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1
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Basaran R, Ning X, Budhadev D, Hondow N, Guo Y, Zhou D. Probing the pH-dependency of DC-SIGN/R multivalent lectin-glycan interactions using polyvalent glycan-gold nanoparticles. NANOSCALE ADVANCES 2024; 6:2198-2208. [PMID: 38633047 PMCID: PMC11019501 DOI: 10.1039/d3na01013a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 03/04/2024] [Indexed: 04/19/2024]
Abstract
The dendritic cell tetrameric lectin, DC-SIGN, and its closely related endothelial cell lectin, DC-SIGNR (collectively abbreviated as DC-SIGN/R) play a key role in the binding and transmission of deadly viruses, including Ebola, HIV, HCV, and SARS-CoV-2. Their virus binding/release processes involve a gradually acidifying environment following the natural intracellular trafficking pathways. Therefore, understanding DC-SIGN/R's pH-dependent binding properties with glycan ligands is of great importance. We have recently developed densely glycosylated gold nanoparticles (glycan-GNPs) as a powerful new tool for probing DC-SIGN/R multivalent lectin-glycan interaction (MLGI) mechanisms. They can provide not only quantitative MLGI affinities but also important structural information, such as binding site orientation and binding modes. Herein, we further employ the glycan-GNP probes to investigate the pH dependency of DC-SIGN/R MLGI properties. We find that DC-SIGN/R MLGIs exhibit distinct pH dependence over the normal physiological (7.4) to lysosomal (∼4.6) pH range. DC-SIGN binds glycan-GNPs strongly and stably from pH 7.4 to ∼5.8, but the binding is weakened significantly as pH decreases to ≤5.4 and may be fully dissociated at pH 4.6. This behaviour is fully consistent with DC-SIGN's role as an endocytic recycling receptor. In contrast, DC-SIGNR's affinity with glycan-GNPs is enhanced with the decreasing pH from 7.4 to 5.4, peaking at pH 5.4, and then reduced as pH is further lowered. Interestingly, both DC-SIGN/R binding with glycan-GNPs are found to be partially reversible in a pH-dependent manner.
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Affiliation(s)
- Rahman Basaran
- School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds Leeds LS2 9JT UK
| | - Xinyu Ning
- School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds Leeds LS2 9JT UK
| | - Darshita Budhadev
- School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds Leeds LS2 9JT UK
| | - Nicole Hondow
- School of Chemical and Process Engineering, University of Leeds Leeds LS2 9JT UK
| | - Yuan Guo
- School of Food Science and Nutrition, Astbury Centre for Structural Molecular Biology, University of Leeds Leeds LS2 9JT UK
| | - Dejian Zhou
- School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds Leeds LS2 9JT UK
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2
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Van Den Bergh A, Bailly B, Guillon P, von Itzstein M, Dirr L. Antiviral strategies against human metapneumovirus: Targeting the fusion protein. Antiviral Res 2022; 207:105405. [PMID: 36084851 DOI: 10.1016/j.antiviral.2022.105405] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/23/2022] [Accepted: 08/31/2022] [Indexed: 11/02/2022]
Abstract
Human metapneumoviruses have emerged in the past decades as an important global pathogen that causes severe upper and lower respiratory tract infections. Children under the age of 2, the elderly and immunocompromised individuals are more susceptible to HMPV infection than the general population due to their suboptimal immune system. Despite the recent discovery of HMPV as a novel important respiratory virus, reports have rapidly described its epidemiology, biology, and pathogenesis. However, progress is still to be made in the development of vaccines and drugs against HMPV infection as none are currently available. Herein, we discuss the importance of HMPV and review the reported strategies for anti-HMPV drug candidates. We also present the fusion protein as a promising antiviral drug target due to its multiple roles in the HMPV lifecycle. This key viral protein has previously been targeted by a range of inhibitors, which will be discussed as they represent opportunities for future drug design.
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Affiliation(s)
| | - Benjamin Bailly
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Patrice Guillon
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Mark von Itzstein
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia.
| | - Larissa Dirr
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia.
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3
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Losada-Garcia N, Garcia-Sanz C, Andreu A, Velasco-Torrijos T, Palomo JM. Glyconanomaterials for Human Virus Detection and Inhibition. NANOMATERIALS (BASEL, SWITZERLAND) 2021; 11:1684. [PMID: 34206886 PMCID: PMC8308178 DOI: 10.3390/nano11071684] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 01/23/2023]
Abstract
Viruses are among the most infectious pathogens, responsible for the highest death toll around the world. Lack of effective clinical drugs for most viral diseases emphasizes the need for speedy and accurate diagnosis at early stages of infection to prevent rapid spread of the pathogens. Glycans are important molecules which are involved in different biological recognition processes, especially in the spread of infection by mediating virus interaction with endothelial cells. Thus, novel strategies based on nanotechnology have been developed for identifying and inhibiting viruses in a fast, selective, and precise way. The nanosized nature of nanomaterials and their exclusive optical, electronic, magnetic, and mechanical features can improve patient care through using sensors with minimal invasiveness and extreme sensitivity. This review provides an overview of the latest advances of functionalized glyconanomaterials, for rapid and selective biosensing detection of molecules as biomarkers or specific glycoproteins and as novel promising antiviral agents for different kinds of serious viruses, such as the Dengue virus, Ebola virus, influenza virus, human immunodeficiency virus (HIV), influenza virus, Zika virus, or coronavirus SARS-CoV-2 (COVID-19).
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Affiliation(s)
- Noelia Losada-Garcia
- Department of Biocatalysis, Institute of Catalysis (CSIC), Marie Curie 2, 28049 Madrid, Spain; (N.L.-G.); (C.G.-S.); (A.A.)
| | - Carla Garcia-Sanz
- Department of Biocatalysis, Institute of Catalysis (CSIC), Marie Curie 2, 28049 Madrid, Spain; (N.L.-G.); (C.G.-S.); (A.A.)
| | - Alicia Andreu
- Department of Biocatalysis, Institute of Catalysis (CSIC), Marie Curie 2, 28049 Madrid, Spain; (N.L.-G.); (C.G.-S.); (A.A.)
| | | | - Jose M. Palomo
- Department of Biocatalysis, Institute of Catalysis (CSIC), Marie Curie 2, 28049 Madrid, Spain; (N.L.-G.); (C.G.-S.); (A.A.)
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4
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Sung PS, Hsieh SL. C-type lectins and extracellular vesicles in virus-induced NETosis. J Biomed Sci 2021; 28:46. [PMID: 34116654 PMCID: PMC8193014 DOI: 10.1186/s12929-021-00741-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
Dysregulated formation of neutrophil extracellular traps (NETs) is observed in acute viral infections. Moreover, NETs contribute to the pathogenesis of acute viral infections, including those caused by the dengue virus (DV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Furthermore, excessive NET formation (NETosis) is associated with disease severity in patients suffering from SARS-CoV-2-induced multiple organ injuries. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and other members of C-type lectin family (L-SIGN, LSECtin, CLEC10A) have been reported to interact with viral glycans to facilitate virus spreading and exacerbates inflammatory reactions. Moreover, spleen tyrosine kinase (Syk)-coupled C-type lectin member 5A (CLEC5A) has been shown as the pattern recognition receptor for members of flaviviruses, and is responsible for DV-induced cytokine storm and Japanese encephalomyelitis virus (JEV)-induced neuronal inflammation. Moreover, DV activates platelets via CLEC2 to release extracellular vesicles (EVs), including microvesicles (MVs) and exosomes (EXOs). The DV-activated EXOs (DV-EXOs) and MVs (DV-MVs) stimulate CLEC5A and Toll-like receptor 2 (TLR2), respectively, to enhance NET formation and inflammatory reactions. Thus, EVs from virus-activated platelets (PLT-EVs) are potent endogenous danger signals, and blockade of C-type lectins is a promising strategy to attenuate virus-induced NETosis and intravascular coagulopathy.
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Affiliation(s)
- Pei-Shan Sung
- Genomics Research Center, Academia Sinica, 128, Academia Road, Sec. 2, Nankang District, Taipei, 115 Taiwan
| | - Shie-Liang Hsieh
- Genomics Research Center, Academia Sinica, 128, Academia Road, Sec. 2, Nankang District, Taipei, 115 Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
- Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
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5
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Campana P, Parisi V, Leosco D, Bencivenga D, Della Ragione F, Borriello A. Dendritic Cells and SARS-CoV-2 Infection: Still an Unclarified Connection. Cells 2020; 9:E2046. [PMID: 32911691 PMCID: PMC7564940 DOI: 10.3390/cells9092046] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 01/19/2023] Open
Abstract
The ongoing pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has so far infected about 2.42 × 107 (as at 27 August 2020) subjects with more than 820,000 deaths. It is the third zoonotic coronavirus-dependent outbreak in the last twenty years and represents a major infective threat for public health worldwide. A main aspect of the infection, in analogy to other viral infections, is the so-called "cytokine storm", an inappropriate molecular response to virus spread which plays major roles in tissue and organ damage. Immunological therapies, including vaccines and humanized monoclonal antibodies, have been proposed as major strategies for prevention and treatment of the disease. Accordingly, a detailed mechanistic knowledge of the molecular events with which the virus infects cells and induces an immunological response appears necessary. In this review, we will report details of the initial process of SARS-CoV-2 cellular entry with major emphasis on the maturation of the spike protein. Then, a particular focus will be devoted to describe the possible mechanisms by which dendritic cells, a major cellular component of innate and adaptive immune responses, may play a role in the spread of the virus in the human body and in the clinical evolution of the disease.
