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Du Y, Gao J, He M, Yi M, Wu J, Feng L, Zeng B, Li Y, He R, Wang Y, Qin CF, Cui Z, Wang C. Simultaneous Blockade of CD209 and CD209L by Monoclonal Antibody Does Not Provide Sufficient Protection Against Multiple Viral Infections In Vivo. Immunology 2025; 174:411-422. [PMID: 39783143 DOI: 10.1111/imm.13889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/18/2024] [Accepted: 12/10/2024] [Indexed: 01/12/2025] Open
Abstract
Many virus species, including Ebola virus, Marburg virus, SARS-CoV-2, dengue virus (DENV) and Zika virus (ZIKV), exploit CD209 and CD209L as alternative or attachment receptors for viral cis- or trans-infection. Thus, CD209 and CD209L may be critical targets for the development of therapeutic monoclonal blocking antibody drugs to disrupt the infection process caused by multiple viruses. Here, we produced a human chimeric monoclonal blocking antibody that simultaneously blocks CD209 and CD209L, namely 7-H7-B1. We show that 7-H7-B1 effectively blocks multiple pseudotyped or live viral infections in vitro, including SARS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, ZIKV and DENV infections. However, the 7-H7-B1 mAb does not provide favourable protection against Zaire Ebola virus or ZIKV infection in hCD209 knock-in mice in vivo. Thus, our findings indicate that although CD209 and CD209L are critical for multiple viral infections in vitro, they may play only a partial role in viral infections in vivo.
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Affiliation(s)
- Yanyun Du
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jiawang Gao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, P.R. China
- University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Mengjiao He
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, China
- Research Unit of Discovery and Tracing of Natural Focus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Ming Yi
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jiaqi Wu
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Lingyun Feng
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Bo Zeng
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yangyang Li
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Ruirui He
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yuan Wang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Cheng-Feng Qin
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, China
- Research Unit of Discovery and Tracing of Natural Focus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Zongqiang Cui
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, P.R. China
- University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Chenhui Wang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
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Baek H, Yang SW, Kim S, Lee Y, Park H, Park M, Jeon BJ, Park H, Hwang HS, Kim JY, Kim JH, Kang YS. Development of Anti-Inflammatory Agents Utilizing DC-SIGN Mediated IL-10 Secretion in Autoimmune and Immune-Mediated Disorders: Bridging Veterinary and Human Health. Int J Mol Sci 2025; 26:2329. [PMID: 40076949 PMCID: PMC11901132 DOI: 10.3390/ijms26052329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 02/21/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) is a C-type lectin receptor expressed on dendritic cells and M2 macrophages, playing a key role in immune regulation and pathogen recognition. Its ability to mediate anti-inflammatory effects by interacting with specific ligands triggers pathways that suppress pro-inflammatory responses and promote tissue repair, making it a potential therapeutic target for inflammatory and autoimmune diseases. DC-SIGN homologs in various animal species share structural similarities and perform comparable immune functions, offering valuable insights into its broader application across species. By recognizing carbohydrate ligands on pathogens, DC-SIGN facilitates immune modulation, which can be harnessed for developing therapies aimed at controlling inflammation. In veterinary medicine, autoimmune and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, represent significant challenges, and the anti-inflammatory properties of DC-SIGN could provide new therapeutic options to improve disease management and enhance animal health. Future investigations should focus on the structural and functional analysis of DC-SIGN homologs in various species, as well as the development of preclinical models to translate these findings into clinical interventions bridging veterinary and human health.
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Affiliation(s)
- Hayeon Baek
- Department of KONKUK-KIST Biomedical Science & Technology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea; (H.B.); (M.P.)
| | - Seung-Woo Yang
- Sanford Consortium for Regenerative Medicine, School of Medicine, University of California, San Diego, CA 92037, USA;
- Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, Research Institute of Medical Science, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea;
| | - Seulki Kim
- Department of Veterinary Pharmacology and Toxicology, Veterinary Science Research Institute, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; (S.K.); (Y.L.)
| | - Yunseok Lee
- Department of Veterinary Pharmacology and Toxicology, Veterinary Science Research Institute, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; (S.K.); (Y.L.)
| | - Hwi Park
- Department of Veterinary Ophthalmology, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; (H.P.); (B.-J.J.); (H.P.); (J.-Y.K.)
| | - Min Park
- Department of KONKUK-KIST Biomedical Science & Technology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea; (H.B.); (M.P.)
| | - Byung-Ju Jeon
- Department of Veterinary Ophthalmology, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; (H.P.); (B.-J.J.); (H.P.); (J.-Y.K.)
| | - Hanwool Park
- Department of Veterinary Ophthalmology, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; (H.P.); (B.-J.J.); (H.P.); (J.-Y.K.)
| | - Han-Sung Hwang
- Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, Research Institute of Medical Science, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea;
| | - Joon-Young Kim
- Department of Veterinary Ophthalmology, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; (H.P.); (B.-J.J.); (H.P.); (J.-Y.K.)
| | - Jung-Hyun Kim
- Department of Veterinary Internal Medicine, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea;
| | - Young-Sun Kang
- Department of KONKUK-KIST Biomedical Science & Technology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea; (H.B.); (M.P.)
- Department of Veterinary Pharmacology and Toxicology, Veterinary Science Research Institute, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; (S.K.); (Y.L.)
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Pastor F, Delphin M, Lucifora J, Verrier ER. [Non-alphabetic viral hepatitis]. Med Sci (Paris) 2025; 41:145-153. [PMID: 40028952 DOI: 10.1051/medsci/2025010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025] Open
Abstract
The liver is the target of various viruses that can cause significant damage, impair function and potentially threaten a patient's life. While the "alphabetic" hepatitis viruses A, B, C, D, and E are well-characterized, and their impact on liver function well-documented, many emerging and re-emerging viruses, some of which are considered by the WHO to be potential pandemic threats, also infect the liver. In this review, we describe the current state of knowledge regarding liver infections caused by major non-alphabetic hepatotropic viruses and their effects on liver functions.
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Affiliation(s)
- Florentin Pastor
- CIRI, Centre international de recherche en infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | | | - Julie Lucifora
- CIRI, Centre international de recherche en infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Eloi R Verrier
- Université de Strasbourg, Inserm, ITM UMR_S1110, Strasbourg, France
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Wanninger TG, Saldarriaga OA, Arroyave E, Millian DE, Comer JE, Paessler S, Stevenson HL. Hepatic and pulmonary macrophage activity in a mucosal challenge model of Ebola virus disease. Front Immunol 2024; 15:1439971. [PMID: 39635525 PMCID: PMC11615675 DOI: 10.3389/fimmu.2024.1439971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 09/26/2024] [Indexed: 12/07/2024] Open
Abstract
Background The inflammatory macrophage response contributes to severe Ebola virus disease, with liver and lung injury in humans. Objective We sought to further define the activation status of hepatic and pulmonary macrophage populations in Ebola virus disease. Methods We compared liver and lung tissue from terminal Ebola virus (EBOV)-infected and uninfected control cynomolgus macaques challenged via the conjunctival route. Gene and protein expression was quantified using the nCounter and GeoMx Digital Spatial Profiling platforms. Macrophage phenotypes were further quantified by digital pathology analysis. Results Hepatic macrophages in the EBOV-infected group demonstrated a mixed inflammatory/non-inflammatory profile, with upregulation of CD163 protein expression, associated with macrophage activation syndrome. Hepatic macrophages also showed differential expression of gene sets related to monocyte/macrophage differentiation, antigen presentation, and T cell activation, which were associated with decreased MHC-II allele expression. Moreover, hepatic macrophages had enriched expression of genes and proteins targetable with known immunomodulatory therapeutics, including S100A9, IDO1, and CTLA-4. No statistically significant differences in M1/M2 gene expression were observed in hepatic macrophages compared to controls. The significant changes that occurred in both the liver and lung were more pronounced in the liver. Conclusion These data demonstrate that hepatic macrophages in terminal conjunctivally challenged cynomolgus macaques may express a unique inflammatory profile compared to other macaque models and that macrophage-related pharmacologically druggable targets are expressed in both the liver and the lung in Ebola virus disease.
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Affiliation(s)
- Timothy G. Wanninger
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States
| | - Omar A. Saldarriaga
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Esteban Arroyave
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Daniel E. Millian
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Jason E. Comer
- Department of Microbiology and Immunology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Slobodan Paessler
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Heather L. Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
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Nemli DD, Jiang X, Jakob RP, Gloder LM, Schwardt O, Rabbani S, Maier T, Ernst B, Cramer J. Thermodynamics-Guided Design Reveals a Cooperative Hydrogen Bond in DC-SIGN-targeted Glycomimetics. J Med Chem 2024; 67:13813-13828. [PMID: 38771131 DOI: 10.1021/acs.jmedchem.4c00623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Due to the shallow and hydrophilic binding sites of carbohydrate-binding proteins, the design of glycomimetics is often complicated by high desolvation costs as well as competition with solvent. Therefore, a careful optimization of interaction vectors and ligand properties is required in the design and optimization of glycomimetics. Here, we employ thermodynamics-guided design to optimize mannose-based glycomimetics targeting the human C-type lectin receptor dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN), a pathogenic host factor in viral infections. By exploring ligand rigidification and hydrogen bond engineering, a monovalent glycomimetic with an unprecedented affinity for DC-SIGN in the low μM range was discovered. A matched molecular pair analysis based on microcalorimetric data revealed a stereospecific hydrogen bond interaction with Glu358/Ser360 as the origin of this cooperative and enthalpically dominated interaction. This detailed insight into the binding mechanism paves the way for an improvement of monovalent glycomimetics targeting DC-SIGN.
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Affiliation(s)
- Dilara D Nemli
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany
| | - Xiaohua Jiang
- Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Pharmazentrum, University of Basel, Klingelbergstrasse 50, Basel CH-4056, Switzerland
| | - Roman P Jakob
- Department Biozentrum, Structural Area Focal Biology, University of Basel, Spitalstrasse 41, Basel 4056, Switzerland
| | - Laura Muñoz Gloder
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany
| | - Oliver Schwardt
- Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Pharmazentrum, University of Basel, Klingelbergstrasse 50, Basel CH-4056, Switzerland
| | - Said Rabbani
- Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Pharmazentrum, University of Basel, Klingelbergstrasse 50, Basel CH-4056, Switzerland
| | - Timm Maier
- Department Biozentrum, Structural Area Focal Biology, University of Basel, Spitalstrasse 41, Basel 4056, Switzerland
| | - Beat Ernst
- Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Pharmazentrum, University of Basel, Klingelbergstrasse 50, Basel CH-4056, Switzerland
| | - Jonathan Cramer
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany
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Gong M, Peng C, Yang C, Wang Z, Qian H, Hu X, Zhou P, Shan C, Ding Q. Genome-wide CRISPR/Cas9 screen identifies SLC39A9 and PIK3C3 as crucial entry factors for Ebola virus infection. PLoS Pathog 2024; 20:e1012444. [PMID: 39173055 PMCID: PMC11341029 DOI: 10.1371/journal.ppat.1012444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 07/23/2024] [Indexed: 08/24/2024] Open
Abstract
The Ebola virus (EBOV) has emerged as a significant global health concern, notably during the 2013-2016 outbreak in West Africa. Despite the clinical approval of two EBOV antibody drugs, there is an urgent need for more diverse and effective antiviral drugs, along with comprehensive understanding of viral-host interactions. In this study, we harnessed a biologically contained EBOVΔVP30-EGFP cell culture model which could recapitulate the entire viral life cycle, to conduct a genome-wide CRISPR/Cas9 screen. Through this, we identified PIK3C3 (phosphatidylinositide 3-kinase) and SLC39A9 (zinc transporter) as crucial host factors for EBOV infection. Genetic depletion of SLC39A9 and PIK3C3 lead to reduction of EBOV entry, but not impact viral genome replication, suggesting that SLC39A9 and PIK3C3 act as entry factors, facilitating viral entry into host cells. Moreover, PIK3C3 kinase activity is indispensable for the internalization of EBOV virions, presumably through the regulation of endocytic and autophagic membrane traffic, which has been previously recognized as essential for EBOV internalization. Notably, our study demonstrated that PIK3C3 kinase inhibitor could effectively block EBOV infection, underscoring PIK3C3 as a promising drug target. Furthermore, biochemical analysis showed that recombinant SLC39A9 protein could directly bind viral GP protein, which further promotes the interaction of viral GP protein with cellular receptor NPC1. These findings suggests that SLC39A9 plays dual roles in EBOV entry. Initially, it serves as an attachment factor during the early entry phase by engaging with the viral GP protein. Subsequently, SLC39A9 functions an adaptor protein, facilitating the interaction between virions and the NPC1 receptor during the late entry phase, prior to cathepsin cleavage on the viral GP. In summary, this study offers novel insights into virus-host interactions, contributing valuable information for the development of new therapies against EBOV infection.
