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1
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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] [Download PDF] [Figures] [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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Liu J, Quan Y, Tong H, Zhu Y, Shi X, Liu Y, Cheng G. Insights into mosquito-borne arbovirus receptors. CELL INSIGHT 2024; 3:100196. [PMID: 39391003 PMCID: PMC11462183 DOI: 10.1016/j.cellin.2024.100196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/13/2024] [Accepted: 08/13/2024] [Indexed: 10/12/2024]
Abstract
The increasing global prevalence of mosquito-borne viruses has emerged as a significant threat to human health and life. Identifying receptors for these viruses is crucial for improving our knowledge of viral pathogenesis and developing effective antiviral strategies. The widespread application of CRISPR-Cas9 screening have led to the discovery of many mosquito-borne virus receptors. The revealed structures of virus-receptor complexes also provide important information for understanding their interaction mechanisms. This review provides a comprehensive summary of both conventional and novel approaches for identifying new viral receptors and the putative entry factors of the most prevalent mosquito-borne viruses within the Flaviviridae, Togaviridae, and Bunyavirales. At the same time, we emphasize the common receptors utilized by these viruses for entry into both vertebrate hosts and mosquito vectors. We discuss promising avenues for developing anti-mosquito-borne viral strategies that target these receptors. Notably, targeting universal receptors of specific mosquito-borne viruses in both vertebrates and mosquitoes offers dual benefits for disease prevention. Additionally, the widespread use of AI-based machine learning and protein structure prediction will accelerate the identification of new viral receptors and provide new avenues for antiviral drug discovery.
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Affiliation(s)
- Jianying Liu
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, 518000, China
| | - Yixin Quan
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, 518000, China
- School of Life Science, Southern University of Science and Technology, Shenzhen, 518052, China
| | - Hua Tong
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, 518000, China
| | - Yibin Zhu
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China
| | - Xiaolu Shi
- Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China
| | - Yang Liu
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, 518000, China
| | - Gong Cheng
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, 518000, China
- Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China
- Southwest United Graduate School, Kunming, 650092, China
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3
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Chabert M, Lacôte S, Marianneau P, Confort MP, Aurine N, Pédarrieu A, Doumbia B, Ould Baba Ould Gueya M, Habiboullah H, Beyatt ABEM, Lo MM, Nichols J, Sreenu VB, da Silva Filipe A, Colle MA, Pain B, Cêtre-Sossah C, Arnaud F, Ratinier M. Comparative study of two Rift Valley fever virus field strains originating from Mauritania. PLoS Negl Trop Dis 2024; 18:e0012728. [PMID: 39652604 DOI: 10.1371/journal.pntd.0012728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 12/19/2024] [Accepted: 11/26/2024] [Indexed: 12/21/2024] Open
Abstract
Rift Valley fever (RVF) is one of the major viral arthropod-borne diseases in Africa. In recent decades, RVF virus (RVFV), the causative agent of RVF, has been responsible for multiple outbreaks in West Africa with important consequences on human and animal health. In particular, an outbreak occurred in 2010 after heavy rains in the desertic region of Adrar, Mauritania. It was characterized by the appearance of severe clinical signs among dromedary camels. Another one occurred in 2013-2014 across Senegal and the southern part of Mauritania. In this study, we characterized two RVFV field strains isolated during these two outbreaks. The first strain, MRU25010-30, was isolated from a camel (2010) while the second, MRU2687-3, was isolated from a goat (2013). By deep-sequencing and rapid amplification of cDNA-ends by polymerase chain reaction, we successfully sequenced the complete genome of these two RVFV strains as well as the reference laboratory strain ZH548. Phylogenetic analysis showed that the two field viruses belong to two different RVFV genetic lineages. Moreover, we showed that MRU25010-30 replicates more efficiently in various in vitro cell culture models than MRU2687-3 and ZH548. In vivo, MRU25010-30 caused rapid death of BALB/c mice and proved to be more virulent than MRU2687-3, regardless of the route of inoculation (subcutaneous or intranasal). The virulence of MRU25010-30 is associated with a high viral load in the liver and serum of infected mice, while the death of mice infected with MRU2687-3 and ZH548 correlated with a high viral load in the brain. Altogether, the data presented in this study provide new avenues to unveil the molecular viral determinants that modulate RVFV virulence and replication capacity.