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Affiliation(s)
- Pasquale Campana
- Department of Translational Medical Sciences, University of Naples ‘Federico II’, Via Sergio Pansini 5, 80131 Naples, Italy; (P.C.); (V.P.); (D.L.)
| | - Valentina Parisi
- Department of Translational Medical Sciences, University of Naples ‘Federico II’, Via Sergio Pansini 5, 80131 Naples, Italy; (P.C.); (V.P.); (D.L.)
| | - Dario Leosco
- Department of Translational Medical Sciences, University of Naples ‘Federico II’, Via Sergio Pansini 5, 80131 Naples, Italy; (P.C.); (V.P.); (D.L.)
| | - Debora Bencivenga
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via De Crecchio 7, 80138 Naples, Italy;
| | - Fulvio Della Ragione
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via De Crecchio 7, 80138 Naples, Italy;
| | - Adriana Borriello
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via De Crecchio 7, 80138 Naples, Italy;
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6
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Jan M, Upadhyay C, Hioe CE. HIV-1 Envelope Glycan Composition as a Key Determinant of Efficient Virus Transmission via DC-SIGN and Resistance to Inhibitory Lectins. iScience 2019; 21:413-427. [PMID: 31704652 PMCID: PMC6889591 DOI: 10.1016/j.isci.2019.10.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 09/17/2019] [Accepted: 10/15/2019] [Indexed: 02/04/2023] Open
Abstract
The HIV-1 envelope (Env) surface is shrouded with an assortment of oligomannose-, hybrid-, and complex-type glycans that enable virus interaction with carbohydrate-recognizing lectins. This study examined the importance of glycan heterogeneity for HIV-1 transmission through the trans-infection pathway by the host mannose-binding lectin DC-SIGN. A diversity of glycan content was observed among HIV-1 strains and associated with varying degrees of trans-infection via DC-SIGN and sensitivity to trans-infection blockage by antiviral lectins. When Env glycans were modified to display only the oligomannose type, DC-SIGN-mediated virus capture was enhanced; however, virus trans-infection was diminished because of increased degradation, which was alleviated by incorporation with hybrid-type glycans. Amino acid changes in the Env signal peptide (SP) modulated the Env glycan content, leading to alterations in DC-SIGN-dependent trans-infection and virus sensitivity to antiviral lectins. Hence, SP variation and glycosylation that confer varied types of oligosaccharides to HIV-1 Env are critical determinants for virus fitness and phenotypic diversity.
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Affiliation(s)
- Muzafar Jan
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Chitra Upadhyay
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA,Research Service, James J. Peters VA Medical Center, Bronx, NY 10468, USA
| | - Catarina E. Hioe
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA,Research Service, James J. Peters VA Medical Center, Bronx, NY 10468, USA,Corresponding author
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7
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Olukitibi TA, Ao Z, Mahmoudi M, Kobinger GA, Yao X. Dendritic Cells/Macrophages-Targeting Feature of Ebola Glycoprotein and its Potential as Immunological Facilitator for Antiviral Vaccine Approach. Microorganisms 2019; 7:E402. [PMID: 31569539 PMCID: PMC6843631 DOI: 10.3390/microorganisms7100402] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/19/2019] [Accepted: 09/26/2019] [Indexed: 01/06/2023] Open
Abstract
In the prevention of epidemic and pandemic viral infection, the use of the antiviral vaccine has been the most successful biotechnological and biomedical approach. In recent times, vaccine development studies have focused on recruiting and targeting immunogens to dendritic cells (DCs) and macrophages to induce innate and adaptive immune responses. Interestingly, Ebola virus (EBOV) glycoprotein (GP) has a strong binding affinity with DCs and macrophages. Shreds of evidence have also shown that the interaction between EBOV GP with DCs and macrophages leads to massive recruitment of DCs and macrophages capable of regulating innate and adaptive immune responses. Therefore, studies for the development of vaccine can utilize the affinity between EBOV GP and DCs/macrophages as a novel immunological approach to induce both innate and acquired immune responses. In this review, we will discuss the unique features of EBOV GP to target the DC, and its potential to elicit strong immune responses while targeting DCs/macrophages. This review hopes to suggest and stimulate thoughts of developing a stronger and effective DC-targeting vaccine for diverse virus infection using EBOV GP.
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Affiliation(s)
- Titus Abiola Olukitibi
- Laboratory of Molecular Human Retrovirology, Department of Medical Microbiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
| | - Zhujun Ao
- Laboratory of Molecular Human Retrovirology, Department of Medical Microbiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
| | - Mona Mahmoudi
- Laboratory of Molecular Human Retrovirology, Department of Medical Microbiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
| | - Gary A Kobinger
- Centre de Recherche en Infectiologie de l' Université Laval/Centre Hospitalier de l' Université Laval (CHUL), Québec, QC G1V 4G2, Canada.
| | - Xiaojian Yao
- Laboratory of Molecular Human Retrovirology, Department of Medical Microbiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
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8
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Martínez JD, Valverde P, Delgado S, Romanò C, Linclau B, Reichardt NC, Oscarson S, Ardá A, Jiménez-Barbero J, Cañada FJ. Unraveling Sugar Binding Modes to DC-SIGN by Employing Fluorinated Carbohydrates. Molecules 2019; 24:molecules24122337. [PMID: 31242623 PMCID: PMC6631030 DOI: 10.3390/molecules24122337] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/12/2019] [Accepted: 06/23/2019] [Indexed: 12/27/2022] Open
Abstract
A fluorine nuclear magnetic resonance (19F-NMR)-based method is employed to assess the binding preferences and interaction details of a library of synthetic fluorinated monosaccharides towards dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), a lectin of biomedical interest, which is involved in different viral infections, including HIV and Ebola, and is able to recognize a variety of self- and non-self-glycans. The strategy employed allows not only screening of a mixture of compounds, but also obtaining valuable information on the specific sugar–protein interactions. The analysis of the data demonstrates that monosaccharides Fuc, Man, Glc, and Gal are able to bind DC-SIGN, although with decreasing affinity. Moreover, a new binding mode between Man moieties and DC-SIGN, which might have biological implications, is also detected for the first time. The combination of the 19F with standard proton saturation transfer difference (1H-STD-NMR) data, assisted by molecular dynamics (MD) simulations, permits us to successfully define this new binding epitope, where Man coordinates a Ca2+ ion of the lectin carbohydrate recognition domain (CRD) through the axial OH-2 and equatorial OH-3 groups, thus mimicking the Fuc/DC-SIGN binding architecture.
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Affiliation(s)
- J Daniel Martínez
- CIC bioGUNE, Bizkaia Technology Park, Building 800, 48160 Derio, Bizkaia, Spain.
| | - Pablo Valverde
- CIC bioGUNE, Bizkaia Technology Park, Building 800, 48160 Derio, Bizkaia, Spain.
| | - Sandra Delgado
- CIC bioGUNE, Bizkaia Technology Park, Building 800, 48160 Derio, Bizkaia, Spain.
| | - Cecilia Romanò
- Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
| | - Bruno Linclau
- School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK.
| | - Niels C Reichardt
- CIC biomaGUNE, Paseo Miramon 182, 20009 San Sebastián, Gipuzkoa, Spain.
- CIBER-BBN, Paseo Miramon 182, 20009 San Sebastián, Gipuzkoa, Spain.
| | - Stefan Oscarson
- Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
| | - Ana Ardá
- CIC bioGUNE, Bizkaia Technology Park, Building 800, 48160 Derio, Bizkaia, Spain.
| | - Jesús Jiménez-Barbero
- CIC bioGUNE, Bizkaia Technology Park, Building 800, 48160 Derio, Bizkaia, Spain.
- Ikerbasque, Basque Foundation for Science, Maria Diaz de Haro 3, 48013 Bilbao, Bizkaia, Spain.