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Affiliation(s)
- Mingli Gong
- School of Basic Medical Sciences, Tsinghua University, Beijing, China
| | - Cheng Peng
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Chen Yang
- School of Basic Medical Sciences, Tsinghua University, Beijing, China
| | - Zhenhua Wang
- The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Hongwu Qian
- The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xue Hu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Peng Zhou
- CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Chao Shan
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
- CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Qiang Ding
- School of Basic Medical Sciences, Tsinghua University, Beijing, China
- SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, China
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Munyeku-Bazitama Y, Saito T, Hattori T, Miyamoto H, Lombe BP, Mori-Kajihara A, Kajihara M, Muyembe-Tamfum JJ, Igarashi M, Park ES, Morikawa S, Makiala-Mandanda S, Takada A. Characterization of human tibrovirus envelope glycoproteins. J Virol 2024; 98:e0049924. [PMID: 38953631 PMCID: PMC11265436 DOI: 10.1128/jvi.00499-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 06/11/2024] [Indexed: 07/04/2024] Open
Abstract
Tibroviruses are novel rhabdoviruses detected in humans, cattle, and arthropods. Four tibroviruses are known to infect humans: Bas-Congo virus (BASV), Ekpoma virus 1 (EKV-1), Ekpoma virus 2, and Mundri virus. However, since none of them has been isolated, their biological properties are largely unknown. We aimed to characterize the human tibrovirus glycoprotein (G), which likely plays a pivotal role in viral tropism and pathogenicity. Human tibrovirus Gs were found to share some primary structures and display 14 conserved cysteine residues, although their overall amino acid homology was low (29%-48%). Multiple potential glycosylation sites were found on the G molecules, and endoglycosidase H- and peptide-N-glycosidase F-sensitive glycosylation was confirmed. AlphaFold-predicted three-dimensional (3D) structures of human tibrovirus Gs were overall similar. Membrane fusion mediated by these tibrovirus Gs was induced by acidic pH. The low pH-induced conformational change that triggers fusion was reversible. Virus-like particles (VLPs) were produced by transient expression of Gs in cultured cells and used to produce mouse antisera. Using vesicular stomatitis Indiana virus pseudotyped with Gs, we found that the antisera to the respective tibrovirus VLPs showed limited cross-neutralizing activity. It was also found that human C-type lectins and T-cell immunoglobulin mucin 1 acted as attachment factors for G-mediated entry into cells. Interestingly, BASV-G showed the highest ability to utilize these molecules. The viruses infected a wide range of cell lines with preferential tropism for human-derived cells whereas the preference of EKV-1 was unique compared with the other human tibroviruses. These findings provide fundamental information to understand the biological properties of the human tibroviruses. IMPORTANCE Human tibroviruses are poorly characterized emerging rhabdoviruses associated with either asymptomatic infection or severe disease with a case fatality rate as high as 60% in humans. However, the extent and burden of human infection as well as factors behind differences in infection outcomes are largely unknown. In this study, we characterized human tibrovirus glycoproteins, which play a key role in virus-host interactions, mainly focusing on their structural and antigenic differences and cellular tropism. Our results provide critical information for understanding the biological properties of these novel viruses and for developing appropriate preparedness interventions such as diagnostic tools, vaccines, and effective therapies.
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Affiliation(s)
- Yannick Munyeku-Bazitama
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- Institut National de Recherche Biomédicale, Kinshasa, Democratic Republic of Congo
- Département de Biologie Médicale, Faculté de Médecine, Université de Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Takeshi Saito
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Takanari Hattori
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Hiroko Miyamoto
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Boniface Pongombo Lombe
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- Faculté de Médecine Vétérinaire, Université Pédagogique National, Kinshasa, Democratic Republic of Congo
- Central Veterinary Laboratory of Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Akina Mori-Kajihara
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Masahiro Kajihara
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Jean-Jacques Muyembe-Tamfum
- Institut National de Recherche Biomédicale, Kinshasa, Democratic Republic of Congo
- Département de Biologie Médicale, Faculté de Médecine, Université de Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Manabu Igarashi
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Eun-sil Park
- Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan
| | - Shigeru Morikawa
- Department of Microbiology, Faculty of Veterinary Medicine, Okayama University of Science, Ehime, Japan
| | - Sheila Makiala-Mandanda
- Institut National de Recherche Biomédicale, Kinshasa, Democratic Republic of Congo
- Département de Biologie Médicale, Faculté de Médecine, Université de Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Ayato Takada
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- One Health Research Center, Hokkaido University, Sapporo, Japan
- Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka, Zambia
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8
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Reis E Sousa C, Yamasaki S, Brown GD. Myeloid C-type lectin receptors in innate immune recognition. Immunity 2024; 57:700-717. [PMID: 38599166 DOI: 10.1016/j.immuni.2024.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/01/2024] [Accepted: 03/05/2024] [Indexed: 04/12/2024]
Abstract
C-type lectin receptors (CLRs) expressed by myeloid cells constitute a versatile family of receptors that play a key role in innate immune recognition. Myeloid CLRs exhibit a remarkable ability to recognize an extensive array of ligands, from carbohydrates and beyond, and encompass pattern-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and markers of altered self. These receptors, classified into distinct subgroups, play pivotal roles in immune recognition and modulation of immune responses. Their intricate signaling pathways orchestrate a spectrum of cellular responses, influencing processes such as phagocytosis, cytokine production, and antigen presentation. Beyond their contributions to host defense in viral, bacterial, fungal, and parasitic infections, myeloid CLRs have been implicated in non-infectious diseases such as cancer, allergies, and autoimmunity. A nuanced understanding of myeloid CLR interactions with endogenous and microbial triggers is starting to uncover the context-dependent nature of their roles in innate immunity, with implications for therapeutic intervention.
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Affiliation(s)
- Caetano Reis E Sousa
- Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
| | - Sho Yamasaki
- Molecular Immunology, Research Institute for Microbial Diseases, Immunology Frontier Research Center (IFReC), Osaka University, Suita 565-0871, Japan.
| | - Gordon D Brown
- MRC Centre for Medical Mycology at the University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK.
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9
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Coler B, Cervantes O, Li M, Coler C, Li A, Shivakumar M, Every E, Schwartz D, Adams Waldorf KM. Common pathways targeted by viral hemorrhagic fever viruses to infect the placenta and increase the risk of stillbirth. Placenta 2023; 141:2-9. [PMID: 36939178 PMCID: PMC10102255 DOI: 10.1016/j.placenta.2022.10.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 09/19/2022] [Accepted: 10/02/2022] [Indexed: 01/06/2023]
Abstract
Viral hemorrhagic fevers (VHF) are endemic to Africa, South America and Asia and contribute to significant maternal and fetal morbidity and mortality. Viruses causing VHFs are typically zoonotic, spreading to humans through livestock, wildlife, or mosquito vectors. Some of the most lethal VHF viruses also impart a high-risk of stillbirth including ebolaviruses, Marburg virus (MARV), Lassa virus (LASV), and Rift Valley Fever Virus (RVFV). Large outbreaks and epidemics are common, though the impact on the mother, fetus and placenta is understudied from a public health, clinical and basic science perspective. Notably, these viruses utilize ubiquitous cellular surface entry receptors critical for normal placental function to enable viral invasion into multiple key cell types of the placenta and set the stage for maternal-fetal transmission and stillbirth. We employ insights from molecular virology and viral immunology to discuss how trophoblast expression of viral entry receptors for VHF viruses may increase the risk for viral transmission to the fetus and stillbirth. As the frequency of VHF outbreaks is expected to increase with worsening climate change, understanding the pathogenesis of VHF-related diseases in the placenta is paramount to predicting the impact of emerging viruses on the placenta and perinatal outcomes.
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Affiliation(s)
- Brahm Coler
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA; Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA
| | - Orlando Cervantes
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA
| | - Miranda Li
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA; Department of Biological Sciences, Columbia University, New York City, NY, USA
| | | | - Amanda Li
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA; Case Western Reserve, Cleveland, OH, USA
| | - Megana Shivakumar
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
| | - Emma Every
- School of Medicine, University of Washington, Seattle, WA, USA
| | | | - Kristina M Adams Waldorf
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA.
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10
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Raïch-Regué D, Resa-Infante P, Gallemí M, Laguia F, Muñiz-Trabudua X, Muñoz-Basagoiti J, Perez-Zsolt D, Chojnacki J, Benet S, Clotet B, Martinez-Picado J, Izquierdo-Useros N. Role of Siglecs in viral infections: A double-edged sword interaction. Mol Aspects Med 2023; 90:101113. [PMID: 35981912 PMCID: PMC9923124 DOI: 10.1016/j.mam.2022.101113] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/25/2022] [Accepted: 08/01/2022] [Indexed: 01/21/2023]
Abstract
Sialic-acid-binding immunoglobulin-like lectins are cell surface immune receptors known as Siglecs that play a paramount role as modulators of immunity. In recent years, research has underscored how the underlaying biology of this family of receptors influences the outcome of viral infections. While Siglecs are needed to promote effective antiviral immune responses, they can also pave the way to viral dissemination within tissues. Here, we review how recent preclinical findings focusing on the interplay between Siglecs and viruses may translate into promising broad-spectrum therapeutic interventions or key biomarkers to monitor the course of viral infections.
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Affiliation(s)
- Dàlia Raïch-Regué
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, 08916, Badalona, Spain
| | - Patricia Resa-Infante
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, 08916, Badalona, Spain; University of Vic-Central University of Catalonia (UVic-UCC), 08500, Vic, Spain
| | - Marçal Gallemí
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, 08916, Badalona, Spain
| | - Fernando Laguia
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, 08916, Badalona, Spain
| | - Xabier Muñiz-Trabudua
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, 08916, Badalona, Spain
| | | | - Daniel Perez-Zsolt
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, 08916, Badalona, Spain
| | - Jakub Chojnacki
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, 08916, Badalona, Spain; Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916, Badalona, Spain
| | - Susana Benet
- Fundació lluita contra la SIDA, Infectious Diseases Department, Hospital Germans Trias i Pujol, 08916, Badalona, Spain
| | - Bonaventura Clotet
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, 08916, Badalona, Spain; University of Vic-Central University of Catalonia (UVic-UCC), 08500, Vic, Spain; Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916, Badalona, Spain; Fundació lluita contra la SIDA, Infectious Diseases Department, Hospital Germans Trias i Pujol, 08916, Badalona, Spain; Consorcio Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Javier Martinez-Picado
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, 08916, Badalona, Spain; University of Vic-Central University of Catalonia (UVic-UCC), 08500, Vic, Spain; Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916, Badalona, Spain; Consorcio Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain; Catalan Institution for Research and Advanced Studies (ICREA), 08010, Barcelona, Spain
| | - Nuria Izquierdo-Useros
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, 08916, Badalona, Spain; Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916, Badalona, Spain; Consorcio Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain.
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11
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Ratra S, Pant B, Roy K, Manohar S, Kumar P, Singh S, Tumba K, Kumari K, Singh P. A review on synthesis of antiviral drugs, in silico studies and their toxicity. J INDIAN CHEM SOC 2023. [DOI: 10.1016/j.jics.2023.100936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
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12
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Pseudotyped Viruses for Marburgvirus and Ebolavirus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1407:105-132. [PMID: 36920694 DOI: 10.1007/978-981-99-0113-5_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
Marburg virus (MARV) and Ebola virus (EBOV) of the Filoviridae family are the most lethal viruses in terms of mortality rate. However, the development of antiviral treatment is hampered by the requirement for biosafety level-4 (BSL-4) containment. The establishment of BSL-2 pseudotyped viruses can provide important tools for the study of filoviruses. This chapter summarizes general information on the filoviruses and then focuses on the construction of replication-deficient pseudotyped MARV and EBOV (e.g., lentivirus system and vesicular stomatitis virus system). It also details the potential applications of the pseudotyped viruses, including neutralization antibody detection, the study of infection mechanisms, the evaluation of antibody-dependent enhancement, virus entry inhibitor screening, and glycoprotein mutation analysis.
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13
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Lu J, Gullett JM, Kanneganti TD. Filoviruses: Innate Immunity, Inflammatory Cell Death, and Cytokines. Pathogens 2022; 11:1400. [PMID: 36558734 PMCID: PMC9785368 DOI: 10.3390/pathogens11121400] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/17/2022] [Accepted: 11/19/2022] [Indexed: 11/24/2022] Open
Abstract
Filoviruses are a group of single-stranded negative sense RNA viruses. The most well-known filoviruses that affect humans are ebolaviruses and marburgviruses. During infection, they can cause life-threatening symptoms such as inflammation, tissue damage, and hemorrhagic fever, with case fatality rates as high as 90%. The innate immune system is the first line of defense against pathogenic insults such as filoviruses. Pattern recognition receptors (PRRs), including toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors, AIM2-like receptors, and NOD-like receptors, detect pathogens and activate downstream signaling to induce the production of proinflammatory cytokines and interferons, alert the surrounding cells to the threat, and clear infected and damaged cells through innate immune cell death. However, filoviruses can modulate the host inflammatory response and innate immune cell death, causing an aberrant immune reaction. Here, we discuss how the innate immune system senses invading filoviruses and how these deadly pathogens interfere with the immune response. Furthermore, we highlight the experimental difficulties of studying filoviruses as well as the current state of filovirus-targeting therapeutics.