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Affiliation(s)
- Mehdi Chabert
- IVPC UMR754, INRAE, Universite Claude Bernard Lyon 1, EPHE, Université PSL, Lyon, France
- CIRAD, UMR ASTRE, Montpellier Cedex, France
- ASTRE, Univ Montpellier, CIRAD, INRAE, Montpellier, France
| | | | | | - Marie-Pierre Confort
- IVPC UMR754, INRAE, Universite Claude Bernard Lyon 1, EPHE, Université PSL, Lyon, France
| | - Noémie Aurine
- Université Lyon 1, INSERM, INRAE, Stem Cell and Brain Research Institute, U1208, USC1361, Bron, France
| | - Aurélie Pédarrieu
- CIRAD, UMR ASTRE, Montpellier Cedex, France
- ASTRE, Univ Montpellier, CIRAD, INRAE, Montpellier, France
| | - Baba Doumbia
- Direction des Services Vétérinaires, Ministère de l'élevage, Nouakchott, Mauritania
| | | | | | | | | | - Jenna Nichols
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Vattipally B Sreenu
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Ana da Silva Filipe
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | | | - Bertrand Pain
- Université Lyon 1, INSERM, INRAE, Stem Cell and Brain Research Institute, U1208, USC1361, Bron, France
| | - Catherine Cêtre-Sossah
- CIRAD, UMR ASTRE, Montpellier Cedex, France
- ASTRE, Univ Montpellier, CIRAD, INRAE, Montpellier, France
| | - Frédérick Arnaud
- IVPC UMR754, INRAE, Universite Claude Bernard Lyon 1, EPHE, Université PSL, Lyon, France
| | - Maxime Ratinier
- IVPC UMR754, INRAE, Universite Claude Bernard Lyon 1, EPHE, Université PSL, Lyon, France
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4
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Cheng M, Zhang R, Li J, Ma W, Li L, Jiang N, Liu B, Wu J, Zheng N, Wu Z. MβCD inhibits SFTSV entry by disrupting lipid raft structure of the host cells. Antiviral Res 2024; 231:106004. [PMID: 39265655 DOI: 10.1016/j.antiviral.2024.106004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/31/2024] [Accepted: 09/08/2024] [Indexed: 09/14/2024]
Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV), recently named as Dabie bandavirus, belongs to the family Phenuiviridae of the order Bunyavirales, is a newly-identified bunyavirus with a case fatality rate of up to 30%, posing a serious threat to public health. Lipid rafts on plasm membranes are important for the entry of enveloped viruses; however, the role of lipid rafts in bunyavirus entry remains unclear. In this study, we found that methyl-beta-cyclodextrin (MβCD), a drug that disrupts cholesterol in lipid rafts of cell membranes, inhibits SFTSV infection. Additionally, there is a back-complementary effect of SFTSV infection upon the addition of cholesterol. Moreover, the concentration of SFTSV particles in lipid rafts during entry directly indicated the role of lipid rafts as a gateway, whereas MβCD could inhibit SFTSV entry by affecting the structure of lipid rafts. In an in vivo study, MβCD also reduced the susceptibility of mice to SFTSV infection. Our results suggest that SFTSV can interact with Talin1 proteins on lipid rafts to enter host cells by endocytosis of lipid rafts and reveal the potential therapeutic value of MβCD for SFTSV infection.
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Affiliation(s)
- Min Cheng
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, People's Republic of China
| | - Rui Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, People's Republic of China
| | - Jianshu Li
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, People's Republic of China
| | - Wenyuan Ma
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, People's Republic of China
| | - Linrun Li
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, People's Republic of China
| | - Na Jiang
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, People's Republic of China
| | - Bingxin Liu
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, People's Republic of China
| | - Jing Wu
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, People's Republic of China
| | - Nan Zheng
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, People's Republic of China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, People's Republic of China.
| | - Zhiwei Wu
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, People's Republic of China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, People's Republic of China.
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5
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Basaran R, Ning X, Budhadev D, Hondow N, Guo Y, Zhou D. Probing the pH-dependency of DC-SIGN/R multivalent lectin-glycan interactions using polyvalent glycan-gold nanoparticles. NANOSCALE ADVANCES 2024; 6:2198-2208. [PMID: 38633047 PMCID: PMC11019501 DOI: 10.1039/d3na01013a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 03/04/2024] [Indexed: 04/19/2024]
Abstract
The dendritic cell tetrameric lectin, DC-SIGN, and its closely related endothelial cell lectin, DC-SIGNR (collectively abbreviated as DC-SIGN/R) play a key role in the binding and transmission of deadly viruses, including Ebola, HIV, HCV, and SARS-CoV-2. Their virus binding/release processes involve a gradually acidifying environment following the natural intracellular trafficking pathways. Therefore, understanding DC-SIGN/R's pH-dependent binding properties with glycan ligands is of great importance. We have recently developed densely glycosylated gold nanoparticles (glycan-GNPs) as a powerful new tool for probing DC-SIGN/R multivalent lectin-glycan interaction (MLGI) mechanisms. They can provide not only quantitative MLGI affinities but also important structural information, such as binding site orientation and binding modes. Herein, we further employ the glycan-GNP probes to investigate the pH dependency of DC-SIGN/R MLGI properties. We find that DC-SIGN/R MLGIs exhibit distinct pH dependence over the normal physiological (7.4) to lysosomal (∼4.6) pH range. DC-SIGN binds glycan-GNPs strongly and stably from pH 7.4 to ∼5.8, but the binding is weakened significantly as pH decreases to ≤5.4 and may be fully dissociated at pH 4.6. This behaviour is fully consistent with DC-SIGN's role as an endocytic recycling receptor. In contrast, DC-SIGNR's affinity with glycan-GNPs is enhanced with the decreasing pH from 7.4 to 5.4, peaking at pH 5.4, and then reduced as pH is further lowered. Interestingly, both DC-SIGN/R binding with glycan-GNPs are found to be partially reversible in a pH-dependent manner.