- Department of Organic Chemistry II, Faculty of Science and Technology, EHU-UPV, 48160 Leioa, Spain.
| | - F Javier Cañada
- Centro de Investigaciones Biológicas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
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9
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Rogers KJ, Maury W. The role of mononuclear phagocytes in Ebola virus infection. J Leukoc Biol 2018; 104:717-727. [PMID: 30095866 DOI: 10.1002/jlb.4ri0518-183r] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 07/09/2018] [Accepted: 07/12/2018] [Indexed: 12/17/2022] Open
Abstract
The filovirus, Zaire Ebolavirus (EBOV), infects tissue macrophages (Mϕs) and dendritic cells (DCs) early during infection. Viral infection of both cells types is highly productive, leading to increased viral load. However, virus infection of these two cell types results in different consequences for cellular function. Infection of Mϕs stimulates the production of proinflammatory and immunomodulatory cytokines and chemokines, leading to the production of a cytokine storm, while simultaneously increasing tissue factor production and thus facilitating disseminated intravascular coagulation. In contrast, EBOV infection of DCs blocks DC maturation and antigen presentation rendering these cells unable to communicate with adaptive immune response elements. Details of the known interactions of these cells with EBOV are reviewed here. We also identify a number of unanswered questions that remain about interactions of filoviruses with these cells.
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Affiliation(s)
- Kai J Rogers
- Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USA
| | - Wendy Maury
- Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USA
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10
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Davey RA, Shtanko O, Anantpadma M, Sakurai Y, Chandran K, Maury W. Mechanisms of Filovirus Entry. Curr Top Microbiol Immunol 2017; 411:323-352. [PMID: 28601947 DOI: 10.1007/82_2017_14] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Filovirus entry into cells is complex, perhaps as complex as any viral entry mechanism identified to date. However, over the past 10 years, the important events required for filoviruses to enter into the endosomal compartment and fuse with vesicular membranes have been elucidated (Fig. 1). Here, we highlight the important steps that are required for productive entry of filoviruses into mammalian cells.
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Affiliation(s)
- R A Davey
- Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - O Shtanko
- Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - M Anantpadma
- Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Y Sakurai
- Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - K Chandran
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - W Maury
- Department of Microbiology, The University of Iowa, Iowa City, IA, USA.
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11
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Qian YW, Li C, Jiang AP, Ge S, Gu P, Fan X, Li TS, Jin X, Wang JH, Wang ZL. HIV-1 gp120 Glycoprotein Interacting with Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN) Down-Regulates Tight Junction Proteins to Disrupt the Blood Retinal Barrier and Increase Its Permeability. J Biol Chem 2016; 291:22977-22987. [PMID: 27605665 DOI: 10.1074/jbc.m116.744615] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Indexed: 11/06/2022] Open
Abstract
Approximately 70% of HIV-1 infected patients acquire ocular opportunistic infections and manifest eye disorders during the course of their illness. The mechanisms by which pathogens invade the ocular site, however, are unclear. Under normal circumstances, vascular endothelium and retinal pigment epithelium (RPE), which possess a well developed tight junction complex, form the blood-retinal barrier (BRB) to prevent pathogen invasion. We hypothesize that disruption of the BRB allows pathogen entry into ocular sites. The hypothesis was tested using in vitro models. We discovered that human RPE cells could bind to either HIV-1 gp120 glycoproteins or HIV-1 viral particles. Furthermore, the binding was mediated by dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) expressed on RPE cells. Upon gp120 binding to DC-SIGN, cellular NF-κB signaling was triggered, leading to the induction of matrix metalloproteinases, which subsequently degraded tight junction proteins and disrupted the BRB integrity. DC-SIGN knockdown or prior blocking with a specific antibody abolished gp120-induced matrix metalloproteinase expression and reduced the degradation of tight junction proteins. This study elucidates a novel mechanism by which HIV, type 1 invades ocular tissues and provides additional insights into the translocation or invasion process of ocular complication-associated pathogens.
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Affiliation(s)
- Yi-Wen Qian
- From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Chuan Li
- From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Ai-Ping Jiang
- the Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology and
| | - Shengfang Ge
- From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Ping Gu
- From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Xianqun Fan
- From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Tai-Sheng Li
- the Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xia Jin
- the Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology and.,Viral Disease and Vaccine Translational Research Unit and Vaccine Center, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China, and
| | - Jian-Hua Wang
- the Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology and
| | - Zhi-Liang Wang
- From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China,
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12
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A review of nanotechnological approaches for the prophylaxis of HIV/AIDS. Biomaterials 2013; 34:6202-28. [PMID: 23726227 DOI: 10.1016/j.biomaterials.2013.05.012] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2013] [Accepted: 05/06/2013] [Indexed: 01/06/2023]
Abstract
Successful treatment and control of HIV/AIDS is one of the biggest challenges of 21st century. More than 33 million individuals are infected with HIV worldwide and more than 2 million new cases of HIV infection have been reported. The situation demands development of effective prevention strategies to control the pandemic of AIDS. Due to lack of availability of an effective HIV vaccine, antiretroviral drugs and nucleic acid therapeutics like siRNA have been explored for HIV prophylaxis. Clinical trials shave shown that antiretroviral drugs, tenofovir and emtricitabine can offer some degree of HIV prevention. However, complete prevention of HIV infection has not been achieved yet. Nanotechnology has brought a paradigm shift in the diagnosis, treatment and prevention of many diseases. The current review discusses potential of various nanocarriers such as dendrimers, polymeric nanoparticles, liposomes, lipid nanocarriers, drug nanocrystals, inorganic nanocarriers and nanofibers in improving efficacy of various modalities available for HIV prophylaxis.
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Abstract
Filoviruses cause severe hemorrhagic fever in humans with high case-fatality rates. The cellular factors exploited by filoviruses for their spread constitute potential targets for intervention, but are incompletely defined. The viral glycoprotein (GP) mediates filovirus entry into host cells. Recent studies revealed important insights into the host cell molecules engaged by GP for cellular entry. The binding of GP to cellular lectins was found to concentrate virions onto susceptible cells and might contribute to the early and sustained infection of macrophages and dendritic cells, important viral targets. Tyrosine kinase receptors were shown to promote macropinocytic uptake of filoviruses into a subset of susceptible cells without binding to GP, while interactions between GP and human T cell Ig mucin 1 (TIM-1) might contribute to filovirus infection of mucosal epithelial cells. Moreover, GP engagement of the cholesterol transporter Niemann-Pick C1 was demonstrated to be essential for GP-mediated fusion of the viral envelope with a host cell membrane. Finally, mutagenic and structural analyses defined GP domains which interact with these host cell factors. Here, we will review the recent progress in elucidating the molecular interactions underlying filovirus entry and discuss their implications for our understanding of the viral cell tropism.
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Abstract
Marburg and Ebola viruses cause a severe hemorrhagic disease in humans with high fatality rates. Early target cells of filoviruses are monocytes, macrophages, and dendritic cells. The infection spreads to the liver, spleen and later other organs by blood and lymph flow. A hallmark of filovirus infection is the depletion of non-infected lymphocytes; however, the molecular mechanisms leading to the observed bystander lymphocyte apoptosis are poorly understood. Also, there is limited knowledge about the fate of infected cells in filovirus disease. In this review we will explore what is known about the intracellular events leading to virus amplification and cell damage in filovirus infection. Furthermore, we will discuss how cellular dysfunction and cell death may correlate with disease pathogenesis.
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Affiliation(s)
- Judith Olejnik
- Department of Microbiology, School of Medicine, Boston University, 72 East Concord Street, Boston, MA 02118, USA; E-Mails: (J.O.); (R.B.C.)
- National Emerging Infectious Diseases Laboratories Institute, Boston University, 72 East Concord Street, Boston, MA 02118, USA
| | - Elena Ryabchikova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Science, Pr. Lavrent’eva, 8, Novosibirsk 630090, Russian Federation; E-Mail:
| | - Ronald B. Corley
- Department of Microbiology, School of Medicine, Boston University, 72 East Concord Street, Boston, MA 02118, USA; E-Mails: (J.O.); (R.B.C.)
- National Emerging Infectious Diseases Laboratories Institute, Boston University, 72 East Concord Street, Boston, MA 02118, USA
| | - Elke Mühlberger
- Department of Microbiology, School of Medicine, Boston University, 72 East Concord Street, Boston, MA 02118, USA; E-Mails: (J.O.); (R.B.C.)