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14
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Wanninger TG, Millian DE, Saldarriaga OA, Maruyama J, Saito T, Reyna RA, Taniguchi S, Arroyave E, Connolly ME, Stevenson HL, Paessler S. Macrophage infection, activation, and histopathological findings in ebolavirus infection. Front Cell Infect Microbiol 2022; 12:1023557. [PMID: 36310868 PMCID: PMC9597316 DOI: 10.3389/fcimb.2022.1023557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 09/15/2022] [Indexed: 12/05/2022] Open
Abstract
Macrophages contribute to Ebola virus disease through their susceptibility to direct infection, their multi-faceted response to ebolaviruses, and their association with pathological findings in tissues throughout the body. Viral attachment and entry factors, as well as the more recently described influence of cell polarization, shape macrophage susceptibility to direct infection. Moreover, the study of Toll-like receptor 4 and the RIG-I-like receptor pathway in the macrophage response to ebolaviruses highlight important immune signaling pathways contributing to the breadth of macrophage responses. Lastly, the deep histopathological catalogue of macrophage involvement across numerous tissues during infection has been enriched by descriptions of tissues involved in sequelae following acute infection, including: the eye, joints, and the nervous system. Building upon this knowledge base, future opportunities include characterization of macrophage phenotypes beneficial or deleterious to survival, delineation of the specific roles macrophages play in pathological lesion development in affected tissues, and the creation of macrophage-specific therapeutics enhancing the beneficial activities and reducing the deleterious contributions of macrophages to the outcome of Ebola virus disease.
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Affiliation(s)
- Timothy G. Wanninger
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States
| | - Daniel E. Millian
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Omar A. Saldarriaga
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Junki Maruyama
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Takeshi Saito
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Rachel A. Reyna
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Satoshi Taniguchi
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Esteban Arroyave
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Melanie E. Connolly
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, United States
| | - Heather L. Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Slobodan Paessler
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
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15
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Peng W, Rayaprolu V, Parvate AD, Pronker MF, Hui S, Parekh D, Shaffer K, Yu X, Saphire EO, Snijder J. Glycan shield of the ebolavirus envelope glycoprotein GP. Commun Biol 2022; 5:785. [PMID: 35927436 PMCID: PMC9352669 DOI: 10.1038/s42003-022-03767-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/25/2022] [Indexed: 11/09/2022] Open
Abstract
The envelope glycoprotein GP of the ebolaviruses is essential for host cell entry and the primary target of the host antibody response. GP is heavily glycosylated with up to 17 N-linked sites, numerous O-linked glycans in its disordered mucin-like domain (MLD), and three predicted C-linked mannosylation sites. Glycosylation is important for host cell attachment, GP stability and fusion activity, and shielding from neutralization by serum antibodies. Here, we use glycoproteomics to profile the site-specific glycosylation patterns of ebolavirus GP. We detect up to 16 unique O-linked glycosylation sites in the MLD, and two O-linked sites in the receptor-binding GP1 subunit. Multiple O-linked glycans are observed within N-linked glycosylation sequons, suggesting crosstalk between the two types of modifications. We confirmed C-mannosylation of W288 in full-length trimeric GP. We find complex glycosylation at the majority of N-linked sites, while the conserved sites N257 and especially N563 are enriched in unprocessed glycans, suggesting a role in host-cell attachment via DC-SIGN/L-SIGN. Our findings illustrate how N-, O-, and C-linked glycans together build the heterogeneous glycan shield of GP, guiding future immunological studies and functional interpretation of ebolavirus GP-antibody interactions. Site-specific N-, O-, and C-linked glycans are characterized in the ebolavirus envelope glycoprotein GP using mass spectrometry-based glycoproteomics.
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Affiliation(s)
- Weiwei Peng
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584, CH, Utrecht, The Netherlands
| | - Vamseedhar Rayaprolu
- Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.,Pacific Northwest Center for CryoEM, Portland, OR, 97225, USA
| | - Amar D Parvate
- Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.,Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, 99354, USA
| | - Matti F Pronker
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584, CH, Utrecht, The Netherlands
| | - Sean Hui
- Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.,Molecular Microbiology and Microbial Pathogenesis Program, Washington University School of Medicine, Saint Louis, MO, 63108, USA
| | - Diptiben Parekh
- Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
| | - Kelly Shaffer
- Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.,Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Xiaoying Yu
- Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
| | - Erica O Saphire
- Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.,Department of Medicine, University of California, San Diego, La Jolla, CA, 92039, USA
| | - Joost Snijder
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584, CH, Utrecht, The Netherlands.
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16
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Dienst EGT, Kremer EJ. Adenovirus receptors on antigen-presenting cells of the skin. Biol Cell 2022; 114:297-308. [PMID: 35906865 DOI: 10.1111/boc.202200043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/21/2022] [Accepted: 07/26/2022] [Indexed: 12/01/2022]
Abstract
Skin, the largest human organ, is part of the first line of physical and immunological defense against many pathogens. Understanding how skin antigen-presenting cells (APCs) respond to viruses or virus-based vaccines is crucial to develop antiviral pharmaceutics, and efficient and safe vaccines. Here, we discuss the way resident and recruited skin APCs engage adenoviruses and the impact on innate immune responses. This article is protected by copyright. All rights reserved.
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Affiliation(s)
| | - Eric J Kremer
- Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, CNRS, Montpellier, France
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17
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Arnold JN, Mitchell DA. Tinker, tailor, soldier, cell: the role of C-type lectins in the defense and promotion of disease. Protein Cell 2022; 14:4-16. [PMID: 36726757 PMCID: PMC9871964 DOI: 10.1093/procel/pwac012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 04/25/2022] [Indexed: 02/04/2023] Open
Abstract
C-type lectins (CTLs) represent a large family of soluble and membrane-bound proteins which bind calcium dependently via carbohydrate recognition domains (CRDs) to glycan residues presented on the surface of a variety of pathogens. The deconvolution of a cell's glycan code by CTLs underpins several important physiological processes in mammals such as pathogen neutralization and opsonization, leukocyte trafficking, and the inflammatory response. However, as our knowledge of CTLs has developed it has become apparent that the role of this innate immune family of proteins can be double-edged, where some pathogens have developed approaches to subvert and exploit CTL interactions to promote infection and sustain the pathological state. Equally, CTL interactions with host glycoproteins can contribute to inflammatory diseases such as arthritis and cancer whereby, in certain contexts, they exacerbate inflammation and drive malignant progression. This review discusses the 'dual agent' roles of some of the major mammalian CTLs in both resolving and promoting infection, inflammation and inflammatory disease and highlights opportunities and emerging approaches for their therapeutic modulation.
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18
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Li J, Chen S, Li Y, Zhu Z, Huang H, Wang W, Yang Y, Liang Y, Shu L. Comprehensive Profiling Analysis of CD209 in Malignancies Reveals the Therapeutic Implication for Tumor Patients Infected With SARS-CoV-2. Front Genet 2022; 13:883234. [PMID: 35783255 PMCID: PMC9247358 DOI: 10.3389/fgene.2022.883234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/10/2022] [Indexed: 11/15/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), which is known to be caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is characterized by pneumonia, cytokine storms, and lymphopenia. Patients with malignant tumors may be particularly vulnerable to SARS-CoV-2 infection and possibly more susceptible to severe complications due to immunosuppression. Recent studies have found that CD209 (DC-SIGN) might be a potential binding receptor for SARS-CoV-2 in addition to the well-known receptor ACE2. However, pan-cancer studies of CD209 remain unclear. In this study, we first comprehensively investigated the expression profiles of CD209 in malignancies in both pan-carcinomas and healthy tissues based on bioinformatic techniques. The CD209 expression declined dramatically in various cancer types infected by SARS-CoV-2. Remarkably, CD209 was linked with diverse immune checkpoint genes and infiltrating immune cells. These findings indicate that the elevation of CD209 among specific cancer patients may delineate a mechanism accounting for a higher vulnerability to infection by SARS-CoV-2, as well as giving rise to cytokine storms. Taken together, CD209 plays critical roles in both immunology and metabolism in various cancer types. Pharmacological inhibition of CD209 antigen (D-mannose), together with other anti-SARS-CoV-2 strategies, might provide beneficial therapeutic effects in specific cancer patients.
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Affiliation(s)
- Jinyuan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shuzhao Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yang Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ziang Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hanying Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Weida Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yao Yang
- Institute of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Shenzhen, China
| | - Yang Liang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
- *Correspondence: Yang Liang, ; Lingling Shu,
| | - Lingling Shu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, SAR, China
- *Correspondence: Yang Liang, ; Lingling Shu,
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19
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Zhang H, Daněk O, Makarov D, Rádl S, Kim D, Ledvinka J, Vychodilová K, Hlaváč J, Lefèbre J, Denis M, Rademacher C, Ménová P. Drug-like Inhibitors of DC-SIGN Based on a Quinolone Scaffold. ACS Med Chem Lett 2022; 13:935-942. [DOI: 10.1021/acsmedchemlett.2c00067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/26/2022] [Indexed: 11/28/2022] Open
Affiliation(s)
- Hengxi Zhang
- Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany
- Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
- Department of Pharmaceutical Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
- Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Biocenter 5, 1030 Vienna, Austria
| | - Ondřej Daněk
- University of Chemistry and Technology, Prague, Technická 5, 16628 Prague 6, Czech Republic
| | - Dmytro Makarov
- University of Chemistry and Technology, Prague, Technická 5, 16628 Prague 6, Czech Republic
| | - Stanislav Rádl
- University of Chemistry and Technology, Prague, Technická 5, 16628 Prague 6, Czech Republic
- Zentiva a.s., U Kabelovny 130, 10237 Prague 10, Czech Republic
| | - Dongyoon Kim
- Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany
- Department of Pharmaceutical Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
- Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Biocenter 5, 1030 Vienna, Austria
| | - Jiří Ledvinka
- University of Chemistry and Technology, Prague, Technická 5, 16628 Prague 6, Czech Republic
| | - Kristýna Vychodilová
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic
| | - Jan Hlaváč
- Department of Organic Chemistry, Faculty of Science, Palacký University, Tř. 17. Listopadu 12, 77146 Olomouc, Czech Republic
| | - Jonathan Lefèbre
- Department of Pharmaceutical Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
- Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Biocenter 5, 1030 Vienna, Austria
| | - Maxime Denis
- Department of Pharmaceutical Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
- Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Biocenter 5, 1030 Vienna, Austria
| | - Christoph Rademacher
- Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany
- Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
- Department of Pharmaceutical Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
- Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Biocenter 5, 1030 Vienna, Austria
| | - Petra Ménová
- University of Chemistry and Technology, Prague, Technická 5, 16628 Prague 6, Czech Republic
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20
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Schrottmaier WC, Schmuckenschlager A, Pirabe A, Assinger A. Platelets in Viral Infections - Brave Soldiers or Trojan Horses. Front Immunol 2022; 13:856713. [PMID: 35419008 PMCID: PMC9001014 DOI: 10.3389/fimmu.2022.856713] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/03/2022] [Indexed: 11/13/2022] Open
Abstract
Viral infections are often associated with platelet activation and haemostatic complications. In line, low platelet counts represent a hallmark for poor prognosis in many infectious diseases. The underlying cause of platelet dysfunction in viral infections is multifaceted and complex. While some viruses directly interact with platelets and/or megakaryocytes to modulate their function, also immune and inflammatory responses directly and indirectly favour platelet activation. Platelet activation results in increased platelet consumption and degradation, which contributes to thrombocytopenia in these patients. The role of platelets is often bi-phasic. Initial platelet hyper-activation is followed by a state of platelet exhaustion and/or hypo-responsiveness, which together with low platelet counts promotes bleeding events. Thereby infectious diseases not only increase the thrombotic but also the bleeding risk or both, which represents a most dreaded clinical complication. Treatment options in these patients are limited and new therapeutic strategies are urgently needed to prevent adverse outcome. This review summarizes the current literature on platelet-virus interactions and their impact on viral pathologies and discusses potential intervention strategies. As pandemics and concomitant haemostatic dysregulations will remain a recurrent threat, understanding the role of platelets in viral infections represents a timely and pivotal challenge.