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Affiliation(s)
- Rahman Basaran
- School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds Leeds LS2 9JT UK
| | - Xinyu Ning
- School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds Leeds LS2 9JT UK
| | - Darshita Budhadev
- School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds Leeds LS2 9JT UK
| | - Nicole Hondow
- School of Chemical and Process Engineering, University of Leeds Leeds LS2 9JT UK
| | - Yuan Guo
- School of Food Science and Nutrition, Astbury Centre for Structural Molecular Biology, University of Leeds Leeds LS2 9JT UK
| | - Dejian Zhou
- School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds Leeds LS2 9JT UK
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6
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Gu Y, Lozach PY. Illuminating bunyavirus entry into host cells with fluorescence. Mol Microbiol 2024; 121:671-678. [PMID: 37700704 DOI: 10.1111/mmi.15165] [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: 07/18/2023] [Revised: 09/02/2023] [Accepted: 09/04/2023] [Indexed: 09/14/2023]
Abstract
Bunyavirales constitute the largest order of enveloped RNA viruses, many members of which cause severe diseases in humans and domestic animals. In recent decades, innovative fluorescence-based methods have paved the way to visualize and track single fluorescent bunyaviral particles in fixed and live cells. This technological breakthrough has enabled imaging of the early stages of infection and the quantification of every step in the bunyavirus cell entry process. Here, we describe the latest procedures for rendering bunyaviral particles fluorescent and discuss the advantages and disadvantages of each approach in light of the most recent advances in fluorescence detection and monitoring of bunyavirus entry. In this mini-review, we also illustrate how fluorescent viral particles are a powerful tool for deciphering the cellular entry process of bunyaviruses, the vast majority of which have not yet been analyzed.
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Affiliation(s)
- Yu Gu
- Université Claude Bernard Lyon 1, INRAE, EPHE, IVPC UMR754, Team iWays, Lyon, France
| | - Pierre-Yves Lozach
- Université Claude Bernard Lyon 1, INRAE, EPHE, IVPC UMR754, Team iWays, Lyon, France
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7
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Alatrash R, Herrera BB. The Adaptive Immune Response against Bunyavirales. Viruses 2024; 16:483. [PMID: 38543848 PMCID: PMC10974645 DOI: 10.3390/v16030483] [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: 01/31/2024] [Revised: 03/18/2024] [Accepted: 03/19/2024] [Indexed: 05/23/2024] Open
Abstract
The Bunyavirales order includes at least fourteen families with diverse but related viruses, which are transmitted to vertebrate hosts by arthropod or rodent vectors. These viruses are responsible for an increasing number of outbreaks worldwide and represent a threat to public health. Infection in humans can be asymptomatic, or it may present with a range of conditions from a mild, febrile illness to severe hemorrhagic syndromes and/or neurological complications. There is a need to develop safe and effective vaccines, a process requiring better understanding of the adaptive immune responses involved during infection. This review highlights the most recent findings regarding T cell and antibody responses to the five Bunyavirales families with known human pathogens (Peribunyaviridae, Phenuiviridae, Hantaviridae, Nairoviridae, and Arenaviridae). Future studies that define and characterize mechanistic correlates of protection against Bunyavirales infections or disease will help inform the development of effective vaccines.
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Affiliation(s)
- Reem Alatrash
- Rutgers Global Health Institute, Rutgers University, New Brunswick, NJ 08901, USA
- Department of Medicine, Division of Allergy, Immunology, and Infectious Diseases and Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Bobby Brooke Herrera
- Rutgers Global Health Institute, Rutgers University, New Brunswick, NJ 08901, USA
- Department of Medicine, Division of Allergy, Immunology, and Infectious Diseases and Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
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8
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Uckeley ZM, Duboeuf M, Gu Y, Erny A, Mazelier M, Lüchtenborg C, Winter SL, Schad P, Mathieu C, Koch J, Boulant S, Chlanda P, Maisse C, Brügger B, Lozach PY. Glucosylceramide in bunyavirus particles is essential for virus binding to host cells. Cell Mol Life Sci 2024; 81:71. [PMID: 38300320 PMCID: PMC10834583 DOI: 10.1007/s00018-023-05103-0] [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: 09/23/2023] [Revised: 12/08/2023] [Accepted: 12/21/2023] [Indexed: 02/02/2024]
Abstract
Hexosylceramides (HexCer) are implicated in the infection process of various pathogens. However, the molecular and cellular functions of HexCer in infectious cycles are poorly understood. Investigating the enveloped virus Uukuniemi (UUKV), a bunyavirus of the Phenuiviridae family, we performed a lipidomic analysis with mass spectrometry and determined the lipidome of both infected cells and derived virions. We found that UUKV alters the processing of HexCer to glycosphingolipids (GSL) in infected cells. The infection resulted in the overexpression of glucosylceramide (GlcCer) synthase (UGCG) and the specific accumulation of GlcCer and its subsequent incorporation into viral progeny. UUKV and several pathogenic bunyaviruses relied on GlcCer in the viral envelope for binding to various host cell types. Overall, our results indicate that GlcCer is a structural determinant of virions crucial for bunyavirus infectivity. This study also highlights the importance of glycolipids on virions in facilitating interactions with host cell receptors and infectious entry of enveloped viruses.