- National Emerging Infectious Diseases Laboratories Institute, Boston University, 72 East Concord Street, Boston, MA 02118, USA
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-617-638-0336; Fax: +1-617-638-4286
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15
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Londrigan SL, Tate MD, Brooks AG, Reading PC. Cell-surface receptors on macrophages and dendritic cells for attachment and entry of influenza virus. J Leukoc Biol 2011; 92:97-106. [PMID: 22124137 PMCID: PMC7166464 DOI: 10.1189/jlb.1011492] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Review of interactions between influenza A virus and C‐type lectin receptors on macrophages and dendritic cells that may result in virus entry and infection. Airway MΦ and DCs are important components of innate host defense and can play a critical role in limiting the severity of influenza virus infection. Although it has been well established that cell‐surface SA acts as a primary attachment receptor for IAV, the particular receptor(s) or coreceptor(s) that mediate IAV entry into any cell, including MΦ and DC, have not been clearly defined. Identifying which receptors are involved in attachment and entry of IAV into immune cells may have important implications in regard to understanding IAV tropism and pathogenesis. Recent evidence suggests that specialized receptors on MΦ and DCs, namely CLRs, can act as capture and/or entry receptors for many viral pathogens, including IAV. Herein, we review the early stages of infection of MΦ and DC by IAV. Specifically, we examine the potential role of CLRs expressed on MΦ and DC to act as attachment and/or entry receptors for IAV.
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Affiliation(s)
- Sarah L Londrigan
- The Department of Microbiology and Immunology, The University of Melbourne, Victoria, Australia
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16
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Brindley MA, Hunt CL, Kondratowicz AS, Bowman J, Sinn PL, McCray PB, Quinn K, Weller ML, Chiorini JA, Maury W. Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein. Virology 2011; 415:83-94. [PMID: 21529875 DOI: 10.1016/j.virol.2011.04.002] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Revised: 01/28/2011] [Accepted: 04/04/2011] [Indexed: 12/27/2022]
Abstract
In a bioinformatics-based screen for cellular genes that enhance Zaire ebolavirus (ZEBOV) transduction, AXL mRNA expression strongly correlated with ZEBOV infection. A series of cell lines and primary cells were identified that require Axl for optimal ZEBOV entry. Using one of these cell lines, we identified ZEBOV entry events that are Axl-dependent. Interactions between ZEBOV-GP and the Axl ectodomain were not detected in immunoprecipitations and reduction of surface-expressed Axl by RNAi did not alter ZEBOV-GP binding, providing evidence that Axl does not serve as a receptor for the virus. However, RNAi knock down of Axl reduced ZEBOV pseudovirion internalization and α-Axl antisera inhibited pseudovirion fusion with cellular membranes. Consistent with the importance of Axl for ZEBOV transduction, Axl transiently co-localized on the surface of cells with ZEBOV virus particles and was internalized during virion transduction. In total, these findings indicate that endosomal uptake of filoviruses is facilitated by Axl.
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Affiliation(s)
- Melinda A Brindley
- Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
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17
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Pashov A, Garimalla S, Monzavi-Karbassi B, Kieber-Emmons T. Carbohydrate targets in HIV vaccine research: lessons from failures. Immunotherapy 2011; 1:777-94. [PMID: 20636023 DOI: 10.2217/imt.09.44] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Learning from the successes of other vaccines that enhance natural and existing protective responses to pathogens, the current effort in HIV vaccine research is directed toward inducing cytotoxic responses. Nevertheless, antibodies are fundamental players in vaccine development and are still considered in the context of passive specific immunotherapy of HIV, especially since several broadly neutralizing monoclonals are available. Special interest is directed toward antibodies binding to the glycan array on gp120 since they have the potential of broader reactivity and cross-clade neutralizing capacity. Humoral responses to carbohydrate antigens have proven effective against other pathogens, why not HIV? The variability of the epitope targets on HIV may not be the only problem to developing active or passive immunotherapeutic strategies. The dynamics of the infected immune system leads to ambiguous effects of most of the effector mechanisms calling for new approaches; some may already be available, while others are in the making.
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Affiliation(s)
- Anastas Pashov
- Department of Pathology & Winthrop P Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 West Markham St, #824 Little Rock, AR 72205, USA
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18
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Nanbo A, Imai M, Watanabe S, Noda T, Takahashi K, Neumann G, Halfmann P, Kawaoka Y. Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner. PLoS Pathog 2010; 6:e1001121. [PMID: 20886108 PMCID: PMC2944813 DOI: 10.1371/journal.ppat.1001121] [Citation(s) in RCA: 325] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2010] [Accepted: 08/25/2010] [Indexed: 12/12/2022] Open
Abstract
Ebolavirus (EBOV) is an enveloped, single-stranded, negative-sense RNA virus that causes severe hemorrhagic fever with mortality rates of up to 90% in humans and nonhuman primates. Previous studies suggest roles for clathrin- or caveolae-mediated endocytosis in EBOV entry; however, ebolavirus virions are long, filamentous particles that are larger than the plasma membrane invaginations that characterize clathrin- or caveolae-mediated endocytosis. The mechanism of EBOV entry remains, therefore, poorly understood. To better understand Ebolavirus entry, we carried out internalization studies with fluorescently labeled, biologically contained Ebolavirus and Ebolavirus-like particles (Ebola VLPs), both of which resemble authentic Ebolavirus in their morphology. We examined the mechanism of Ebolavirus internalization by real-time analysis of these fluorescently labeled Ebolavirus particles and found that their internalization was independent of clathrin- or caveolae-mediated endocytosis, but that they co-localized with sorting nexin (SNX) 5, a marker of macropinocytosis-specific endosomes (macropinosomes). Moreover, the internalization of Ebolavirus virions accelerated the uptake of a macropinocytosis-specific cargo, was associated with plasma membrane ruffling, and was dependent on cellular GTPases and kinases involved in macropinocytosis. A pseudotyped vesicular stomatitis virus possessing the Ebolavirus glycoprotein (GP) also co-localized with SNX5 and its internalization and infectivity were affected by macropinocytosis inhibitors. Taken together, our data suggest that Ebolavirus is internalized into cells by stimulating macropinocytosis in a GP-dependent manner. These findings provide new insights into the lifecycle of Ebolavirus and may aid in the development of therapeutics for Ebolavirus infection. Ebolavirus (EBOV) is an enveloped, single-stranded, negative-sense RNA virus that causes severe hemorrhagic fever with high mortality rates in humans and nonhuman primates. Previous studies suggest roles for clathrin- or caveolae-mediated endocytosis in EBOV entry; however, questions remain regarding the mechanism of EBOV entry. Here, we demonstrate that internalization of EBOV particles is independent of clathrin- or caveolae-mediated endocytosis. Specifically, we show that internalized EBOV particles co-localize with macropinocytosis-specific endosomes (macropinosomes) and that their entry is negatively affected by treatment with macropinocytosis inhibitors. Moreover, the internalization of Ebola virions accelerated the uptake of a macropinocytosis-specific cargo, was associated with plasma membrane ruffling, and was dependent on cellular GTPases and kinases involved in macropinocytosis. We further demonstrate that a pseudotyped vesicular stomatitis virus possessing the EBOV glycoprotein (GP) also co-localizes with macropinosomes and its internalization is similarly affected by macropinocytosis inhibitors. Our results indicate that EBOV uptake into cells involves the macropinocytic pathway and is GP-dependent. These findings provide new insights into the lifecycle of EBOV and may aid in the development of therapeutics for EBOV infection.
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Affiliation(s)
- Asuka Nanbo
- Influenza Research Institute, Department of Pathological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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19
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Hanley TM, Blay Puryear W, Gummuluru S, Viglianti GA. PPARgamma and LXR signaling inhibit dendritic cell-mediated HIV-1 capture and trans-infection. PLoS Pathog 2010; 6:e1000981. [PMID: 20617179 PMCID: PMC2895661 DOI: 10.1371/journal.ppat.1000981] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2009] [Accepted: 06/02/2010] [Indexed: 12/22/2022] Open
Abstract
Dendritic cells (DCs) contribute to human immunodeficiency virus type 1 (HIV-1) transmission and dissemination by capturing and transporting infectious virus from the mucosa to draining lymph nodes, and transferring these virus particles to CD4+ T cells with high efficiency. Toll-like receptor (TLR)-induced maturation of DCs enhances their ability to mediate trans-infection of T cells and their ability to migrate from the site of infection. Because TLR-induced maturation can be inhibited by nuclear receptor (NR) signaling, we hypothesized that ligand-activated NRs could repress DC-mediated HIV-1 transmission and dissemination. Here, we show that ligands for peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor (LXR) prevented proinflammatory cytokine production by DCs and inhibited DC migration in response to the chemokine CCL21 by preventing the TLR-induced upregulation of CCR7. Importantly, PPARgamma and LXR signaling inhibited both immature and mature DC-mediated trans-infection by preventing the capture of HIV-1 by DCs independent of the viral envelope glycoprotein. PPARgamma and LXR signaling induced cholesterol efflux from DCs and led to a decrease in DC-associated cholesterol, which has previously been shown to be required for DC capture of HIV-1. Finally, both cholesterol repletion and the targeted knockdown of the cholesterol transport protein ATP-binding cassette A1 (ABCA1) restored the ability of NR ligand treated cells to capture HIV-1 and transfer it to T cells. Our results suggest that PPARgamma and LXR signaling up-regulate ABCA1-mediated cholesterol efflux from DCs and that this accounts for the decreased ability of DCs to capture HIV-1. The ability of NR ligands to repress DC mediated trans-infection, inflammation, and DC migration underscores their potential therapeutic value in inhibiting HIV-1 mucosal transmission.