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Affiliation(s)
- Waltraud C Schrottmaier
- Institute of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Anna Schmuckenschlager
- Institute of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Anita Pirabe
- Institute of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Alice Assinger
- Institute of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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21
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Abstract
Lymphocytic choriomeningitis virus (LCMV) is the prototypic arenavirus and has been utilized for decades as a model to understand the host immune response against viral infection. LCMV infection can lead to fatal meningitis in immunocompromised people and can lead to congenital birth defects and spontaneous abortion if acquired during pregnancy. Using a genetic screen, we uncover host factors involved in LCMV entry that were previously unknown and are candidate therapeutic targets to combat LCMV infection. This study expands our understanding of the entry pathway of LCMV, revealing that its glycoprotein switches from utilizing the known receptor α-DG and heparan sulfate at the plasma membrane to binding the lysosomal mucin CD164 at pH levels found in endolysosomal compartments, facilitating membrane fusion. Lymphocytic choriomeningitis virus (LCMV) is a rodent-borne zoonotic arenavirus that causes congenital abnormalities and can be fatal for transplant recipients. Using a genome-wide loss-of-function screen, we identify host factors required for LCMV entry into cells. We identify the lysosomal mucin CD164, glycosylation factors, the heparan sulfate biosynthesis machinery, and the known receptor alpha-dystroglycan (α-DG). Biochemical analysis revealed that the LCMV glycoprotein binds CD164 at acidic pH and requires a sialylated glycan at residue N104. We demonstrate that LCMV entry proceeds by the virus switching binding from heparan sulfate or α-DG at the plasma membrane to CD164 prior to membrane fusion, thus identifying additional potential targets for therapeutic intervention.
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22
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Duan Y, Yuan C, Suo X, Cao L, Kong X, Li X, Zheng H, Wang Q. TET2 is Required for Type I IFN-mediated Inhibition of Bat-Origin Swine Acute Diarrhea Syndrome Coronavirus. J Med Virol 2022; 94:3251-3256. [PMID: 35211991 DOI: 10.1002/jmv.27673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/16/2022] [Accepted: 02/20/2022] [Indexed: 11/07/2022]
Abstract
Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a newly discovered bat-origin coronavirus with fatal pathogenicity for neonatal piglets. There is no vaccine to prevent SADS-CoV infection or clinically approved drugs targeting SADS-CoV. Therefore, unraveling cellular factors that regulate SADS-CoV for cell entry is critical to understanding the viral transmission mechanism and provides a potential therapeutic target for SADS-CoV cure. Here, we showed that type I interferon (IFN-I) pretreatment potently blocks SADS-CoV entry into cells using lentiviral pseudo-virions as targets whose entry is driven by the SADS-CoV Spike glycoprotein. IFN-I-mediated inhibition of SADS-CoV entry and replication was dramatically impaired in the absence of TET2. These results suggest TET2 is found to serve as a checkpoint of IFN-I-meditated inhibition on the cell entry of SADS-CoV, and our discovery might constitute a novel treatment option to combat against SADS-CoV. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Yueyue Duan
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences (CAAS), Chengdu, 600103, China.,State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.,Chengdu National Agricultural Science and Technology Center, Chengdu, 600103, China
| | - Cong Yuan
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences (CAAS), Chengdu, 600103, China.,State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.,Chengdu National Agricultural Science and Technology Center, Chengdu, 600103, China
| | - Xuepeng Suo
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences (CAAS), Chengdu, 600103, China.,State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.,Chengdu National Agricultural Science and Technology Center, Chengdu, 600103, China
| | - Liyan Cao
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences (CAAS), Chengdu, 600103, China.,State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.,Chengdu National Agricultural Science and Technology Center, Chengdu, 600103, China
| | - Xiangyu Kong
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences (CAAS), Chengdu, 600103, China.,State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.,Chengdu National Agricultural Science and Technology Center, Chengdu, 600103, China
| | - Xiangtong Li
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences (CAAS), Chengdu, 600103, China.,State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.,Chengdu National Agricultural Science and Technology Center, Chengdu, 600103, China
| | - Haixue Zheng
- State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Qi Wang
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences (CAAS), Chengdu, 600103, China.,State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.,Chengdu National Agricultural Science and Technology Center, Chengdu, 600103, China
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23
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Zhang Q, Yang J, Tillieux S, Guo Z, Natividade RDS, Koehler M, Petitjean S, Cui Z, Alsteens D. Stepwise Enzymatic-Dependent Mechanism of Ebola Virus Binding to Cell Surface Receptors Monitored by AFM. NANO LETTERS 2022; 22:1641-1648. [PMID: 35108019 DOI: 10.1021/acs.nanolett.1c04677] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Ebola virus (EBOV) is responsible for several outbreaks of hemorrhagic fever with high mortality, raising great public concern. Several cell surface receptors have been identified to mediate EBOV binding and internalization, including phosphatidylserine (PS) receptors (TIM-1) and C-type lectin receptors (DC-SIGNR). However, the role of TIM-1 during early cell surface binding remains elusive and in particular whether TIM-1 acts as a specific receptor for EBOV. Here, we used force-distance curve-based atomic force microscopy (FD-based AFM) to quantify the binding between TIM-1/DC-SIGNR and EBOV glycoprotein (GP) and observed that both receptors specifically bind to GP with high-affinity. Since TIM-1 can also directly interact with PS at the single-molecule level, we also confirmed that TIM-1 acts as dual-function receptors of EBOV. These results highlight the direct involvement of multiple high-affinity receptors in the first steps of binding to cell surfaces, thus offering new perspectives for the development of anti-EBOV therapeutic molecules.
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Affiliation(s)
- Qingrong Zhang
- Louvain Institute of Biomolecular Science and Technology, Université Catholique de Louvain, Louvain-la-Neuve 1348, Belgium
| | - Jinsung Yang
- Louvain Institute of Biomolecular Science and Technology, Université Catholique de Louvain, Louvain-la-Neuve 1348, Belgium
| | - Sueli Tillieux
- Louvain Institute of Biomolecular Science and Technology, Université Catholique de Louvain, Louvain-la-Neuve 1348, Belgium
| | - Zhengyuan Guo
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China
| | - Rita Dos Santos Natividade
- Louvain Institute of Biomolecular Science and Technology, Université Catholique de Louvain, Louvain-la-Neuve 1348, Belgium
| | - Melanie Koehler
- Louvain Institute of Biomolecular Science and Technology, Université Catholique de Louvain, Louvain-la-Neuve 1348, Belgium
| | - Simon Petitjean
- Louvain Institute of Biomolecular Science and Technology, Université Catholique de Louvain, Louvain-la-Neuve 1348, Belgium
| | - Zongqiang Cui
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China
| | - David Alsteens
- Louvain Institute of Biomolecular Science and Technology, Université Catholique de Louvain, Louvain-la-Neuve 1348, Belgium
- Walloon Excellence in Life sciences and Biotechnology (WELBIO), Wavre 1300, Belgium
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24
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Guleken Z, Jakubczyk P, Wiesław P, Krzysztof P, Bulut H, Öten E, Depciuch J, Tarhan N. Characterization of Covid-19 infected pregnant women sera using laboratory indexes, vibrational spectroscopy, and machine learning classifications. Talanta 2022; 237:122916. [PMID: 34736654 PMCID: PMC8491955 DOI: 10.1016/j.talanta.2021.122916] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/19/2021] [Accepted: 09/29/2021] [Indexed: 01/08/2023]
Abstract
Herein, we show differences in blood serum of asymptomatic and symptomatic pregnant women infected with COVID-19 and correlate them with laboratory indexes, ATR FTIR and multivariate machine learning methods. We collected the sera of COVID-19 diagnosed pregnant women, in the second trimester (n = 12), third-trimester (n = 7), and second-trimester with severe symptoms (n = 7) compared to the healthy pregnant (n = 11) women, which makes a total of 37 participants. To assign the accuracy of FTIR spectra regions where peak shifts occurred, the Random Forest algorithm, traditional C5.0 single decision tree algorithm and deep neural network approach were used. We verified the correspondence between the FTIR results and the laboratory indexes such as: the count of peripheral blood cells, biochemical parameters, and coagulation indicators of pregnant women. CH2 scissoring, amide II, amide I vibrations could be used to differentiate the groups. The accuracy calculated by machine learning methods was higher than 90%. We also developed a method based on the dynamics of the absorbance spectra allowing to determine the differences between the spectra of healthy and COVID-19 patients. Laboratory indexes of biochemical parameters associated with COVID-19 validate changes in the total amount of proteins, albumin and lipase.
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Affiliation(s)
- Zozan Guleken
- Department of Physiology, Uskudar University Faculty of Medicine, Istanbul, Turkey.
| | | | - Paja Wiesław
- College of Natural Sciences, University of Rzeszów, Poland
| | | | - Huri Bulut
- Department of Medical Biochemistry, Faculty of Medicine Istinye University, Istanbul, Turkey
| | - Esra Öten
- Health Science University Istanbul Kanuni Sultan Suleyman Training and Research Hospital, Department of Obstetrics and Gynecology, Turkey
| | - Joanna Depciuch
- Institute of Nuclear Physics Polish Academy of Science, 31-342, Krakow, Poland.
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25
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Abstract
Viruses are essentially, obligate intracellular parasites. They require a host to replicate their genetic material, spread to other cells, and eventually to other hosts. For humans, most viral infections are not considered lethal, regardless if at the cellular level, the virus can obliterate individual cells. Constant genomic mutations, (which can alter the antigenic content of viruses such as influenza or coronaviruses), zoonosis or immunosuppression/immunocompromisation, is when viruses achieve higher host mortality. Frequent examples of the severe consequenses of viral infection can be seen in children and the elderly. In most instances, the immune system will take a multifaceted approach in defending the host against viruses. Depending on the virus, the individual, and the point of entry, the immune system will initiate a robust response which involves multiple components. In this chapter, we expand on the total immune system, breaking it down to the two principal types: Innate and Adaptive Immunity, their different roles in viral recognition and clearance. Finally, how different viruses activate and evade different arms of the immune system.
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26
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Cramer J. Medicinal chemistry of the myeloid C-type lectin receptors Mincle, Langerin, and DC-SIGN. RSC Med Chem 2021; 12:1985-2000. [PMID: 35024612 PMCID: PMC8672822 DOI: 10.1039/d1md00238d] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 09/14/2021] [Indexed: 01/07/2023] Open
Abstract
In their role as pattern-recognition receptors on cells of the innate immune system, myeloid C-type lectin receptors (CLRs) assume important biological functions related to immunity, homeostasis, and cancer. As such, this family of receptors represents an appealing target for therapeutic interventions for modulating the outcome of many pathological processes, in particular related to infectious diseases. This review summarizes the current state of research into glycomimetic or drug-like small molecule ligands for the CLRs Mincle, Langerin, and DC-SIGN, which have potential therapeutic applications in vaccine research and anti-infective therapy.
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Affiliation(s)
- Jonathan Cramer
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University of Düsseldorf Universitätsstr. 1 40225 Düsseldorf Germany
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27
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C-type lectin receptor DCIR contributes to hippocampal injury in acute neurotropic virus infection. Sci Rep 2021; 11:23819. [PMID: 34893671 PMCID: PMC8664856 DOI: 10.1038/s41598-021-03201-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 11/26/2021] [Indexed: 11/16/2022] Open
Abstract
Neurotropic viruses target the brain and contribute to neurologic diseases. C-type lectin receptors (CLRs) are pattern recognition receptors that recognize carbohydrate structures on endogenous molecules and pathogens. The myeloid CLR dendritic cell immunoreceptor (DCIR) is expressed by antigen presenting cells and mediates inhibitory intracellular signalling. To investigate the effect of DCIR on neurotropic virus infection, mice were infected experimentally with Theiler’s murine encephalomyelitis virus (TMEV). Brain tissue of TMEV-infected C57BL/6 mice and DCIR−/− mice were analysed by histology, immunohistochemistry and RT-qPCR, and spleen tissue by flow cytometry. To determine the impact of DCIR deficiency on T cell responses upon TMEV infection in vitro, antigen presentation assays were utilised. Genetic DCIR ablation in C57BL/6 mice was associated with an ameliorated hippocampal integrity together with reduced cerebral cytokine responses and reduced TMEV loads in the brain. Additionally, absence of DCIR favoured increased peripheral cytotoxic CD8+ T cell responses following TMEV infection. Co-culture experiments revealed that DCIR deficiency enhances the activation of antigen-specific CD8+ T cells by virus-exposed dendritic cells (DCs), indicated by increased release of interleukin-2 and interferon-γ. Results suggest that DCIR deficiency has a supportive influence on antiviral immune mechanisms, facilitating virus control in the brain and ameliorates neuropathology during acute neurotropic virus infection.