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Affiliation(s)
- Zina M Uckeley
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, 69120, Heidelberg, Germany
- Cluster of Excellence, CellNetworks, 69120, Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120, Heidelberg, Germany
- Department for Molecular Genetics and Microbiology, University of Florida, Gainesville, USA
| | - Maëva Duboeuf
- Université Claude Bernard Lyon 1, INRAE, EPHE, IVPC UMR754, Team iWays, 69007, Lyon, France
| | - Yu Gu
- Université Claude Bernard Lyon 1, INRAE, EPHE, IVPC UMR754, Team iWays, 69007, Lyon, France
| | - Alexandra Erny
- Université Claude Bernard Lyon 1, INRAE, EPHE, IVPC UMR754, Team iWays, 69007, Lyon, France
| | - Magalie Mazelier
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, 69120, Heidelberg, Germany
- Cluster of Excellence, CellNetworks, 69120, Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | | | - Sophie L Winter
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, 69120, Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120, Heidelberg, Germany
- Schaller Research Groups, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany
| | - Paulina Schad
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, 69120, Heidelberg, Germany
- Cluster of Excellence, CellNetworks, 69120, Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Cyrille Mathieu
- CIRI (Centre International de Recherche en Infectiologie), Team Neuro-Invasion, TROpism and VIRal Encephalitis, INSERM U1111, CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, 69007, Lyon, France
| | - Jana Koch
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, 69120, Heidelberg, Germany
- Cluster of Excellence, CellNetworks, 69120, Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120, Heidelberg, Germany
- Université Claude Bernard Lyon 1, INRAE, EPHE, IVPC UMR754, Team iWays, 69007, Lyon, France
| | - Steeve Boulant
- Department for Molecular Genetics and Microbiology, University of Florida, Gainesville, USA
| | - Petr Chlanda
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, 69120, Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120, Heidelberg, Germany
- Schaller Research Groups, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany
| | - Carine Maisse
- Université Claude Bernard Lyon 1, INRAE, EPHE, IVPC UMR754, Team iWays, 69007, Lyon, France
| | - Britta Brügger
- Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany
| | - Pierre-Yves Lozach
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, 69120, Heidelberg, Germany.
- Cluster of Excellence, CellNetworks, 69120, Heidelberg, Germany.
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
- Université Claude Bernard Lyon 1, INRAE, EPHE, IVPC UMR754, Team iWays, 69007, Lyon, France.
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9
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Weber F, Bouloy M, Lozach PY. An Introduction to Rift Valley Fever Virus. Methods Mol Biol 2024; 2824:1-14. [PMID: 39039402 DOI: 10.1007/978-1-0716-3926-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
Rift Valley fever virus (RVFV) is a pathogen transmitted to humans and livestock via mosquito bites. This virus, which was discovered in Kenya in 1930, is considered by the World Health Organization (WHO) and the World Organisation for Animal Health (WOAH) to be associated with a high risk of causing large-scale epidemics. However, means dedicated to fighting RVFV have been limited, and despite recent research efforts, the virus remains poorly understood at both the molecular and cellular levels as well as at a broader scale of research in the field and in animal and human populations. In this introductory chapter of a methods book, we aim to provide readers with a concise overview of RVFV, from its ecology and transmission to the structural and genomic organization of virions and its life cycle in host cells.
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Affiliation(s)
- Friedemann Weber
- Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
| | - Michèle Bouloy
- Institut Pasteur, Université Paris Cité, Bunyavirus Molecular Genetics Unit, Paris, France
| | - Pierre-Yves Lozach
- IVPC UMR754, INRAE, Université Claude Bernard Lyon 1, EPHE, PSL Research University, Lyon, France.
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10
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Gu Y, Koch J, Garnier C, Erny A, Lozach PY. Making Rift Valley Fever Viral Particles Fluorescent. Methods Mol Biol 2024; 2824:165-188. [PMID: 39039413 DOI: 10.1007/978-1-0716-3926-9_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
Rift Valley fever virus (RVFV) is a mosquito-borne pathogen that represents a significant threat to both human and veterinary public health. Since its discovery in the Great Rift Valley of Kenya in the 1930s, the virus has spread across Africa and beyond, now posing a risk of introduction into Southern Europe and Asia. Despite recent progresses, early RVFV-host cell interactions remain largely uncharacterized. In this method chapter, we delineate the procedure for labeling RVFV particles with fluorescent organic dyes. This approach makes it feasible to visualize single viral particles in both fixed and living cells and study RVFV entry into host cells. We provide additional examples with two viruses closely related to RVFV, namely, Toscana virus and Uukuniemi virus. Furthermore, we illustrate how to utilize fluorescent viral particles to examine and quantify each step of the cell entry program of RVFV, which includes state-of-the-art fluorescence-based detection techniques such as fluorescence microscopy, flow cytometry, and fluorimetry.
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Affiliation(s)
- Yu Gu
- IVPC UMR754, INRAE, Université Claude Bernard Lyon 1, EPHE, PSL Research University, Lyon, France
| | - Jana Koch
- IVPC UMR754, INRAE, Université Claude Bernard Lyon 1, EPHE, PSL Research University, Lyon, France
| | - Céline Garnier
- IVPC UMR754, INRAE, Université Claude Bernard Lyon 1, EPHE, PSL Research University, Lyon, France
| | - Alexandra Erny
- IVPC UMR754, INRAE, Université Claude Bernard Lyon 1, EPHE, PSL Research University, Lyon, France
| | - Pierre-Yves Lozach
- IVPC UMR754, INRAE, Université Claude Bernard Lyon 1, EPHE, PSL Research University, Lyon, France.