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Affiliation(s)
- Timothy M. Hanley
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Wendy Blay Puryear
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Suryaram Gummuluru
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Gregory A. Viglianti
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America
- * E-mail:
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20
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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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21
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Cassol E, Cassetta L, Alfano M, Poli G. Macrophage polarization and HIV-1 infection. J Leukoc Biol 2009; 87:599-608. [PMID: 20042468 DOI: 10.1189/jlb.1009673] [Citation(s) in RCA: 122] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- Edana Cassol
- AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
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22
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Rogers KM, Heise M. Modulation of cellular tropism and innate antiviral response by viral glycans. J Innate Immun 2009; 1:405-12. [PMID: 20375598 DOI: 10.1159/000226422] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2009] [Accepted: 04/08/2009] [Indexed: 01/18/2023] Open
Abstract
Arthropod-borne viruses (arboviruses) are a significant cause of human and animal disease worldwide. Multiple interactions between virus and the host innate immune system ultimately determine the pathogenesis and clinical outcome of the infection. Evidence is rapidly emerging that suggests viral glycans play a key role in viral pathogenesis by regulating host cell tropism and interactions with the host innate immune response. Glycan-mediated interactions are especially important for arboviruses which must adapt to variable glycosylation systems and cellular receptors within both vertebrate and invertebrate hosts. This review focuses on emerging evidence which supports a crucial role for viral glycans in mediating host cell tropism and regulating the innate antiviral response.
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Affiliation(s)
- Kristin M Rogers
- Department of Genetics, Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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23
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Marzi A, Möller P, Hanna SL, Harrer T, Eisemann J, Steinkasserer A, Becker S, Baribaud F, Pöhlmann S. Analysis of the interaction of Ebola virus glycoprotein with DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin) and its homologue DC-SIGNR. J Infect Dis 2008; 196 Suppl 2:S237-46. [PMID: 17940955 PMCID: PMC7110133 DOI: 10.1086/520607] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The lectin DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin) augments Ebola virus (EBOV) infection. However, it its unclear whether DC-SIGN promotes only EBOV attachment (attachment factor function, nonessential) or actively facilitates EBOV entry (receptor function, essential). METHODS We investigated whether DC-SIGN on B cell lines and dendritic cells acts as an EBOV attachment factor or receptor. RESULTS Engineered DC-SIGN expression rendered some B cell lines susceptible to EBOV glycoprotein (EBOV GP)-driven infection, whereas others remained refractory, suggesting that cellular factors other than DC-SIGN are also required for susceptibility to EBOV infection. Augmentation of entry was independent of efficient DC-SIGN internalization and might not involve lectin-mediated endocytic uptake of virions. Therefore, DC-SIGN is unlikely to function as an EBOV receptor on B cell lines; instead, it might concentrate virions onto cells, thereby allowing entry into cell lines expressing low levels of endogenous receptor(s). Indeed, artificial concentration of virions onto cells mirrored DC-SIGN expression, confirming that optimization of viral attachment is sufficient for EBOV GP-driven entry into some B cell lines. Finally, EBOV infection of dendritic cells was only partially dependent on mannose-specific lectins, such as DC-SIGN, suggesting an important contribution of other factors. CONCLUSIONS Our results indicate that DC-SIGN is not an EBOV receptor but, rather, is an attachment-promoting factor that boosts entry into B cell lines susceptible to low levels of EBOV GP-mediated infection.
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Affiliation(s)
- Andrea Marzi
- Institute of Virology, Nikolaus-Fiebiger-Center for Molecular Medicine, Erlangen, Germany
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24
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Johnson TR. Respiratory syncytial virus and innate immunity: a complex interplay of exploitation and subversion. Expert Rev Vaccines 2007; 5:371-80. [PMID: 16827621 DOI: 10.1586/14760584.5.3.371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Respiratory syncytial virus causes significant disease in infants, the elderly and select groups of immunocompromised patients. Healthy individuals are also naturally infected with respiratory syncytial virus repeatedly throughout life. Therefore, safe and effective vaccines and therapies are needed. However, a number of factors have prevented development of such antiviral interventions to date. These include a failed vaccine trial, the very young age of the primary target population (neonates), the inability of natural infection to induce long-term protective immunity, and an incomplete understanding of virus-host interactions. The identification of pattern recognition receptors has led to significant increases in our understanding of induction and regulation of innate immune responses. This review will address the impact of these findings on respiratory syncytial virus research.
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Affiliation(s)
- Teresa R Johnson
- Vaccine Research Center, NIAID, NIH, Building 40 Room 2614, 40 Convent Drive MSC3017, Bethesda, MD 20892, USA.
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25
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Abstract
Several chronic viral infections (such as HIV and hepatitis C virus) are highly prevalent and are a serious health risk. The adaptation of animal viruses to the human host, as recently exemplified by influenza viruses and the severe acute respiratory syndrome coronavirus, is also a continuous threat. There is a high demand, therefore, for new antiviral lead compounds and novel therapeutic concepts. In this Review, an original therapeutic concept for suppressing enveloped viruses is presented that is based on a specific interaction of carbohydrate-binding agents (CBAs) with the glycans present on viral-envelope glycoproteins. This approach may also be extended to other pathogens, including parasites, bacteria and fungi.
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Affiliation(s)
- Jan Balzarini
- Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
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26
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Brindley MA, Hughes L, Ruiz A, McCray PB, Sanchez A, Sanders DA, Maury W. Ebola virus glycoprotein 1: identification of residues important for binding and postbinding events. J Virol 2007; 81:7702-9. [PMID: 17475648 PMCID: PMC1933332 DOI: 10.1128/jvi.02433-06] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The filoviruses Ebola virus (EBOV) and Marburg virus (MARV) are responsible for devastating hemorrhagic fever outbreaks. No therapies are available against these viruses. An understanding of filoviral glycoprotein 1 (GP1) residues involved in entry events would facilitate the development of antivirals. Towards this end, we performed alanine scanning mutagenesis on selected residues in the amino terminus of GP1. Mutant GPs were evaluated for their incorporation onto feline immunodeficiency virus (FIV) particles, transduction efficiency, receptor binding, and ability to be cleaved by cathepsins L and B. FIV virions bearing 39 out of 63 mutant glycoproteins transduced cells efficiently, whereas virions bearing the other 24 had reduced levels of transduction. Virions pseudotyped with 23 of the poorly transducing GPs were characterized for their block in entry. Ten mutant GPs were very poorly incorporated onto viral particles. Nine additional mutant GPs (G87A/F88A, K114A/K115A, K140A, G143A, P146A/C147A, F153A/H154A, F159A, F160A, and Y162A) competed poorly with wild-type GP for binding to permissive cells. Four of these nine mutants (P146A/C147A, F153A/H154A, F159A, and F160A) were also inefficiently cleaved by cathepsins. An additional four mutant GPs (K84A, R134A, D150A, and E305/E306A) that were partially defective in transduction were found to compete effectively for receptor binding and were readily cleaved by cathepsins. This finding suggested that this latter group of mutants might be defective at a postbinding, cathepsin cleavage-independent step. In total, our study confirms the role of some GP1 residues in EBOV entry that had previously been recognized and identifies for the first time other residues that are important for productive entry.
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Affiliation(s)
- Melinda A Brindley
- Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
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27
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Antibodies to the C-type lectin, L-SIGN, as tentative therapeutic agents for induction of antigen-specific tolerance. Expert Opin Ther Pat 2007. [DOI: 10.1517/13543776.17.2.243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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28
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Abstract
Being highly pathogenic for human and nonhuman primates and the subject of former weapon programmes makes Ebola virus one of the most feared pathogens worldwide today. Due to a lack of licensed pre- and postexposure intervention, the current response depends on rapid diagnostics, proper isolation procedures and supportive care of case patients. Consequently, the development of more specific countermeasures is of high priority for the preparedness of many nations. Over the past years, enhanced research efforts directed to better understand virus replication and pathogenesis have identified potential new targets for intervention strategies. The authors discuss the most promising therapeutic approaches for Ebola haemorrhagic fever as judged by their efficacy in animal models. The current development in this field encourages discussions on how to move some of the experimental approaches towards clinical application.
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Affiliation(s)
- Ute Ströher
- National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, Manitoba, R3E3R2, Canada.