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28
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Lee HN, McWilliams IL, Lewkowicz AP, Engel K, Ireland DDC, Kelley-Baker L, Thacker S, Piccardo P, Manangeeswaran M, Verthelyi D. Characterization of the therapeutic effect of antibodies targeting the Ebola glycoprotein using a novel BSL2-compliant rVSVΔG-EBOV-GP infection model. Emerg Microbes Infect 2021; 10:2076-2089. [PMID: 34674613 PMCID: PMC8583756 DOI: 10.1080/22221751.2021.1997075] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/30/2021] [Accepted: 10/18/2021] [Indexed: 11/15/2022]
Abstract
Ebola virus (EBOV) infections cause haemorrhagic fever, multi-organ failure and death, and survivors can experience neurological sequelae. Licensing of monoclonal antibodies targeting EBOV glycoprotein (EBOV-GP) improved its prognosis, however, this treatment is primarily effective during early stages of disease and its effectiveness in reducing neurological sequela remains unknown. Currently, the need for BSL4 containment hinders research and therapeutic development; development of an accessible BSL-2 in vivo mouse model would facilitate preclinical studies to screen and select therapeutics. Previously, we have shown that a subcutaneous inoculation with replicating EBOV-GP pseudotyped vesicular stomatitis virus (rVSVΔG-EBOV-GP or VSV-EBOV) in neonatal mice causes transient viremia and infection of the mid and posterior brain resulting in overt neurological symptoms and death. Here, we demonstrate that the model can be used to test therapeutics that target the EBOV-GP, by using an anti-EBOV-GP therapeutic (SAB-139) previously shown to block EBOV infection in mice and primates. We show that SAB-139 treatment decreases the severity of neurological symptoms and improves survival when administered before (1 day prior to infection) or up to 3 dpi, by which time animals have high virus titres in their brains. Improved survival was associated with reduced viral titres, microglia loss, cellular infiltration/activation, and inflammatory responses in the brain. Interestingly, SAB-139 treatment significantly reduced the severe VSV-EBOV-induced long-term neurological sequalae although convalescent mice showed modest evidence of abnormal fear responses. Together, these data suggest that the neonatal VSV-EBOV infection system can be used to facilitate assessment of therapeutics targeting EBOV-GP in the preclinical setting.
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Affiliation(s)
- Ha-Na Lee
- Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Ian L. McWilliams
- Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Aaron P. Lewkowicz
- Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Kaliroi Engel
- Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Derek D. C. Ireland
- Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Logan Kelley-Baker
- Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Seth Thacker
- Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Pedro Piccardo
- Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Mohanraj Manangeeswaran
- Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Daniela Verthelyi
- Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
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29
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Thakur N, Gallo G, Elreafey AME, Bailey D. Production of Recombinant Replication-defective Lentiviruses Bearing the SARS-CoV or SARS-CoV-2 Attachment Spike Glycoprotein and Their Application in Receptor Tropism and Neutralisation Assays. Bio Protoc 2021; 11:e4249. [PMID: 34859135 PMCID: PMC8595443 DOI: 10.21769/bioprotoc.4249] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 08/29/2021] [Accepted: 09/16/2021] [Indexed: 11/30/2022] Open
Abstract
For enveloped viruses, such as SARS-CoV-2, transmission relies on the binding of viral glycoproteins to cellular receptors. Conventionally, this process is recapitulated in the lab by infection of cells with isolated live virus. However, such studies can be restricted due to the availability of high quantities of replication-competent virus, biosafety precautions and associated trained staff. Here, we present a protocol based on pseudotyping to produce recombinant replication-defective lentiviruses bearing the SARS-CoV or SARS-CoV-2 attachment Spike glycoprotein, allowing the investigation of viral entry in a lower-containment facility. Pseudoparticles are produced by cells transiently transfected with plasmids encoding retroviral RNA packaging signals and Gag-Pol proteins, for the reconstitution of lentiviral particles, and a plasmid coding for the viral attachment protein of interest. This approach allows the investigation of different aspects of viral entry, such as the identification of receptor tropism, the prediction of virus host range, and zoonotic transmission potential, as well as the characterisation of antibodies (sera or monoclonal antibodies) and pharmacological inhibitors that can block entry. Graphic abstract: SARS-CoV and SARS-CoV-2 pseudoparticle generation and applications.
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Affiliation(s)
- Nazia Thakur
- Viral Glycoproteins Group, The Pirbright Institute, Pirbright, Woking, UK.,The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Giulia Gallo
- Viral Glycoproteins Group, The Pirbright Institute, Pirbright, Woking, UK
| | - Ahmed M E Elreafey
- Viral Glycoproteins Group, The Pirbright Institute, Pirbright, Woking, UK
| | - Dalan Bailey
- Viral Glycoproteins Group, The Pirbright Institute, Pirbright, Woking, UK
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30
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Gao M, Li H, Ye C, Chen K, Jiang H, Yu K. Glycan Epitopes and Potential Glycoside Antagonists of DC-SIGN Involved in COVID-19: In Silico Study. Biomolecules 2021; 11:1586. [PMID: 34827585 PMCID: PMC8615854 DOI: 10.3390/biom11111586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/19/2021] [Accepted: 10/19/2021] [Indexed: 12/28/2022] Open
Abstract
Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 Spike glycoprotein has been reported in various articles and is regarded to be a factor in systemic infection and cytokine storm. The mechanism of DC-SIGN recognition offers an alternative method for discovering new medication for COVID-19 treatment. Here, we discovered three potential pockets that hold different glycan epitopes by performing molecular dynamics simulations of previously reported oligosaccharides. The "EPN" motif, "NDD" motif, and Glu354 form the most critical pocket, which is known as the Core site. We proposed that the type of glycan epitopes, rather than the precise amino acid sequence, determines the recognition. Furthermore, we deduced that oligosaccharides could occupy an additional site, which adds to their higher affinity than monosaccharides. Based on our findings and previously described glycoforms on the SARS-CoV-2 Spike, we predicted the potential glycan epitopes for DC-SIGN. It suggested that glycan epitopes could be recognized at multiple sites, not just Asn234, Asn149 and Asn343. Subsequently, we found that Saikosaponin A and Liquiritin, two plant glycosides, were promising DC-SIGN antagonists in silico.
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Affiliation(s)
- Meina Gao
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; (M.G.); (K.C.); (H.J.)
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China;
| | - Hui Li
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
- Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Chenghao Ye
- Department of Chemistry, Shantou University, Shantou 515063, China;
| | - Kaixian Chen
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; (M.G.); (K.C.); (H.J.)
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hualiang Jiang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; (M.G.); (K.C.); (H.J.)
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
- Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Kunqian Yu
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
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31
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Cramer J, Lakkaichi A, Aliu B, Jakob RP, Klein S, Cattaneo I, Jiang X, Rabbani S, Schwardt O, Zimmer G, Ciancaglini M, Abreu Mota T, Maier T, Ernst B. Sweet Drugs for Bad Bugs: A Glycomimetic Strategy against the DC-SIGN-Mediated Dissemination of SARS-CoV-2. J Am Chem Soc 2021; 143:17465-17478. [PMID: 34652144 DOI: 10.1021/jacs.1c06778] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The C-type lectin receptor DC-SIGN is a pattern recognition receptor expressed on macrophages and dendritic cells. It has been identified as a promiscuous entry receptor for many pathogens, including epidemic and pandemic viruses such as SARS-CoV-2, Ebola virus, and HIV-1. In the context of the recent SARS-CoV-2 pandemic, DC-SIGN-mediated virus dissemination and stimulation of innate immune responses has been implicated as a potential factor in the development of severe COVID-19. Inhibition of virus binding to DC-SIGN, thus, represents an attractive host-directed strategy to attenuate overshooting innate immune responses and prevent the progression of the disease. In this study, we report on the discovery of a new class of potent glycomimetic DC-SIGN antagonists from a focused library of triazole-based mannose analogues. Structure-based optimization of an initial screening hit yielded a glycomimetic ligand with a more than 100-fold improved binding affinity compared to methyl α-d-mannopyranoside. Analysis of binding thermodynamics revealed an enthalpy-driven improvement of binding affinity that was enabled by hydrophobic interactions with a loop region adjacent to the binding site and displacement of a conserved water molecule. The identified ligand was employed for the synthesis of multivalent glycopolymers that were able to inhibit SARS-CoV-2 spike glycoprotein binding to DC-SIGN-expressing cells, as well as DC-SIGN-mediated trans-infection of ACE2+ cells by SARS-CoV-2 spike protein-expressing viruses, in nanomolar concentrations. The identified glycomimetic ligands reported here open promising perspectives for the development of highly potent and fully selective DC-SIGN-targeted therapeutics for a broad spectrum of viral infections.
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Affiliation(s)
- Jonathan Cramer
- University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.,Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University of Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany
| | - Adem Lakkaichi
- University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Butrint Aliu
- University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Roman P Jakob
- Department Biozentrum, Focal Area Structural Biology, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland
| | - Sebastian Klein
- University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Ivan Cattaneo
- University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Xiaohua Jiang
- University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Said Rabbani
- University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Oliver Schwardt
- University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Gert Zimmer
- Institute of Virology and Immunology, Sensemattstrasse 293, 3147 Mittelhäusern, Switzerland
| | - Matias Ciancaglini
- Department Biomedicine, University of Basel, Petersplatz 8, 4051 Basel, Switzerland
| | - Tiago Abreu Mota
- Department Biomedicine, University of Basel, Petersplatz 8, 4051 Basel, Switzerland
| | - Timm Maier
- Department Biozentrum, Focal Area Structural Biology, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland
| | - Beat Ernst
- University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
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32
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Structural and Functional Aspects of Ebola Virus Proteins. Pathogens 2021; 10:pathogens10101330. [PMID: 34684279 PMCID: PMC8538763 DOI: 10.3390/pathogens10101330] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 10/11/2021] [Accepted: 10/14/2021] [Indexed: 01/14/2023] Open
Abstract
Ebola virus (EBOV), member of genus Ebolavirus, family Filoviridae, have a non-segmented, single-stranded RNA that contains seven genes: (a) nucleoprotein (NP), (b) viral protein 35 (VP35), (c) VP40, (d) glycoprotein (GP), (e) VP30, (f) VP24, and (g) RNA polymerase (L). All genes encode for one protein each except GP, producing three pre-proteins due to the transcriptional editing. These pre-proteins are translated into four products, namely: (a) soluble secreted glycoprotein (sGP), (b) Δ-peptide, (c) full-length transmembrane spike glycoprotein (GP), and (d) soluble small secreted glycoprotein (ssGP). Further, shed GP is released from infected cells due to cleavage of GP by tumor necrosis factor α-converting enzyme (TACE). This review presents a detailed discussion on various functional aspects of all EBOV proteins and their residues. An introduction to ebolaviruses and their life cycle is also provided for clarity of the available analysis. We believe that this review will help understand the roles played by different EBOV proteins in the pathogenesis of the disease. It will help in targeting significant protein residues for therapeutic and multi-protein/peptide vaccine development.
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33
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Kremsreiter SM, Kroell ASH, Weinberger K, Boehm H. Glycan-Lectin Interactions in Cancer and Viral Infections and How to Disrupt Them. Int J Mol Sci 2021; 22:10577. [PMID: 34638920 PMCID: PMC8508825 DOI: 10.3390/ijms221910577] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/24/2021] [Accepted: 09/26/2021] [Indexed: 02/07/2023] Open
Abstract
Glycan-lectin interactions play an essential role in different cellular processes. One of their main functions is involvement in the immune response to pathogens or inflammation. However, cancer cells and viruses have adapted to avail themselves of these interactions. By displaying specific glycosylation structures, they are able to bind to lectins, thus promoting pathogenesis. While glycan-lectin interactions promote tumor progression, metastasis, and/or chemoresistance in cancer, in viral infections they are important for viral entry, release, and/or immune escape. For several years now, a growing number of investigations have been devoted to clarifying the role of glycan-lectin interactions in cancer and viral infections. Various overviews have already summarized and highlighted their findings. In this review, we consider the interactions of the lectins MGL, DC-SIGN, selectins, and galectins in both cancer and viral infections together. A possible transfer of ways to target and disrupt them might lead to new therapeutic approaches in different pathological backgrounds.
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Affiliation(s)
- Stefanie Maria Kremsreiter
- Institute for Pharmacy and Molecular Biotechnology (IPMB), Ruprecht Karls University Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany; (S.M.K.); (A.-S.H.K.); (K.W.)
| | - Ann-Sophie Helene Kroell
- Institute for Pharmacy and Molecular Biotechnology (IPMB), Ruprecht Karls University Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany; (S.M.K.); (A.-S.H.K.); (K.W.)
| | - Katharina Weinberger
- Institute for Pharmacy and Molecular Biotechnology (IPMB), Ruprecht Karls University Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany; (S.M.K.); (A.-S.H.K.); (K.W.)
| | - Heike Boehm
- Max-Planck-Institute for Medical Research, Jahnstr. 29, 69120 Heidelberg, Germany
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34
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The Methanolic Extract of Perilla frutescens Robustly Restricts Ebola Virus Glycoprotein-Mediated Entry. Viruses 2021; 13:v13091793. [PMID: 34578374 PMCID: PMC8473196 DOI: 10.3390/v13091793] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/25/2021] [Accepted: 09/04/2021] [Indexed: 11/17/2022] Open
Abstract
Ebola virus (EBOV), one of the most infectious human viruses and a leading cause of viral hemorrhagic fever, imposes a potential public health threat with several recent outbreaks. Despite the difficulties associated with working with this pathogen in biosafety level-4 containment, a protective vaccine and antiviral therapeutic were recently approved. However, the high mortality rate of EBOV infection underscores the necessity to continuously identify novel antiviral strategies to help expand the scope of prophylaxis/therapeutic management against future outbreaks. This includes identifying antiviral agents that target EBOV entry, which could improve the management of EBOV infection. Herein, using EBOV glycoprotein (GP)-pseudotyped particles, we screened a panel of natural medicinal extracts, and identified the methanolic extract of Perilla frutescens (PFME) as a robust inhibitor of EBOV entry. We show that PFME dose-dependently impeded EBOV GP-mediated infection at non-cytotoxic concentrations, and exerted the most significant antiviral activity when both the extract and the pseudoparticles are concurrently present on the host cells. Specifically, we demonstrate that PFME could block viral attachment and neutralize the cell-free viral particles. Our results, therefore, identified PFME as a potent inhibitor of EBOV entry, which merits further evaluation for development as a therapeutic strategy against EBOV infection.