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11
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Balaraman V, Indran SV, Li Y, Meekins DA, Jakkula LUMR, Liu H, Hays MP, Souza-Neto JA, Gaudreault NN, Hardwidge PR, Wilson WC, Weber F, Richt JA. Identification of Host Factors for Rift Valley Fever Phlebovirus. Viruses 2023; 15:2251. [PMID: 38005928 PMCID: PMC10675714 DOI: 10.3390/v15112251] [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: 09/28/2023] [Revised: 10/26/2023] [Accepted: 10/30/2023] [Indexed: 11/26/2023] Open
Abstract
Rift Valley fever phlebovirus (RVFV) is a zoonotic pathogen that causes Rift Valley fever (RVF) in livestock and humans. Currently, there is no licensed human vaccine or antiviral drug to control RVF. Although multiple species of animals and humans are vulnerable to RVFV infection, host factors affecting susceptibility are not well understood. To identify the host factors or genes essential for RVFV replication, we conducted CRISPR-Cas9 knockout screening in human A549 cells. We then validated the putative genes using siRNA-mediated knock-downs and CRISPR-Cas9-mediated knock-out studies. The role of a candidate gene in the virus replication cycle was assessed by measuring intracellular viral RNA accumulation, and the virus titers were analyzed using plaque assay or TCID50 assay. We identified approximately 900 genes with potential involvement in RVFV infection and replication. Further evaluation of the effect of six genes on viral replication using siRNA-mediated knock-downs revealed that silencing two genes (WDR7 and LRP1) significantly impaired RVFV replication. For further analysis, we focused on the WDR7 gene since the role of the LRP1 gene in RVFV replication was previously described in detail. WDR7 knockout A549 cell lines were generated and used to dissect the effect of WRD7 on a bunyavirus, RVFV, and an orthobunyavirus, La Crosse encephalitis virus (LACV). We observed significant effects of WDR7 knockout cells on both intracellular RVFV RNA levels and viral titers. At the intracellular RNA level, WRD7 affected RVFV replication at a later phase of its replication cycle (24 h) when compared with the LACV replication, which was affected in an earlier replication phase (12 h). In summary, we identified WDR7 as an essential host factor for the replication of two different viruses, RVFV and LACV, both of which belong to the Bunyavirales order. Future studies will investigate the mechanistic role through which WDR7 facilitates phlebovirus replication.
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Affiliation(s)
- Velmurugan Balaraman
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
| | - Sabarish V. Indran
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
| | - Yonghai Li
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
| | - David A. Meekins
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
| | - Laxmi U. M. R. Jakkula
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
| | - Heidi Liu
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
| | - Micheal P. Hays
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
| | - Jayme A. Souza-Neto
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
| | - Natasha N. Gaudreault
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
| | - Philip R. Hardwidge
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
| | - William C. Wilson
- Foreign Arthropod-Borne Animal Diseases Research Unit, United States Department of Agriculture, National Bio and Agro-Defense Facility, Agricultural Research Service, 1980 Denison Ave, Manhattan, KS 66506, USA
| | - Friedemann Weber
- Institute for Virology, FB10—Veterinary Medicine, Justus-Liebig University, 35392 Giessen, Germany
| | - Juergen A. Richt
- Center of Excellence for Emerging and Zoonotic Animal Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, KS 66506, USA
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12
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Balaraman V, Indran SV, Li Y, Meekins DA, Jakkula LU, Liu H, Hays MP, Souza-Neto JA, Gaudreault NN, Hardwidge PR, Wilson WC, Weber F, Richt JA. Identification of host factors for Rift Valley Fever Phlebovirus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.28.559935. [PMID: 37808812 PMCID: PMC10557628 DOI: 10.1101/2023.09.28.559935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Background Rift Valley fever phlebovirus (RVFV) is a zoonotic pathogen that causes Rift Valley fever (RVF) in livestock and humans. Currently, there is no licensed human vaccine or antiviral drug to control RVF. Although multiple species of animals and humans are vulnerable to RVFV infection, host factors affecting susceptibility are not well understood. Methodology To identify the host factors or genes essential for RVFV replication, we conducted a CRISPR-Cas9 knock-out screen in human A549 cells. We then validated the putative genes using siRNA-mediated knockdowns and CRISPR-Cas9-mediated knockout studies, respectively. The role of a candidate gene in the virus replication cycle was assessed by measuring intracellular viral RNA accumulation, and the virus titers by plaque assay or TCID50 assay. Findings We identified approximately 900 genes with potential involvement in RVFV infection and replication. Further evaluation of the effect of six genes on viral replication using siRNA-mediated knockdowns found that silencing two genes (WDR7 and LRP1) significantly impaired RVFV replication. For further analysis, we focused on the WDR7 gene since the role of LRP1 in RVFV replication was previously described in detail. Knock-out A549 cell lines were generated and used to dissect the effect of WRD7 on RVFV and another bunyavirus, La Crosse encephalitis virus (LACV). We observed significant effects of WDR7 knock-out cells on both intracellular RVFV RNA levels and viral titers. At the intracellular RNA level, WRD7 affected RVFV replication at a later phase of its replication cycle (24h) when compared to LACV which was affected an earlier replication phase (12h). Conclusion In summary, we have identified WDR7 as an essential host factor for the replication of two relevant bunyaviruses, RVFV and LACV. Future studies will investigate the mechanistic role by which WDR7 facilitates Phlebovirus replication.