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29
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Chaipan C, Soilleux EJ, Simpson P, Hofmann H, Gramberg T, Marzi A, Geier M, Stewart EA, Eisemann J, Steinkasserer A, Suzuki-Inoue K, Fuller GL, Pearce AC, Watson SP, Hoxie JA, Baribaud F, Pöhlmann S. DC-SIGN and CLEC-2 mediate human immunodeficiency virus type 1 capture by platelets. J Virol 2006; 80:8951-60. [PMID: 16940507 PMCID: PMC1563896 DOI: 10.1128/jvi.00136-06] [Citation(s) in RCA: 198] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Platelets can engulf human immunodeficiency virus type 1 (HIV-1), and a significant amount of HIV-1 in the blood of infected individuals is associated with these cells. However, it is unclear how platelets capture HIV-1 and whether platelet-associated virus remains infectious. DC-SIGN and other lectins contribute to capture of HIV-1 by dendritic cells (DCs) and facilitate HIV-1 spread in DC/T-cell cocultures. Here, we show that platelets express both the C-type lectin-like receptor 2 (CLEC-2) and low levels of DC-SIGN. CLEC-2 bound to HIV-1, irrespective of the presence of the viral envelope protein, and facilitated HIV-1 capture by platelets. However, a substantial fraction of the HIV-1 binding activity of platelets was dependent on DC-SIGN. A combination of DC-SIGN and CLEC-2 inhibitors strongly reduced HIV-1 association with platelets, indicating that these lectins are required for efficient HIV-1 binding to platelets. Captured HIV-1 was maintained in an infectious state over several days, suggesting that HIV-1 can escape degradation by platelets and might use these cells to promote its spread. Our results identify CLEC-2 as a novel HIV-1 attachment factor and provide evidence that platelets capture and transfer infectious HIV-1 via DC-SIGN and CLEC-2, thereby possibly facilitating HIV-1 dissemination in infected patients.
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Affiliation(s)
- Chawaree Chaipan
- Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany
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30
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Marzi A, Akhavan A, Simmons G, Gramberg T, Hofmann H, Bates P, Lingappa VR, Pöhlmann S. The signal peptide of the ebolavirus glycoprotein influences interaction with the cellular lectins DC-SIGN and DC-SIGNR. J Virol 2006; 80:6305-17. [PMID: 16775318 PMCID: PMC1488929 DOI: 10.1128/jvi.02545-05] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The C-type lectins DC-SIGN and DC-SIGNR (collectively referred to as DC-SIGN/R) bind to the ebolavirus glycoprotein (EBOV-GP) and augment viral infectivity. DC-SIGN/R strongly enhance infection driven by the GP of EBOV subspecies. Zaire (ZEBOV) but have a much less pronounced effect on infection mediated by the GP of EBOV subspecies. Sudan (SEBOV). For this study, we analyzed the determinants of the differential DC-SIGN/R interactions with ZEBOV- and SEBOV-GP. The efficiency of DC-SIGN engagement by ZEBOV-GP was dependent on the rate of GP incorporation into lentiviral particles, while appreciable virion incorporation of SEBOV-GP did not allow robust DC-SIGN/R usage. Forced incorporation of high-mannose carbohydrates into SEBOV-GP augmented the engagement of DC-SIGN/R to the levels observed with ZEBOV-GP, indicating that appropriate glycosylation of SEBOV-GP is sufficient for efficient DC-SIGN/R usage. However, neither signals for N-linked glycosylation unique to SEBOV- or ZEBOV-GP nor the highly variable and heavily glycosylated mucin-like domain modulated the interaction with DC-SIGN/R. In contrast, analysis of chimeric GPs identified the signal peptide as a determinant of DC-SIGN/R engagement. Thus, ZEBOV- but not SEBOV-GP was shown to harbor high-mannose carbohydrates, and GP modification with these glycans was controlled by the signal peptide. These results suggest that the signal peptide governs EBOV-GP interactions with DC-SIGN/R by modulating the incorporation of high-mannose carbohydrates into EBOV-GP. In summary, we identified the level of GP incorporation into virions and signal peptide-controlled glycosylation of GP as determinants of attachment factor engagement.
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Affiliation(s)
- Andrea Marzi
- Institute for Clinical and Molecular Virology and Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany
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Marzi A, Wegele A, Pöhlmann S. Modulation of virion incorporation of Ebolavirus glycoprotein: effects on attachment, cellular entry and neutralization. Virology 2006; 352:345-56. [PMID: 16777170 DOI: 10.1016/j.virol.2006.04.038] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2006] [Revised: 02/23/2006] [Accepted: 04/27/2006] [Indexed: 01/09/2023]
Abstract
The filoviruses Ebolavirus (EBOV) and Marburgvirus (MARV) cause severe hemorrhagic fever in humans and are potential agents of biological warfare. The envelope glycoprotein (GP) of filoviruses mediates viral entry into cells and is an attractive target for therapeutic intervention and vaccine design. Here, we asked if the efficiency of virion incorporation of EBOV-GP impacts attachment and entry into target cells and modulates susceptibility to neutralizing antibodies. In order to control the level of EBOV-GP expression, we generated cell lines expressing the GPs of the four known EBOV subspecies in an inducible fashion. Regulated expression of GP on the cell surface allowed production of reporter viruses harboring different amounts of GP. A pronounced reduction of virion incorporation of EBOV-GP had relatively little effect on virion infectivity, suggesting that only a few copies of GP might be sufficient for efficient engagement of cellular receptors. In contrast, optimal interactions with cellular attachment factors like the DC-SIGN protein required incorporation of high amounts of GP. Antibody-mediated neutralization of virions bearing high amounts of GP was slightly more efficient than neutralization of virions harboring low amounts of GP, suggesting that the efficiency of GP incorporation into virions might modulate susceptibility to neutralizing antibodies. Finally, regulated expression of GP in permissive 293 cells did not reduce EBOV-GP-driven infection but diminished vesicular stomatitis virus GP (VSV-G) and amphotropic murine leukemia virus (A-MLV) GP mediated entry in a dose-dependent manner. Therefore, intracellular GP does not seem to downmodulate expression of its receptor(s) but might alter expression and/or function of molecules involved in VSV-G and A-MLV-GP-dependent entry. Our results suggest that the efficiency of virion incorporation of GP could impact EBOV attachment to target cells and might modulate control of viral spread by the humoral immune response.
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Affiliation(s)
- Andrea Marzi
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
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Gramberg T, Zhu T, Chaipan C, Marzi A, Liu H, Wegele A, Andrus T, Hofmann H, Pöhlmann S. Impact of polymorphisms in the DC-SIGNR neck domain on the interaction with pathogens. Virology 2006; 347:354-63. [PMID: 16413044 PMCID: PMC7111803 DOI: 10.1016/j.virol.2005.11.033] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2005] [Revised: 09/19/2005] [Accepted: 11/23/2005] [Indexed: 11/28/2022]
Abstract
The lectins DC-SIGN and DC-SIGNR augment infection by human immunodeficiency virus (HIV), Ebolavirus (EBOV) and other pathogens. The neck domain of these proteins drives multimerization, which is believed to be required for efficient recognition of multivalent ligands. The neck domain of DC-SIGN consists of seven sequence repeats with rare variations. In contrast, the DC-SIGNR neck domain is polymorphic and, in addition to the wild type (wt) allele with seven repeat units, allelic forms with five and six sequence repeats are frequently found. A potential association of the DC-SIGNR genotype and risk of HIV-1 infection is currently under debate. Therefore, we investigated if DC-SIGNR alleles with five and six repeat units exhibit defects in pathogen capture. Here, we show that wt DC-SIGNR and patient derived alleles with five and six repeats bind viral glycoproteins, augment viral infection and tetramerize with comparable efficiency. Moreover, coexpression of wt DC-SIGNR and alleles with five repeats did not decrease the interaction with pathogens compared to expression of each allele alone, suggesting that potential formation of hetero-oligomers does not appreciably reduce pathogen binding, at least under conditions of high expression. Thus, our results do not provide evidence for diminished pathogen capture by DC-SIGNR alleles with five and six repeat units. Albeit, we cannot exclude that subtle, but in vivo relevant differences remained undetected, our analysis suggests that indirect mechanisms could account for the association of polymorphisms in the DC-SIGNR neck region with reduced risk of HIV-1 infection.