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35
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Jarahian M, Marstaller K, Banna N, Ahani R, Etemadzadeh MH, Boller LK, Azadmanesh K, Cid-Arregui A, Khezri A, Berger MR, Momburg F, Watzl C. Activating Natural Killer Cell Receptors, Selectins, and Inhibitory Siglecs Recognize Ebolavirus Glycoprotein. J Innate Immun 2021; 14:135-147. [PMID: 34425576 DOI: 10.1159/000517628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 05/28/2021] [Indexed: 11/19/2022] Open
Abstract
Expression of the extensively glycosylated Ebolavirus glycoprotein (EBOV-GP) induces physical alterations of surface molecules and plays a crucial role in viral pathogenicity. Here we investigate the interactions of EBOV-GP with host surface molecules using purified EBOV-GP, EBOV-GP-transfected cell lines, and EBOV-GP-pseudotyped lentiviral particles. Subsequently, we wanted to examine which receptors are involved in this recognition by binding studies to cells transfected with the EBOV-GP as well as to recombinant soluble EBOV-GP. As the viral components can also bind to inhibitory receptors of immune cells (e.g., Siglecs, TIM-1), they can even suppress the activity of immune effector cells. Our data show that natural killer (NK) cell receptors NKp44 and NKp46, selectins (CD62E/P/L), the host factors DC-SIGNR/DC-SIGN, and inhibitory Siglecs function as receptors for EBOV-GP. Our results show also moderate to strong avidity of homing receptors (P-, L-, and E-selectin) and DC-SIGNR/DC-SIGN to purified EBOV-GP, to cells transfected with EBOV-GP, as well as to the envelope of a pseudotyped lentiviral vector carrying the EBOV-GP. The concomitant activation and inhibition of the immune system exemplifies the evolutionary antagonism between the immune system and pathogens. Altogether these interactions with activating and inhibitory receptors result in a reduced NK cell-mediated lysis of EBOV-GP-expressing cells. Modulation of these interactions may provide new strategies for treating infections caused by this virus.
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Affiliation(s)
- Mostafa Jarahian
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Katharina Marstaller
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Banna
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Roshanak Ahani
- Department of Virology, Pasteur Institute of Iran, Tehran, Iran
| | | | - Lea K Boller
- Department of Immunology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany
| | | | - Angel Cid-Arregui
- Targeted Tumor Vaccines Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Abdolrahman Khezri
- Department of Biotechnology, Inland Norway University of Applied Sciences, Hamar, Norway
| | - Martin R Berger
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Frank Momburg
- Antigen Presentation and T/NK Cell Activation Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Carsten Watzl
- Department of Immunology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany
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36
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Marongiu L, Protti G, Facchini FA, Valache M, Mingozzi F, Ranzani V, Putignano AR, Salviati L, Bevilacqua V, Curti S, Crosti M, Sarnicola ML, D'Angiò M, Bettini LR, Biondi A, Nespoli L, Tamini N, Clementi N, Mancini N, Abrignani S, Spreafico R, Granucci F. Maturation signatures of conventional dendritic cell subtypes in COVID-19 suggest direct viral sensing. Eur J Immunol 2021; 52:109-122. [PMID: 34333764 PMCID: PMC8420462 DOI: 10.1002/eji.202149298] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/09/2021] [Accepted: 07/29/2021] [Indexed: 11/11/2022]
Abstract
Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID‐19, which negatively affects T‐cell activation. The presence of effector T cells in patients with mild disease and dysfunctional T cells in severely ill patients suggests that adequate T‐cell responses limit disease severity. Understanding how cDCs cope with SARS‐CoV‐2 can help elucidate how protective immune responses are generated. Here, we report that cDC2 subtypes exhibit similar infection‐induced gene signatures, with the upregulation of IFN‐stimulated genes and IL‐6 signaling pathways. Furthermore, comparison of cDCs between patients with severe and mild disease showed severely ill patients to exhibit profound downregulation of genes encoding molecules involved in antigen presentation, such as MHCII, TAP, and costimulatory proteins, whereas we observed the opposite for proinflammatory molecules, such as complement and coagulation factors. Thus, as disease severity increases, cDC2s exhibit enhanced inflammatory properties and lose antigen presentation capacity. Moreover, DC3s showed upregulation of anti‐apoptotic genes and accumulated during infection. Direct exposure of cDC2s to the virus in vitro recapitulated the activation profile observed in vivo. Our findings suggest that SARS‐CoV‐2 interacts directly with cDC2s and implements an efficient immune escape mechanism that correlates with disease severity by downregulating crucial molecules required for T‐cell activation.
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Affiliation(s)
- Laura Marongiu
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.,National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy
| | - Giulia Protti
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.,National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy
| | - Fabio A Facchini
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Mihai Valache
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Francesca Mingozzi
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Valeria Ranzani
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy
| | - Anna Rita Putignano
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy
| | - Lorenzo Salviati
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.,National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy
| | - Valeria Bevilacqua
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy
| | - Serena Curti
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy
| | - Mariacristina Crosti
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy
| | | | - Mariella D'Angiò
- Pediatric Department and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Italy
| | - Laura Rachele Bettini
- Pediatric Department and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Italy
| | - Andrea Biondi
- Pediatric Department and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Italy
| | - Luca Nespoli
- ASST san Gerardo Hospital, School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Nicolò Tamini
- ASST san Gerardo Hospital, School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Nicola Clementi
- Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy.,IRCCS San Raffaele Hospital, Milan, Italy
| | - Nicasio Mancini
- Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy.,IRCCS San Raffaele Hospital, Milan, Italy
| | - Sergio Abrignani
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy
| | - Roberto Spreafico
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles
| | - Francesca Granucci
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.,National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy
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37
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Schön K, Lepenies B, Goyette-Desjardins G. Impact of Protein Glycosylation on the Design of Viral Vaccines. ADVANCES IN BIOCHEMICAL ENGINEERING/BIOTECHNOLOGY 2021; 175:319-354. [PMID: 32935143 DOI: 10.1007/10_2020_132] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Glycans play crucial roles in various biological processes such as cell proliferation, cell-cell interactions, and immune responses. Since viruses co-opt cellular biosynthetic pathways, viral glycosylation mainly depends on the host cell glycosylation machinery. Consequently, several viruses exploit the cellular glycosylation pathway to their advantage. It was shown that viral glycosylation is strongly dependent on the host system selected for virus propagation and/or protein expression. Therefore, the use of different expression systems results in various glycoforms of viral glycoproteins that may differ in functional properties. These differences clearly illustrate that the choice of the expression system can be important, as the resulting glycosylation may influence immunological properties. In this review, we will first detail protein N- and O-glycosylation pathways and the resulting glycosylation patterns; we will then discuss different aspects of viral glycosylation in pathogenesis and in vaccine development; and finally, we will elaborate on how to harness viral glycosylation in order to optimize the design of viral vaccines. To this end, we will highlight specific examples to demonstrate how glycoengineering approaches and exploitation of different expression systems could pave the way towards better self-adjuvanted glycan-based viral vaccines.
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Affiliation(s)
- Kathleen Schön
- Immunology Unit and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hanover, Germany
- Institute for Parasitology, Centre for Infection Medicine, University of Veterinary Medicine Hannover, Hanover, Germany
| | - Bernd Lepenies
- Immunology Unit and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hanover, Germany.
| | - Guillaume Goyette-Desjardins
- Immunology Unit and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hanover, Germany.
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38
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Amraei R, Yin W, Napoleon MA, Suder EL, Berrigan J, Zhao Q, Olejnik J, Chandler KB, Xia C, Feldman J, Hauser BM, Caradonna TM, Schmidt AG, Gummuluru S, Mühlberger E, Chitalia V, Costello CE, Rahimi N. CD209L/L-SIGN and CD209/DC-SIGN Act as Receptors for SARS-CoV-2. ACS CENTRAL SCIENCE 2021; 7:1156-1165. [PMID: 34341769 PMCID: PMC8265543 DOI: 10.1021/acscentsci.0c01537] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Indexed: 05/17/2023]
Abstract
As the COVID-19 pandemic continues to spread, investigating the processes underlying the interactions between SARS-CoV-2 and its hosts is of high importance. Here, we report the identification of CD209L/L-SIGN and the related protein CD209/DC-SIGN as receptors capable of mediating SARS-CoV-2 entry into human cells. Immunofluorescence staining of human tissues revealed prominent expression of CD209L in the lung and kidney epithelia and endothelia. Multiple biochemical assays using a purified recombinant SARS-CoV-2 spike receptor-binding domain (S-RBD) or S1 encompassing both N termal domain and RBD and ectopically expressed CD209L and CD209 revealed that CD209L and CD209 interact with S-RBD. CD209L contains two N-glycosylation sequons, at sites N92 and N361, but we determined that only site N92 is occupied. Removal of the N-glycosylation at this site enhances the binding of S-RBD with CD209L. CD209L also interacts with ACE2, suggesting a role for heterodimerization of CD209L and ACE2 in SARS-CoV-2 entry and infection in cell types where both are present. Furthermore, we demonstrate that human endothelial cells are permissive to SARS-CoV-2 infection, and interference with CD209L activity by a knockdown strategy or with soluble CD209L inhibits virus entry. Our observations demonstrate that CD209L and CD209 serve as alternative receptors for SARS-CoV-2 in disease-relevant cell types, including the vascular system. This property is particularly important in tissues where ACE2 has low expression or is absent and may have implications for antiviral drug development.
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Affiliation(s)
- Razie Amraei
- Department
of Pathology, School of Medicine, Boston
University Medical Campus, Boston, Massachusetts 02118, United States
| | - Wenqing Yin
- Renal
Section, Department of Medicine, Boston
University Medical Center, Boston, Massachusetts 02118, United States
| | - Marc A. Napoleon
- Renal
Section, Department of Medicine, Boston
University Medical Center, Boston, Massachusetts 02118, United States
| | - Ellen L. Suder
- Department
of Microbiology, Boston University School
of Medicine, Boston, Massachusetts 02118, United States
- National
Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, Massachusetts 02118, United States
| | - Jacob Berrigan
- Department
of Microbiology, Boston University School
of Medicine, Boston, Massachusetts 02118, United States
| | - Qing Zhao
- Department
of Pathology, School of Medicine, Boston
University Medical Campus, Boston, Massachusetts 02118, United States
| | - Judith Olejnik
- Department
of Microbiology, Boston University School
of Medicine, Boston, Massachusetts 02118, United States
- National
Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, Massachusetts 02118, United States
| | - Kevin Brown Chandler
- Center
for Biomedical Mass Spectrometry, Boston
University School of Medicine, Boston, Massachusetts 02118, United States
| | - Chaoshuang Xia
- Center
for Biomedical Mass Spectrometry, Boston
University School of Medicine, Boston, Massachusetts 02118, United States
| | - Jared Feldman
- Ragon Institute
of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
| | - Blake M. Hauser
- Ragon Institute
of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
| | - Timothy M. Caradonna
- Ragon Institute
of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
| | - Aaron G. Schmidt
- Ragon Institute
of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
- Department
of Microbiology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Suryaram Gummuluru
- Department
of Microbiology, Boston University School
of Medicine, Boston, Massachusetts 02118, United States
| | - Elke Mühlberger
- Department
of Microbiology, Boston University School
of Medicine, Boston, Massachusetts 02118, United States
- National
Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, Massachusetts 02118, United States
| | - Vipul Chitalia
- Renal
Section, Department of Medicine, Boston
University Medical Center, Boston, Massachusetts 02118, United States
| | - Catherine E. Costello
- Center
for Biomedical Mass Spectrometry, Boston
University School of Medicine, Boston, Massachusetts 02118, United States
| | - Nader Rahimi
- Department
of Pathology, School of Medicine, Boston
University Medical Campus, Boston, Massachusetts 02118, United States
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39
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Cramer J, Aliu B, Jiang X, Sharpe T, Pang L, Hadorn A, Rabbani S, Ernst B. Poly-l-lysine Glycoconjugates Inhibit DC-SIGN-mediated Attachment of Pandemic Viruses. ChemMedChem 2021; 16:2345-2353. [PMID: 34061468 DOI: 10.1002/cmdc.202100348] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Indexed: 12/27/2022]
Abstract
The C-type lectin receptor DC-SIGN mediates interactions with envelope glycoproteins of many viruses such as SARS-CoV-2, ebola, and HIV and contributes to virus internalization and dissemination. In the context of the recent SARS-CoV-2 pandemic, involvement of DC-SIGN has been linked to severe cases of COVID-19. Inhibition of the interaction between DC-SIGN and viral glycoproteins has the potential to generate broad spectrum antiviral agents. Here, we demonstrate that mannose-functionalized poly-l-lysine glycoconjugates efficiently inhibit the attachment of viral glycoproteins to DC-SIGN-presenting cells with picomolar affinity. Treatment of these cells leads to prolonged receptor internalization and inhibition of virus binding for up to 6 h. Furthermore, the polymers are fully bio-compatible and readily cleared by target cells. The thermodynamic analysis of the multivalent interactions reveals enhanced enthalpy-driven affinities and promising perspectives for the future development of multivalent therapeutics.