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Affiliation(s)
- Velmurugan Balaraman
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - Sabarish V. Indran
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - Yonghai Li
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - David A. Meekins
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - Laxmi U.M.R. Jakkula
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - Heidi Liu
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - Micheal P. Hays
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - Jayme A. Souza-Neto
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - Natasha N. Gaudreault
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - Philip R. Hardwidge
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - William C. Wilson
- United States Department of Agriculture, Agricultural Research Service, National Bio and Agro-Defense Facility, Foreign Arthropod-Borne Animal Diseases Research Unit, Manhattan, Kansas, United States of America
| | - Friedemann Weber
- Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
| | - Juergen A. Richt
- Center of Excellence for Emerging and Zoonotic Animal Diseases and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
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13
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Labiod N, Luczkowiak J, Tapia MM, Lasala F, Delgado R. The role of DC-SIGN as a trans-receptor in infection by MERS-CoV. Front Cell Infect Microbiol 2023; 13:1177270. [PMID: 37808906 PMCID: PMC10552186 DOI: 10.3389/fcimb.2023.1177270] [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: 03/01/2023] [Accepted: 08/28/2023] [Indexed: 10/10/2023] Open
Abstract
DC-SIGN is a C-type lectin expressed in myeloid cells such as immature dendritic cells and macrophages. Through glycan recognition in viral envelope glycoproteins, DC-SIGN has been shown to act as a receptor for a number of viral agents such as HIV, Ebola virus, SARS-CoV, and SARS-CoV-2. Using a system of Vesicular Stomatitis Virus pseudotyped with MERS-CoV spike protein, here, we show that DC-SIGN is partially responsible for MERS-CoV infection of dendritic cells and that DC-SIGN efficiently mediates trans-infection of MERS-CoV from dendritic cells to susceptible cells, indicating a potential role of DC-SIGN in MERS-CoV dissemination and pathogenesis.
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Affiliation(s)
- Nuria Labiod
- Department of Microbiology, Instituto de Investigación Hospital Universitario 12 de Octubre (Imas12), Madrid, Spain
| | - Joanna Luczkowiak
- Department of Microbiology, Instituto de Investigación Hospital Universitario 12 de Octubre (Imas12), Madrid, Spain
| | - María M. Tapia
- Department of Microbiology, Instituto de Investigación Hospital Universitario 12 de Octubre (Imas12), Madrid, Spain
| | - Fátima Lasala
- Department of Microbiology, Instituto de Investigación Hospital Universitario 12 de Octubre (Imas12), Madrid, Spain
| | - Rafael Delgado
- Department of Microbiology, Instituto de Investigación Hospital Universitario 12 de Octubre (Imas12), Madrid, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad Complutense, Madrid, Spain
- CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
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14
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Nair N, Osterhaus ADME, Rimmelzwaan GF, Prajeeth CK. Rift Valley Fever Virus-Infection, Pathogenesis and Host Immune Responses. Pathogens 2023; 12:1174. [PMID: 37764982 PMCID: PMC10535968 DOI: 10.3390/pathogens12091174] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/09/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Rift Valley Fever Virus is a mosquito-borne phlebovirus causing febrile or haemorrhagic illness in ruminants and humans. The virus can prevent the induction of the antiviral interferon response through its NSs proteins. Mutations in the NSs gene may allow the induction of innate proinflammatory immune responses and lead to attenuation of the virus. Upon infection, virus-specific antibodies and T cells are induced that may afford protection against subsequent infections. Thus, all arms of the adaptive immune system contribute to prevention of disease progression. These findings will aid the design of vaccines using the currently available platforms. Vaccine candidates have shown promise in safety and efficacy trials in susceptible animal species and these may contribute to the control of RVFV infections and prevention of disease progression in humans and ruminants.
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15
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Koch J, Xin Q, Obr M, Schäfer A, Rolfs N, Anagho HA, Kudulyte A, Woltereck L, Kummer S, Campos J, Uckeley ZM, Bell-Sakyi L, Kräusslich HG, Schur FKM, Acuna C, Lozach PY. The phenuivirus Toscana virus makes an atypical use of vacuolar acidity to enter host cells. PLoS Pathog 2023; 19:e1011562. [PMID: 37578957 PMCID: PMC10449198 DOI: 10.1371/journal.ppat.1011562] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 08/24/2023] [Accepted: 07/17/2023] [Indexed: 08/16/2023] Open
Abstract
Toscana virus is a major cause of arboviral disease in humans in the Mediterranean basin during summer. However, early virus-host cell interactions and entry mechanisms remain poorly characterized. Investigating iPSC-derived human neurons and cell lines, we found that virus binding to the cell surface was specific, and 50% of bound virions were endocytosed within 10 min. Virions entered Rab5a+ early endosomes and, subsequently, Rab7a+ and LAMP-1+ late endosomal compartments. Penetration required intact late endosomes and occurred within 30 min following internalization. Virus entry relied on vacuolar acidification, with an optimal pH for viral membrane fusion at pH 5.5. The pH threshold increased to 5.8 with longer pre-exposure of virions to the slightly acidic pH in early endosomes. Strikingly, the particles remained infectious after entering late endosomes with a pH below the fusion threshold. Overall, our study establishes Toscana virus as a late-penetrating virus and reveals an atypical use of vacuolar acidity by this virus to enter host cells.