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MESH Headings
- Cell Adhesion Molecules/chemistry
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/metabolism
- Cell Adhesion Molecules/physiology
- Cell Culture Techniques
- HIV Infections/metabolism
- HIV-1/metabolism
- Lectins, C-Type/chemistry
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Lectins, C-Type/physiology
- Polymorphism, Genetic
- Protein Structure, Tertiary/genetics
- Receptors, Cell Surface/chemistry
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Receptors, Cell Surface/physiology
- Repetitive Sequences, Nucleic Acid/genetics
- Viral Envelope Proteins/genetics
- Viral Envelope Proteins/metabolism
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Affiliation(s)
- Thomas Gramberg
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Tuofu Zhu
- Department of Laboratory Medicine, University of Washington, School of Medicine, Seattle, WA 98195, USA
- Microbiology, University of Washington, School of Medicine, Seattle, WA 98195, USA
| | - Chawaree Chaipan
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Andrea Marzi
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Huanliang Liu
- Department of Laboratory Medicine, University of Washington, School of Medicine, Seattle, WA 98195, USA
| | - Anja Wegele
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Thomas Andrus
- Department of Laboratory Medicine, University of Washington, School of Medicine, Seattle, WA 98195, USA
| | - Heike Hofmann
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Department of Medical Microbiology and Virology, University of Kiel, 24105 Kiel, Germany
| | - Stefan Pöhlmann
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
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Kuhn JH, Radoshitzky SR, Guth AC, Warfield KL, Li W, Vincent MJ, Towner JS, Nichol ST, Bavari S, Choe H, Aman MJ, Farzan M. Conserved receptor-binding domains of Lake Victoria marburgvirus and Zaire ebolavirus bind a common receptor. J Biol Chem 2006; 281:15951-8. [PMID: 16595665 DOI: 10.1074/jbc.m601796200] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The GP(1,2) envelope glycoproteins (GP) of filoviruses (marburg- and ebolaviruses) mediate cell-surface attachment, membrane fusion, and entry into permissive cells. Here we show that a 151-amino acid fragment of the Lake Victoria marburgvirus GP1 subunit bound filovirus-permissive cell lines more efficiently than full-length GP1. An homologous 148-amino acid fragment of the Zaire ebolavirus GP1 subunit similarly bound the same cell lines more efficiently than a series of longer GP1 truncation variants. Neither the marburgvirus GP1 fragment nor that of ebolavirus bound a nonpermissive lymphocyte cell line. Both fragments specifically inhibited replication of infectious Zaire ebolavirus, as well as entry of retroviruses pseudotyped with either Lake Victoria marburgvirus or Zaire ebolavirus GP(1,2). These studies identify the receptor-binding domains of both viruses, indicate that these viruses utilize a common receptor, and suggest that a single small molecule or vaccine can be developed to inhibit infection of all filoviruses.
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Affiliation(s)
- Jens H Kuhn
- Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA
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Davis CW, Nguyen HY, Hanna SL, Sánchez MD, Doms RW, Pierson TC. West Nile virus discriminates between DC-SIGN and DC-SIGNR for cellular attachment and infection. J Virol 2006; 80:1290-301. [PMID: 16415006 PMCID: PMC1346927 DOI: 10.1128/jvi.80.3.1290-1301.2006] [Citation(s) in RCA: 249] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The C-type lectins DC-SIGN and DC-SIGNR bind mannose-rich glycans with high affinity. In vitro, cells expressing these attachment factors efficiently capture, and are infected by, a diverse array of appropriately glycosylated pathogens, including dengue virus. In this study, we investigated whether these lectins could enhance cellular infection by West Nile virus (WNV), a mosquito-borne flavivirus related to dengue virus. We discovered that DC-SIGNR promoted WNV infection much more efficiently than did DC-SIGN, particularly when the virus was grown in human cell types. The presence of a single N-linked glycosylation site on either the prM or E glycoprotein of WNV was sufficient to allow DC-SIGNR-mediated infection, demonstrating that uncleaved prM protein present on a flavivirus virion can influence viral tropism under certain circumstances. Preferential utilization of DC-SIGNR was a specific property conferred by the WNV envelope glycoproteins. Chimeras between DC-SIGN and DC-SIGNR demonstrated that the ability of DC-SIGNR to promote WNV infection maps to its carbohydrate recognition domain. WNV virions and subviral particles bound to DC-SIGNR with much greater affinity than DC-SIGN. We believe this is the first report of a pathogen interacting more efficiently with DC-SIGNR than with DC-SIGN. Our results should lead to the discovery of new mechanisms by which these well-studied lectins discriminate among ligands.
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Affiliation(s)
- Carl W Davis
- Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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Gramberg T, Caminschi I, Wegele A, Hofmann H, Pöhlmann S. Evidence that multiple defects in murine DC-SIGN inhibit a functional interaction with pathogens. Virology 2006; 345:482-91. [PMID: 16297949 PMCID: PMC7111805 DOI: 10.1016/j.virol.2005.10.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2005] [Revised: 08/09/2005] [Accepted: 10/12/2005] [Indexed: 12/14/2022]
Abstract
Certain viruses, bacteria, fungi and parasites target dendritic cells through the interaction with the cellular attachment factor DC-SIGN, making this C-type lectin an attractive target for therapeutic intervention. Studies on DC-SIGN function would be greatly aided by the establishment of a mouse model, however, it is unclear if the murine (m) homologue of human (h) DC-SIGN also binds to pathogens. Here, we investigated the interaction of mDC-SIGN, also termed CIRE, with the Ebolavirus glycoprotein (EBOV-GP), a ligand of hDC-SIGN. We found that mDC-SIGN neither binds EBOV-GP nor enhances infection by reporterviruses pseudotyped with EBOV-GP. Analysis of chimeras between mDC-SIGN and hDC-SIGN provided evidence that determinants in the carbohydrate recognition domain and in the neck domain of mDC-SIGN inhibit a functional interaction with EBOV-GP. Moreover, mDC-SIGN was found be monomeric, suggesting that lack of multimerization, which is believed to be required for efficient pathogen recognition by hDC-SIGN, might be one factor that prevents binding of mDC-SIGN to EBOV-GP. Our results suggest that mDC-SIGN on murine dendritic cells is not an adequate model for pathogen interactions with hDC-SIGN.
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Affiliation(s)
- Thomas Gramberg
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
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36
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Gramberg T, Hofmann H, Möller P, Lalor PF, Marzi A, Geier M, Krumbiegel M, Winkler T, Kirchhoff F, Adams DH, Becker S, Münch J, Pöhlmann S. LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus. Virology 2005; 340:224-36. [PMID: 16051304 PMCID: PMC7111772 DOI: 10.1016/j.virol.2005.06.026] [Citation(s) in RCA: 169] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2005] [Revised: 05/10/2005] [Accepted: 06/13/2005] [Indexed: 11/23/2022]
Abstract
Cellular attachment factors like the C-type lectins DC-SIGN and DC-SIGNR (collectively referred to as DC-SIGN/R) can augment viral infection and might promote viral dissemination in and between hosts. The lectin LSECtin is encoded in the same chromosomal locus as DC-SIGN/R and is coexpressed with DC-SIGNR on sinusoidal endothelial cells in liver and lymphnodes. Here, we show that LSECtin enhances infection driven by filovirus glycoproteins (GP) and the S protein of SARS coronavirus, but does not interact with human immunodeficiency virus type-1 and hepatitis C virus envelope proteins. Ligand binding to LSECtin was inhibited by EGTA but not by mannan, suggesting that LSECtin unlike DC-SIGN/R does not recognize high-mannose glycans on viral GPs. Finally, we demonstrate that LSECtin is N-linked glycosylated and that glycosylation is required for cell surface expression. In summary, we identified LSECtin as an attachment factor that in conjunction with DC-SIGNR might concentrate viral pathogens in liver and lymph nodes.
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Affiliation(s)
- Thomas Gramberg
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Heike Hofmann
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Peggy Möller
- Institute for Virology, Philipps-University Marburg, 35037 Marburg, Germany
| | - Patricia F. Lalor
- Liver Research Group, Institute for Biomedical Science, The University of Birmingham Medical School, Edgbaston, Birmingham, UK
- MRC Centre for Immune Regulation, The University of Birmingham Medical School, Edgbaston, Birmingham, UK
| | - Andrea Marzi
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Martina Geier
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Mandy Krumbiegel
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Thomas Winkler
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Chair of Genetics, University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Frank Kirchhoff
- Department of Virology, Universitätsklinikum Ulm, 89081 Ulm, Germany
| | - David H. Adams
- Liver Research Group, Institute for Biomedical Science, The University of Birmingham Medical School, Edgbaston, Birmingham, UK
- MRC Centre for Immune Regulation, The University of Birmingham Medical School, Edgbaston, Birmingham, UK
| | - Stephan Becker
- Institute for Virology, Philipps-University Marburg, 35037 Marburg, Germany
| | - Jan Münch
- Department of Virology, Universitätsklinikum Ulm, 89081 Ulm, Germany
| | - Stefan Pöhlmann
- Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Corresponding author. Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, Glückstraße 6, 91054 Erlangen, Germany. Fax: +49 9131 8529111.