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Affiliation(s)
- Jonathan Cramer
- Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.,Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University of Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Butrint Aliu
- Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Xiaohua Jiang
- Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Timothy Sharpe
- Biophysics Facility, Biocenter of the University of Basel, Klingelbergstrasse 70, 4056, Basel, Switzerland
| | - Lijuan Pang
- Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Adrian Hadorn
- Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Said Rabbani
- Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Beat Ernst
- Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
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40
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Amraei R, Yin W, Napoleon MA, Suder EL, Berrigan J, Zhao Q, Olejnik J, Chandler KB, Xia C, Feldman J, Hauser BM, Caradonna TM, Schmidt AG, Gummuluru S, Muhlberger E, Chitalia V, Costello CE, Rahimi N. CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021:2020.06.22.165803. [PMID: 32607506 PMCID: PMC7325172 DOI: 10.1101/2020.06.22.165803] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
As the COVID-19 pandemic continues to spread, investigating the processes underlying the interactions between SARS-CoV-2 and its hosts is of high importance. Here, we report the identification of CD209L/L-SIGN and the related protein CD209/DC-SIGN as receptors capable of mediating SARS-CoV-2 entry into human cells. Immunofluorescence staining of human tissues revealed prominent expression of CD209L in the lung and kidney epithelium and endothelium. Multiple biochemical assays using a purified recombinant SARS-CoV-2 spike receptor binding domain (S-RBD) or S1 encompassing both NTB and RBD and ectopically expressed CD209L and CD209 revealed that CD209L and CD209 interact with S-RBD. CD209L contains two N-glycosylation sequons, at sites N92 and N361, but we determined that only site N92 is occupied. Removal of the N-glycosylation at this site enhances the binding of S-RBD with CD209L. CD209L also interacts with ACE2, suggesting a role for heterodimerization of CD209L and ACE2 in SARS-CoV-2 entry and infection in cell types where both are present. Furthermore, we demonstrate that human endothelial cells are permissive to SARS-CoV-2 infection and interference with CD209L activity by knockdown strategy or with soluble CD209L inhibits virus entry. Our observations demonstrate that CD209L and CD209 serve as alternative receptors for SARS-CoV-2 in disease-relevant cell types, including the vascular system. This property is particularly important in tissues where ACE2 has low expression or is absent, and may have implications for antiviral drug development.
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Affiliation(s)
- Razie Amraei
- Department of Pathology, School of Medicine, Boston University Medical Campus, Boston, MA 02118
| | - Wenqing Yin
- Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA
| | - Marc A. Napoleon
- Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA
| | - Ellen L. Suder
- Department of Microbiology, Boston University School of Medicine, Boston, MA
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA
| | - Jacob Berrigan
- Department of Microbiology, Boston University School of Medicine, Boston, MA
| | - Qing Zhao
- Department of Pathology, School of Medicine, Boston University Medical Campus, Boston, MA 02118
| | - Judith Olejnik
- Department of Microbiology, Boston University School of Medicine, Boston, MA
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA
| | - Kevin Brown Chandler
- Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA 02118
| | - Chaoshuang Xia
- Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA 02118
| | - Jared Feldman
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139
| | - Blake M. Hauser
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139
| | | | - Aaron G. Schmidt
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139
- Department of Microbiology, Harvard Medical School, Boston, MA 02115
| | - Suryaram Gummuluru
- Department of Microbiology, Boston University School of Medicine, Boston, MA
| | - Elke Muhlberger
- Department of Microbiology, Boston University School of Medicine, Boston, MA
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA
| | - Vipul Chitalia
- Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA
| | - Catherine E. Costello
- Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA 02118
| | - Nader Rahimi
- Department of Pathology, School of Medicine, Boston University Medical Campus, Boston, MA 02118
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Filipczak N, Yalamarty SSK, Li X, Parveen F, Torchilin V. Developments in Treatment Methodologies Using Dendrimers for Infectious Diseases. MOLECULES (BASEL, SWITZERLAND) 2021; 26:molecules26113304. [PMID: 34072765 PMCID: PMC8198206 DOI: 10.3390/molecules26113304] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/22/2021] [Accepted: 05/23/2021] [Indexed: 02/02/2023]
Abstract
Dendrimers comprise a specific group of macromolecules, which combine structural properties of both single molecules and long expanded polymers. The three-dimensional form of dendrimers and the extensive possibilities for use of additional substrates for their construction creates a multivalent potential and a wide possibility for medical, diagnostic and environmental purposes. Depending on their composition and structure, dendrimers have been of interest in many fields of science, ranging from chemistry, biotechnology to biochemical applications. These compounds have found wide application from the production of catalysts for their use as antibacterial, antifungal and antiviral agents. Of particular interest are peptide dendrimers as a medium for transport of therapeutic substances: synthetic vaccines against parasites, bacteria and viruses, contrast agents used in MRI, antibodies and genetic material. This review focuses on the description of the current classes of dendrimers, the methodology for their synthesis and briefly drawbacks of their properties and their use as potential therapies against infectious diseases.
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Affiliation(s)
- Nina Filipczak
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA; (N.F.); (S.S.K.Y.); (X.L.); (F.P.)
| | - Satya Siva Kishan Yalamarty
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA; (N.F.); (S.S.K.Y.); (X.L.); (F.P.)
| | - Xiang Li
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA; (N.F.); (S.S.K.Y.); (X.L.); (F.P.)
- State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Farzana Parveen
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA; (N.F.); (S.S.K.Y.); (X.L.); (F.P.)
- The Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan
| | - Vladimir Torchilin
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA; (N.F.); (S.S.K.Y.); (X.L.); (F.P.)
- Department of Oncology, Radiotherapy and Plastic Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
- Correspondence:
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Ceramide and Related Molecules in Viral Infections. Int J Mol Sci 2021; 22:ijms22115676. [PMID: 34073578 PMCID: PMC8197834 DOI: 10.3390/ijms22115676] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/21/2021] [Accepted: 05/21/2021] [Indexed: 02/08/2023] Open
Abstract
Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit.
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Densumite J, Phanthong S, Seesuay W, Sookrung N, Chaisri U, Chaicumpa W. Engineered Human Monoclonal scFv to Receptor Binding Domain of Ebolavirus. Vaccines (Basel) 2021; 9:vaccines9050457. [PMID: 34064480 PMCID: PMC8147973 DOI: 10.3390/vaccines9050457] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 01/29/2023] Open
Abstract
(1) Background: Ebolavirus (EBOV) poses as a significant threat for human health by frequently causing epidemics of the highly contagious Ebola virus disease (EVD). EBOV glycoprotein (GP), as a sole surface glycoprotein, needs to be cleaved in endosomes to fully expose a receptor-binding domain (RBD) containing a receptor-binding site (RBS) for receptor binding and genome entry into cytoplasm for replication. RBDs are highly conserved among EBOV species, so they are an attractive target for broadly effective anti-EBOV drug development. (2) Methods: Phage display technology was used as a tool to isolate human single-chain antibodies (HuscFv) that bind to recombinant RBDs from a human scFv (HuscFv) phage display library. The RBD-bound HuscFvs were fused with cell-penetrating peptide (CPP), and cell-penetrating antibodies (transbodies) were made, produced from the phage-infected E. coli clones and characterized. (3) Results: Among the HuscFvs obtained from phage-infected E. coli clones, HuscFvs of three clones, HuscFv4, HuscFv11, and HuscFv14, the non-cell-penetrable or cell-penetrable HuscFv4 effectively neutralized cellular entry of EBOV-like particles (VLPs). While all HuscFvs were found to bind cleaved GP (GPcl), their presumptive binding sites were markedly different, as determined by molecular docking. (4) Conclusions: The HuscFv4 could be a promising therapeutic agent against EBOV infection.
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Affiliation(s)
- Jaslan Densumite
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (J.D.); (S.P.); (W.S.)
- Center of Research Excellence on Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Siratcha Phanthong
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (J.D.); (S.P.); (W.S.)
- Center of Research Excellence on Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Watee Seesuay
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (J.D.); (S.P.); (W.S.)
- Center of Research Excellence on Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Nitat Sookrung
- Biomedical Research Incubation Unit, Department of Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand;
| | - Urai Chaisri
- Department of Tropical Pathology, Faculty of Topical Medicine, Mahidol University, Bangkok 10400, Thailand;
| | - Wanpen Chaicumpa
- Center of Research Excellence on Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Correspondence: ; Tel.: +662-419-2936; Fax: +662-419-6470
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The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways. PLoS Pathog 2021; 17:e1009500. [PMID: 33886690 PMCID: PMC8061995 DOI: 10.1371/journal.ppat.1009500] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/24/2021] [Indexed: 12/13/2022] Open
Abstract
The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which is not observed for the other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features of the coronavirus spike (S) protein, which optimize the virus towards the human respiratory tract. First, the S proteins exhibit an intrinsic temperature preference, corresponding with the temperature of the upper or lower airways. Pseudoviruses bearing the SARS-CoV-2 spike (SARS-2-S) were more infectious when produced at 33°C instead of 37°C, a property shared with the S protein of HCoV-229E, a common cold coronavirus. In contrast, the S proteins of SARS-CoV and MERS-CoV favored 37°C, in accordance with virus preference for the lower airways. Next, SARS-2-S-driven entry was efficiently activated by not only TMPRSS2, but also the TMPRSS13 protease, thus broadening the cell tropism of SARS-CoV-2. Both proteases proved relevant in the context of authentic virus replication. TMPRSS13 appeared an effective spike activator for the virulent coronaviruses but not the low pathogenic HCoV-229E virus. Activation of SARS-2-S by these surface proteases requires processing of the S1/S2 cleavage loop, in which both the furin recognition motif and extended loop length proved critical. Conversely, entry of loop deletion mutants is significantly increased in cathepsin-rich cells. Finally, we demonstrate that the D614G mutation increases SARS-CoV-2 stability, particularly at 37°C, and, enhances its use of the cathepsin L pathway. This indicates a link between S protein stability and usage of this alternative route for virus entry. Since these spike properties may promote virus spread, they potentially explain why the spike-G614 variant has replaced the early D614 variant to become globally predominant. Collectively, our findings reveal adaptive mechanisms whereby the coronavirus spike protein is adjusted to match the temperature and protease conditions of the airways, to enhance virus transmission and pathology. The devastating COVID-19 pandemic is caused by SARS-CoV-2, a novel virus that despite recent zoonotic introduction is already very well adapted to its human host. Its rapid spread is related to abundant replication in the upper airways, which is not observed for other highly pathogenic human coronaviruses. To understand the role of the viral spike protein in this airway adaptation, we constructed pseudoviruses of SARS-CoV-2 and other coronaviruses that cause severe pneumonia or, on the contrary, a mild common cold. The key findings were verified with authentic virus. We reveal features of the spike proteins, which optimize the coronavirus towards specific parts of the respiratory tract. Namely, we show that the spike proteins exhibit intrinsic temperature preference to precisely match the upper (~33°C) or lower (37°C) airways. We recognized which proteases of human airways activate the spike for virus entry, in particular one protease that may mediate coronavirus virulence. Finally, a link was perceived between spike stability and entry via endosomal proteases. We propose that these mechanisms of spike fine-tuning may have contributed to a global shift in SARS-CoV-2 epidemiology, from the early spike-D614 to the currently predominating G614 variant.