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Affiliation(s)
- Jana Koch
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany
- CellNetworks–Cluster of Excellence, Heidelberg, Germany
- Univ. Lyon, INRAE, EPHE, IVPC, Lyon, France
| | - Qilin Xin
- Univ. Lyon, INRAE, EPHE, IVPC, Lyon, France
| | - Martin Obr
- Institute of Science and Technology Austria (ISTA), Klosterneuburg, Austria
| | - Alicia Schäfer
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany
- CellNetworks–Cluster of Excellence, Heidelberg, Germany
| | - Nina Rolfs
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany
- CellNetworks–Cluster of Excellence, Heidelberg, Germany
| | - Holda A. Anagho
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany
- CellNetworks–Cluster of Excellence, Heidelberg, Germany
| | - Aiste Kudulyte
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany
- CellNetworks–Cluster of Excellence, Heidelberg, Germany
| | - Lea Woltereck
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany
- CellNetworks–Cluster of Excellence, Heidelberg, Germany
| | - Susann Kummer
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany
| | - Joaquin Campos
- Chica and Heinz Schaller Research Group, Institute of Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany
| | - Zina M. Uckeley
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany
- CellNetworks–Cluster of Excellence, Heidelberg, Germany
| | - Lesley Bell-Sakyi
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United-Kingdom
| | - Hans-Georg Kräusslich
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany
| | - Florian KM. Schur
- Institute of Science and Technology Austria (ISTA), Klosterneuburg, Austria
| | - Claudio Acuna
- Chica and Heinz Schaller Research Group, Institute of Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany
| | - Pierre-Yves Lozach
- Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany
- CellNetworks–Cluster of Excellence, Heidelberg, Germany
- Univ. Lyon, INRAE, EPHE, IVPC, Lyon, France
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16
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Devignot S, Sha TW, Burkard TR, Schmerer P, Hagelkruys A, Mirazimi A, Elling U, Penninger JM, Weber F. Low-density lipoprotein receptor-related protein 1 (LRP1) as an auxiliary host factor for RNA viruses. Life Sci Alliance 2023; 6:e202302005. [PMID: 37072184 PMCID: PMC10114362 DOI: 10.26508/lsa.202302005] [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: 02/22/2023] [Revised: 04/04/2023] [Accepted: 04/05/2023] [Indexed: 04/20/2023] Open
Abstract
Viruses with an RNA genome are often the cause of zoonotic infections. In order to identify novel pro-viral host cell factors, we screened a haploid insertion-mutagenized mouse embryonic cell library for clones that are resistant to Rift Valley fever virus (RVFV). This screen returned the low-density lipoprotein receptor-related protein 1 (LRP1) as a top hit, a plasma membrane protein involved in a wide variety of cell activities. Inactivation of LRP1 in human cells reduced RVFV RNA levels already at the attachment and entry stages of infection. Moreover, the role of LRP1 in promoting RVFV infection was dependent on physiological levels of cholesterol and on endocytosis. In the human cell line HuH-7, LRP1 also promoted early infection stages of sandfly fever Sicilian virus and La Crosse virus, but had a minor effect on late infection by vesicular stomatitis virus, whereas encephalomyocarditis virus was entirely LRP1-independent. Moreover, siRNA experiments in human Calu-3 cells demonstrated that also SARS-CoV-2 infection benefitted from LRP1. Thus, we identified LRP1 as a host factor that supports infection by a spectrum of RNA viruses.
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Affiliation(s)
- Stephanie Devignot
- Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
| | - Tim Wai Sha
- Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
| | - Thomas R Burkard
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
| | - Patrick Schmerer
- Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
| | - Astrid Hagelkruys
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
| | - Ali Mirazimi
- Public Health Agency of Sweden, Solna, Sweden
- Department of Laboratory Medicine, Karolinska Institutet, Solna, Sweden
| | - Ulrich Elling
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
| | - Josef M Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | - Friedemann Weber
- Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
- German Centre for Infection Research (DZIF), Partner Site Giessen, Giessen, Germany
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17
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Snyman J, Snyman LP, Buhler KJ, Villeneuve CA, Leighton PA, Jenkins EJ, Kumar A. California Serogroup Viruses in a Changing Canadian Arctic: A Review. Viruses 2023; 15:1242. [PMID: 37376542 DOI: 10.3390/v15061242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/24/2023] [Accepted: 05/18/2023] [Indexed: 06/29/2023] Open
Abstract
The Arctic is warming at four times the global rate, changing the diversity, activity and distribution of vectors and associated pathogens. While the Arctic is not often considered a hotbed of vector-borne diseases, Jamestown Canyon virus (JCV) and Snowshoe Hare virus (SSHV) are mosquito-borne zoonotic viruses of the California serogroup endemic to the Canadian North. The viruses are maintained by transovarial transmission in vectors and circulate among vertebrate hosts, both of which are not well characterized in Arctic regions. While most human infections are subclinical or mild, serious cases occur, and both JCV and SSHV have recently been identified as leading causes of arbovirus-associated neurological diseases in North America. Consequently, both viruses are currently recognised as neglected and emerging viruses of public health concern. This review aims to summarise previous findings in the region regarding the enzootic transmission cycle of both viruses. We identify key gaps and approaches needed to critically evaluate, detect, and model the effects of climate change on these uniquely northern viruses. Based on limited data, we predict that (1) these northern adapted viruses will increase their range northwards, but not lose range at their southern limits, (2) undergo more rapid amplification and amplified transmission in endemic regions for longer vector-biting seasons, (3) take advantage of northward shifts of hosts and vectors, and (4) increase bite rates following an increase in the availability of breeding sites, along with phenological synchrony between the reproduction cycle of theorized reservoirs (such as caribou calving) and mosquito emergence.
