designated liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin), is a type II integral membrane protein of approximately 40 kDa in size with a single C-type lectin-like domain at the COOH terminus, closest in homology to DC-SIGNR, DC-SIGN, and CD23. LSECtin mRNA was only expressed in liver and lymph node among 15 human tissues tested, intriguingly neither expressed on hematopoietic cell lines nor on monocyte-derived dendritic cells (DCs). Moreover, LSECtin is expressed predominantly by sinusoidal endothelial cells of human liver and lymph node and co-expressed with DC-SIGNR. LSECtin binds to mannose, GlcNAc, and fucose in a Ca(2+)-dependent manner but not to galactose. Our results indicate that LSECtin is a novel member of a family of proteins comprising CD23, DC-SIGN, and DC-SIGNR and might function in vivo as a lectin receptor.
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MESH Headings
- Base Sequence
- Binding Sites
- Carbohydrate Metabolism
- Cell Adhesion Molecules/genetics
- Cell Line, Tumor
- Cells, Cultured
- Chromosome Mapping
- Chromosomes, Human, Pair 19
- Cloning, Molecular
- Dendritic Cells/cytology
- Endothelial Cells/chemistry
- Humans
- Lectins, C-Type/analysis
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Liver/chemistry
- Liver/cytology
- Lymph Nodes/chemistry
- Lymph Nodes/cytology
- Molecular Sequence Data
- RNA, Messenger/analysis
- Receptors, Cell Surface/genetics
- Receptors, IgE/genetics
- Tissue Distribution
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Affiliation(s)
- Wanli Liu
- Department of Genomics and Proteomics, Beijing Institute of Radiation Medicine, Chinese Human Genome Center at Beijing, 27 Taiping Road, Beijing 100850, People's Republic of China
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