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Rutten L, Gilman MSA, Blokland S, Juraszek J, McLellan JS, Langedijk JPM. Structure-Based Design of Prefusion-Stabilized Filovirus Glycoprotein Trimers. Cell Rep 2021; 30:4540-4550.e3. [PMID: 32234486 PMCID: PMC7118701 DOI: 10.1016/j.celrep.2020.03.025] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 01/27/2020] [Accepted: 03/10/2020] [Indexed: 12/16/2022] Open
Abstract
Ebola virus causes severe hemorrhagic fever, often leading to death in humans. The trimeric fusion glycoprotein (GP) is the sole target for neutralizing antibodies and is the major focus of vaccine development. Soluble GP ectodomains are unstable and mostly monomeric when not fused to a heterologous trimerization domain. Here, we report structure-based designs of Ebola and Marburg GP trimers based on a stabilizing mutation in the hinge loop in refolding region 1 and substitution of a partially buried charge at the interface of the GP1 and GP2 subunits. The combined substitutions (T577P and K588F) substantially increased trimer expression for Ebola GP proteins. We determined the crystal structure of stabilized GP from the Makona Zaire ebolavirus strain without a trimerization domain or complexed ligand. The structure reveals that the stabilized GP adopts the same trimeric prefusion conformation, provides insight into triggering of GP conformational changes, and should inform future filovirus vaccine development.
Filovirus GP expression increases by stabilizing mutations in hinge loop and base helix Charged lysine in base helix and GP1 N terminus are trapped in metastable conformation Crystal structure of stabilized Makona Δmucin GP confirms successful stabilization These findings may be useful for understanding fusion mechanisms and vaccine design
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Affiliation(s)
- Lucy Rutten
- Janssen Vaccines & Prevention, Archimedesweg 4-6, Leiden 2333 CN, the Netherlands
| | - Morgan S A Gilman
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
| | - Sven Blokland
- Janssen Vaccines & Prevention, Archimedesweg 4-6, Leiden 2333 CN, the Netherlands
| | - Jarek Juraszek
- Janssen Vaccines & Prevention, Archimedesweg 4-6, Leiden 2333 CN, the Netherlands
| | - Jason S McLellan
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
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Imre G, Krähling V, Eichler M, Trautmann S, Ferreirós N, Aman MJ, Kashanchi F, Rajalingam K, Pöhlmann S, Becker S, Meyer Zu Heringdorf D, Pfeilschifter J. The sphingosine kinase 1 activator, K6PC-5, attenuates Ebola virus infection. iScience 2021; 24:102266. [PMID: 33817572 PMCID: PMC8005759 DOI: 10.1016/j.isci.2021.102266] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 02/08/2021] [Accepted: 03/01/2021] [Indexed: 12/18/2022] Open
Abstract
Ebola virus (EBOV) is responsible for outbreaks with case fatality rates of up to 90% and for an epidemic in West Africa with more than ten thousand deaths. EBOV glycoprotein (EBOV-GP) is the only viral surface protein and is responsible for viral entry into cells. Here, by employing pseudotyped EBOV-GP viral particles, we uncover a critical role for sphingolipids in inhibiting viral entry. Sphingosine kinase 1 (SphK1) catalyzes the phosphorylation of sphingosine to sphingosine 1-phosphate (S1P). The administration of the SphK1 activator, K6PC-5, or S1P, or the overexpression of SphK1 consistently exhibited striking inhibitory effects in EBOV-GP-driven entry in diverse cell lines. Finally, K6PC-5 markedly reduced the EBOV titer in infected cells and the de novo production of viral proteins. These data present K6PC-5 as an efficient tool to inhibit EBOV infection in endothelial cells and suggest further studies to evaluate its systemic effects.
K6PC-5, a sphingosine kinase 1 activator, inhibits Ebola virus infection Sphingosine 1-phosphate, the product of SphK1, attenuates the viral entry Inhibiton/activation of S1P receptors has no influence on Ebola virus entry These data support the endogen effect of S1P in Ebola virus infection
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Affiliation(s)
- Gergely Imre
- Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
| | - Verena Krähling
- Institute of Virology, Philipps University Marburg, Marburg, Germany.,German Center for Infection Research (DZIF), partner site Gießen-Marburg-Langen, Marburg, Germany
| | - Madeleine Eichler
- Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
| | - Sandra Trautmann
- Institute of Clinical Pharmacology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
| | - Nerea Ferreirós
- Institute of Clinical Pharmacology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
| | - M Javad Aman
- Integrated BioTherapeutics, Inc., Gaithersburg, MD 20850, USA
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, George Mason University Manassas, VA 20110, USA
| | - Krishnaraj Rajalingam
- Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Stefan Pöhlmann
- Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, 37077 Göttingen, Germany.,Faculty of Biology and Psychology, University Göttingen, 37077 Göttingen, Germany
| | - Stephan Becker
- Institute of Virology, Philipps University Marburg, Marburg, Germany.,German Center for Infection Research (DZIF), partner site Gießen-Marburg-Langen, Marburg, Germany
| | - Dagmar Meyer Zu Heringdorf
- Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
| | - Josef Pfeilschifter
- Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
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Lee CCD, Watanabe Y, Wu NC, Han J, Kumar S, Pholcharee T, Seabright GE, Allen JD, Lin CW, Yang JR, Liu MT, Wu CY, Ward AB, Crispin M, Wilson IA. A cross-neutralizing antibody between HIV-1 and influenza virus. PLoS Pathog 2021; 17:e1009407. [PMID: 33750987 PMCID: PMC8016226 DOI: 10.1371/journal.ppat.1009407] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 04/01/2021] [Accepted: 02/17/2021] [Indexed: 11/19/2022] Open
Abstract
Incessant antigenic evolution enables the persistence and spread of influenza virus in the human population. As the principal target of the immune response, the hemagglutinin (HA) surface antigen on influenza viruses continuously acquires and replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, target the HIV-1 envelope protein (Env), which is even more extensively glycosylated and contains under-processed oligomannose-type clusters on its dense glycan shield. Here, we illustrate that 2G12 can also neutralize human seasonal influenza A H3N2 viruses that have evolved to present similar oligomannose-type clusters on their HAs from around 20 years after the 1968 pandemic. Using structural biology and mass spectrometric approaches, we find that two N-glycosylation sites close to the receptor binding site (RBS) on influenza hemagglutinin represent the oligomannose cluster recognized by 2G12. One of these glycan sites is highly conserved in all human H3N2 strains and the other emerged during virus evolution. These two N-glycosylation sites have also become crucial for fitness of recent H3N2 strains. These findings shed light on the evolution of the glycan shield on influenza virus and suggest 2G12-like antibodies can potentially act as broad neutralizers to target human enveloped viruses.
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Affiliation(s)
- Chang-Chun D. Lee
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Yasunori Watanabe
- School of Biological Sciences, University of Southampton, Southampton, England, United Kingdom
- Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, England, United Kingdom
- Division of Structural Biology, University of Oxford, Wellcome Centre for Human Genetics, Oxford, England, United Kingdom
| | - Nicholas C. Wu
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Julianna Han
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Sonu Kumar
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Tossapol Pholcharee
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Gemma E. Seabright
- School of Biological Sciences, University of Southampton, Southampton, England, United Kingdom
- Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, England, United Kingdom
| | - Joel D. Allen
- School of Biological Sciences, University of Southampton, Southampton, England, United Kingdom
| | - Chih-Wei Lin
- Department of Chemistry, The Scripps Research Institute, La Jolla, California, United States of America
| | - Ji-Rong Yang
- Centers for Disease Control, Taipei City, Taiwan
| | | | - Chung-Yi Wu
- Genomics Research Center, Academia Sinica, Taipei City, Taiwan
| | - Andrew B. Ward
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Max Crispin
- School of Biological Sciences, University of Southampton, Southampton, England, United Kingdom
| | - Ian A. Wilson
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
- The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America
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Misasi J, Sullivan NJ. Immunotherapeutic strategies to target vulnerabilities in the Ebolavirus glycoprotein. Immunity 2021; 54:412-436. [PMID: 33691133 DOI: 10.1016/j.immuni.2021.01.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 01/15/2021] [Accepted: 01/20/2021] [Indexed: 12/18/2022]
Abstract
The 2014 Ebola virus disease (EVD) outbreak in West Africa and the subsequent outbreaks of 2018-2020 in Equator and North Kivu provinces of the Democratic Republic of the Congo illustrate the public health challenges of emerging and reemerging viruses. EVD has a high case fatality rate with a rapidly progressing syndrome of fever, rash, vomiting, diarrhea, and bleeding diathesis. Recently, two monoclonal-antibody-based therapies received United States Food and Drug Administration (FDA) approval, and there are several other passive immunotherapies that hold promise as therapeutics against other species of Ebolavirus. Here, we review concepts needed to understand mechanisms of action, present an expanded schema to define additional sites of vulnerability on the viral glycoprotein, and review current antibody-based therapeutics. The concepts described are used to gain insights into the key characteristics that represent functional targets for immunotherapies against Zaire Ebolavirus and other emerging viruses within the Ebolavirus genus.
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Affiliation(s)
- John Misasi
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Vaccine Research Center, 40 Convent Drive, Bethesda, MD 20892, USA
| | - Nancy J Sullivan
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Vaccine Research Center, 40 Convent Drive, Bethesda, MD 20892, USA.
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49
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Fosse JH, Haraldsen G, Falk K, Edelmann R. Endothelial Cells in Emerging Viral Infections. Front Cardiovasc Med 2021; 8:619690. [PMID: 33718448 PMCID: PMC7943456 DOI: 10.3389/fcvm.2021.619690] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/01/2021] [Indexed: 12/11/2022] Open
Abstract
There are several reasons to consider the role of endothelial cells in COVID-19 and other emerging viral infections. First, severe cases of COVID-19 show a common breakdown of central vascular functions. Second, SARS-CoV-2 replicates in endothelial cells. Third, prior deterioration of vascular function exacerbates disease, as the most common comorbidities of COVID-19 (obesity, hypertension, and diabetes) are all associated with endothelial dysfunction. Importantly, SARS-CoV-2's ability to infect endothelium is shared by many emerging viruses, including henipaviruses, hantavirus, and highly pathogenic avian influenza virus, all specifically targeting endothelial cells. The ability to infect endothelium appears to support generalised dissemination of infection and facilitate the access to certain tissues. The disturbed vascular function observed in severe COVID-19 is also a prominent feature of many other life-threatening viral diseases, underscoring the need to understand how viruses modulate endothelial function. We here review the role of vascular endothelial cells in emerging viral infections, starting with a summary of endothelial cells as key mediators and regulators of vascular and immune responses in health and infection. Next, we discuss endotheliotropism as a possible virulence factor and detail features that regulate viruses' ability to attach to and enter endothelial cells. We move on to review how endothelial cells detect invading viruses and respond to infection, with particular focus on pathways that may influence vascular function and the host immune system. Finally, we discuss how endothelial cell function can be dysregulated in viral disease, either by viral components or as bystander victims of overshooting or detrimental inflammatory and immune responses. Many aspects of how viruses interact with the endothelium remain poorly understood. Considering the diversity of such mechanisms among different emerging viruses allows us to highlight common features that may be of general validity and point out important challenges.
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Affiliation(s)
| | - Guttorm Haraldsen
- Department of Pathology, Oslo University Hospital, Oslo, Norway.,Department of Pathology, University of Oslo, Oslo, Norway
| | - Knut Falk
- Norwegian Veterinary Institute, Oslo, Norway.,AquaMed Consulting AS, Oslo, Norway
| | - Reidunn Edelmann
- Department of Clinical Medicine, Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway
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Singh H, Koury J, Kaul M. Innate Immune Sensing of Viruses and Its Consequences for the Central Nervous System. Viruses 2021; 13:170. [PMID: 33498715 PMCID: PMC7912342 DOI: 10.3390/v13020170] [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: 12/18/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 12/13/2022] Open
Abstract
Viral infections remain a global public health concern and cause a severe societal and economic burden. At the organismal level, the innate immune system is essential for the detection of viruses and constitutes the first line of defense. Viral components are sensed by host pattern recognition receptors (PRRs). PRRs can be further classified based on their localization into Toll-like receptors (TLRs), C-type lectin receptors (CLR), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors (NLRs) and cytosolic DNA sensors (CDS). TLR and RLR signaling results in production of type I interferons (IFNα and -β) and pro-inflammatory cytokines in a cell-specific manner, whereas NLR signaling leads to the production of interleukin-1 family proteins. On the other hand, CLRs are capable of sensing glycans present in viral pathogens, which can induce phagocytic, endocytic, antimicrobial, and pro- inflammatory responses. Peripheral immune sensing of viruses and the ensuing cytokine response can significantly affect the central nervous system (CNS). But viruses can also directly enter the CNS via a multitude of routes, such as the nasal epithelium, along nerve fibers connecting to the periphery and as cargo of infiltrating infected cells passing through the blood brain barrier, triggering innate immune sensing and cytokine responses directly in the CNS. Here, we review mechanisms of viral immune sensing and currently recognized consequences for the CNS of innate immune responses to viruses.
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Affiliation(s)
- Hina Singh
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA; (H.S.); (J.K.)
- Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Jeffrey Koury
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA; (H.S.); (J.K.)
| | - Marcus Kaul
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA; (H.S.); (J.K.)
- Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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