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Nobile C, Petit C, Moris A, Skrabal K, Abastado JP, Mammano F, Schwartz O. Covert human immunodeficiency virus replication in dendritic cells and in DC-SIGN-expressing cells promotes long-term transmission to lymphocytes. J Virol 2005; 79:5386-99. [PMID: 15827153 PMCID: PMC1082762 DOI: 10.1128/jvi.79.9.5386-5399.2005] [Citation(s) in RCA: 117] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
HIV-1 virions are efficiently captured by monocyte-derived immature dendritic cells (iDCs), as well as by cell lines expressing the lectin DC-SIGN. Viral infectivity can be retained for several days, and even enhanced, before transmission to CD4+ lymphocytes. The role of DC-SIGN in viral retention and enhancement of infection is not fully understood and varies according to the cell line expressing the lectin. We studied here the mechanisms underlying this process. We focused our study on X4-tropic human immunodeficiency virus (HIV) strains, since they were widely believed not to replicate in iDCs. However, we first show that X4 HIV replicates covertly and slowly in iDCs. This is also the case in Raji-DC-SIGN cells, which are classically used to study HIV transmission. We used either single-cycle or replicative HIV and measured viral RT and replication to further demonstrate that transfer of incoming virions from iDCs or DC-SIGN+ cells occurs only on the short-term (i.e., a few hours after viral exposure). There is no long-term storage of original HIV particles in these cells. A few days after viral exposure, replicative viruses, and not single-cycle virions, are transmitted to CD4+ cells. The cell-type-dependent activity of DC-SIGN reflects the ability of HIV to replicate covertly in some cells, and not in others.
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Affiliation(s)
- Cinzia Nobile
- Institut Pasteur, Groupe Virus et Immunité, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France.
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Abstract
The filoviruses, marburgvirus and ebolavirus, cause epidemics of haemorrhagic fever with high case-fatality rates. The severe illness results from a complex of pathogenetic mechanisms that enable the virus to suppress innate and adaptive immune responses, infect and kill a broad variety of cell types, and elicit strong inflammatory responses and disseminated intravascular coagulation, producing a syndrome resembling septic shock. Most experimental data have been obtained on Zaire ebolavirus, which causes uniformly lethal disease in experimentally infected non-human primates but produces a broader range of outcomes in naturally infected human beings. 10-30% of patients can survive the illness by mobilising adaptive immune responses, and there is limited evidence that mild or symptomless infections also occur. The other filoviruses that have caused human disease, Sudan ebolavirus, Ivory Coast ebolavirus, and marburgvirus, produce a similar illness but with somewhat lower case-fatality rates. Variations in outcome during an epidemic might be due partly to genetically determined differences in innate immune responses to the viruses. Recent studies in non-human primates have shown that blocking of certain host responses, such as the coagulation cascade, can result in reduced viral replication and improved host survival.
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Affiliation(s)
- Siddhartha Mahanty
- Malaria Vaccine Development Unit, at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
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Abstract
The worldwide infection rate for HIV-1 is estimated to be 14,000 per day, but only now, more than 20 years into the epidemic, are the immediate events between exposure to infectious virus and the establishment of infection becoming clear. Defining the mechanisms of HIV-1 transmission, the target cells involved and how the virus attaches to and fuses with these cells, could reveal ways to block the sexual spread of the virus. In this review, we will discuss how our increasing knowledge of the ways in which HIV-1 is transmitted is shaping the development of new, more sophisticated intervention strategies based on the application of vaginal or rectal microbicides.
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Affiliation(s)
- Robin J Shattock
- Department of Cellular and Molecular Medicine, Infectious Diseases, St. George's Hospital Medical School, London, UK.
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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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Geijtenbeek TBH, van Vliet SJ, Engering A, 't Hart BA, van Kooyk Y. Self- and nonself-recognition by C-type lectins on dendritic cells. Annu Rev Immunol 2004; 22:33-54. [PMID: 15032573 DOI: 10.1146/annurev.immunol.22.012703.104558] [Citation(s) in RCA: 364] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to naive T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class I and II molecules. DCs are well equipped to distinguish between self- and nonself-antigens by the variable expression of cell-surface receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically quiescent but use their antigen-handling capacities to maintain peripheral tolerance. DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.
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Affiliation(s)
- Teunis B H Geijtenbeek
- Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center Amsterdam, 1081 BT Amsterdam, Netherlands
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N/A, 卢 丙, 李 军, 张 岩, 贾 战, 白 宪. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12:209-211. [DOI: 10.11569/wcjd.v12.i1.209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/05/2023] Open
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Chehimi J, Luo Q, Azzoni L, Shawver L, Ngoubilly N, June R, Jerandi G, Farabaugh M, Montaner LJ. HIV-1 transmission and cytokine-induced expression of DC-SIGN in human monocyte-derived macrophages. J Leukoc Biol 2003; 74:757-63. [PMID: 12960240 DOI: 10.1189/jlb.0503231] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) has been described as an attachment molecule for human immunodeficiency virus type 1 (HIV-1) with the potential to mediate its transmission. We examined DC-SIGN expression in monocyte-derived macrophages (MDM) and its role in viral transmission when MDM were exposed to interleukin (IL)-13, IL-4, or interferon-gamma (IFN-gamma). We show that IL-13 and IL-4 increase transcripts, total protein, and cell-surface expression of DC-SIGN in all MDM tested, IFN-gamma results ranged from no change to up-regulation of surface expression, and message and total protein were, respectively, induced in all and 86% of donors tested. Transmission experiments of HIV-1 X4 between cytokine-treated MDM to Sup-T1 cells showed no association between total transmission and DC-SIGN up-regulation. IL-4 but not IL-13 resulted in a less than twofold increase in MDM viral transmission to CD4+ T cells in spite of a fourfold up-regulation in DC-SIGN expression by either cytokine. In contrast, IFN-gamma treatment induced a decrease in total transmission by at least two-thirds, despite its induction of DC-SIGN. Soluble mannan resulted in a greater inhibition of viral transmission to CD4+ T cells than neutralizing anti-DC-SIGN monoclonal antibody (67-75% vs. 39-48%), supporting the role of mannose-binding receptors in viral transmission. Taken together, results show that DC-SIGN regulation in MDM does not singly predict the transmission potential of this cell type.
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Affiliation(s)
- Jihed Chehimi
- HIV Immunopathogenesis Laboratory, The Wistar Institute, Philadelphia, PA, USA
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Abstract
Dendritic cells (DCs) are crucial in the defence against pathogens. Invading pathogens are recognized by Toll-like receptors (TLRs) and receptors such as C-type lectins expressed on the surface of DCs. However, it is becoming evident that some pathogens, including viruses, such as HIV-1, and non-viral pathogens, such as Mycobacterium tuberculosis, subvert DC functions to escape immune surveillance by targeting the C-type lectin DC-SIGN (DC-specific intercellular adhesion molecule-grabbing nonintegrin). Notably, these pathogens misuse DC-SIGN by distinct mechanisms that either circumvent antigen processing or alter TLR-mediated signalling, skewing T-cell responses. This implies that adaptation of pathogens to target DC-SIGN might support pathogen survival.
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Affiliation(s)
- Yvette van Kooyk
- Department of Molecular Cell Biology and Immunology Vrije Universiteit Medical Center Amsterdam, v.d. Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
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45
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van Kooyk Y, Appelmelk B, Geijtenbeek TBH. A fatal attraction: Mycobacterium tuberculosis and HIV-1 target DC-SIGN to escape immune surveillance. Trends Mol Med 2003; 9:153-9. [PMID: 12727141 DOI: 10.1016/s1471-4914(03)00027-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Dendritic cells (DCs) are vital in the defense against pathogens. However, it is becoming increasingly clear that some pathogens subvert DC functions to escape immune surveillance. For example, HIV-1 targets the DC-specific C-type lectin DC-SIGN (DC-specific intercellular-adhesion-molecule-3-grabbing nonintegrin) to hijack DCs for viral dissemination. Binding to DC-SIGN protects HIV-1 from antigen processing and facilitates its transport to lymphoid tissues, where DC-SIGN promotes HIV-1 infection of T cells. Recent studies demonstrate that DC-SIGN is a universal pathogen receptor that also recognizes Ebola, cytomegalovirus and mycobacteria. Mycobacterium tuberculosis targets DC-SIGN by a mechanism that is distinct from that of HIV-1, leading to inhibition of the immunostimulatory function of DC and, hence, promotion of pathogen survival. A better understanding of DC-SIGN-pathogen interactions and their effects on DC function should help to combat infections.
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Affiliation(s)
- Yvette van Kooyk
- Department of Molecular Cell Biology, Vrije Universiteit Medical Center Amsterdam, v.d. Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
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Abstract
In the past 30 years, more than 30 new aetiological agents of infectious disease have been identified. Some of these are responsible for entirely novel and life-threatening disorders, such as AIDS, Ebola fever, hantavirus pulmonary syndrome and Nipah virus encephalitis. During the same period, some longstanding infectious diseases (such as tuberculosis) have became resurgent, as a result of a combination of complacency, increased travel and social dislocation, and also increasing drug resistance. This review looks at some of the key unmet needs in this therapeutic area and discusses strategies to address them.
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Affiliation(s)
- Noel J C Snell
- National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, SW3 6LY, London, UK.
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