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Affiliation(s)
- Jumari Snyman
- Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - Louwrens P Snyman
- Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada
| | - Kayla J Buhler
- Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada
| | - Carol-Anne Villeneuve
- Research Group on Epidemiology of Zoonoses and Public Health (GREZOSP), Faculty of Veterinary Medicine, Université de Montréal, Saint-Hyacinthe, QC J2S 2M2, Canada
| | - Patrick A Leighton
- Research Group on Epidemiology of Zoonoses and Public Health (GREZOSP), Faculty of Veterinary Medicine, Université de Montréal, Saint-Hyacinthe, QC J2S 2M2, Canada
| | - Emily J Jenkins
- Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada
| | - Anil Kumar
- Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
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18
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Intact Type I Interferon Receptor Signaling Prevents Hepatocellular Necrosis but Not Encephalitis in a Dose-Dependent Manner in Rift Valley Fever Virus Infected Mice. Int J Mol Sci 2022; 23:ijms232012492. [DOI: 10.3390/ijms232012492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/30/2022] [Accepted: 10/11/2022] [Indexed: 11/17/2022] Open
Abstract
Rift Valley fever (RVF) is a zoonotic and emerging disease, caused by the RVF virus (RVFV). In ruminants, it leads to “abortion storms” and enhanced mortality rates in young animals, whereas in humans it can cause symptoms like severe hemorrhagic fever or encephalitis. The role of the innate and adaptive immune response in disease initiation and progression is still poorly defined. The present study used the attenuated RVFV strain clone 13 to investigate viral spread, tissue tropism, and histopathological lesions after intranasal infection in C57BL/6 wild type (WT) and type I interferon (IFN-I) receptor I knockout (IFNAR−/−) mice. In WT mice, 104 PFU RVFV (high dose) resulted in a fatal encephalitis, but no hepatitis 7–11 days post infection (dpi), whereas 103 PFU RVFV (low dose) did not cause clinical disease or significant histopathological lesions in liver and the central nervous system (CNS). In contrast, IFNAR−/− mice infected with 103 PFU RVFV developed hepatocellular necrosis resulting in death at 2–5 dpi and lacked encephalitis. These results show that IFNAR signaling prevents systemic spread of the attenuated RVFV strain clone 13, but not the dissemination to the CNS and subsequent fatal disease. Consequently, neurotropic viruses may be able to evade antiviral IFN-I signaling pathways by using the transneuronal instead of the hematogenous route.
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19
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Boshra H. An Overview of the Infectious Cycle of Bunyaviruses. Viruses 2022; 14:2139. [PMID: 36298693 PMCID: PMC9610998 DOI: 10.3390/v14102139] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/17/2022] Open
Abstract
Bunyaviruses represent the largest group of RNA viruses and are the causative agent of a variety of febrile and hemorrhagic illnesses. Originally characterized as a single serotype in Africa, the number of described bunyaviruses now exceeds over 500, with its presence detected around the world. These predominantly tri-segmented, single-stranded RNA viruses are transmitted primarily through arthropod and rodent vectors and can infect a wide variety of animals and plants. Although encoding for a small number of proteins, these viruses can inflict potentially fatal disease outcomes and have even developed strategies to suppress the innate antiviral immune mechanisms of the infected host. This short review will attempt to provide an overall description of the order Bunyavirales, describing the mechanisms behind their infection, replication, and their evasion of the host immune response. Furthermore, the historical context of these viruses will be presented, starting from their original discovery almost 80 years ago to the most recent research pertaining to viral replication and host immune response.
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Affiliation(s)
- Hani Boshra
- Global Urgent and Advanced Research and Development (GUARD), 911 Rue Principale, Batiscan, QC G0X 1A0, Canada
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20
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Schön K, Lindenwald DL, Monteiro JT, Glanz J, Jung K, Becker SC, Lepenies B. Vector and Host C-Type Lectin Receptor (CLR)-Fc Fusion Proteins as a Cross-Species Comparative Approach to Screen for CLR-Rift Valley Fever Virus Interactions. Int J Mol Sci 2022; 23:ijms23063243. [PMID: 35328665 PMCID: PMC8954825 DOI: 10.3390/ijms23063243] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 12/25/2022] Open
Abstract
Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus endemic to Africa and the Arabian Peninsula, which causes diseases in humans and livestock. C-type lectin receptors (CLRs) represent a superfamily of pattern recognition receptors that were reported to interact with diverse viruses and contribute to antiviral immune responses but may also act as attachment factors or entry receptors in diverse species. Human DC-SIGN and L-SIGN are known to interact with RVFV and to facilitate viral host cell entry, but the roles of further host and vector CLRs are still unknown. In this study, we present a CLR–Fc fusion protein library to screen RVFV–CLR interaction in a cross-species approach and identified novel murine, ovine, and Aedes aegypti RVFV candidate receptors. Furthermore, cross-species CLR binding studies enabled observations of the differences and similarities in binding preferences of RVFV between mammalian CLR homologues, as well as more distant vector/host CLRs.
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Affiliation(s)
- Kathleen Schön
- Institute for Parasitology & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hanover, Germany;
- Institute for Immunology & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hanover, Germany; (D.L.L.); (J.T.M.)
| | - Dimitri L. Lindenwald
- Institute for Immunology & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hanover, Germany; (D.L.L.); (J.T.M.)
| | - João T. Monteiro
- Institute for Immunology & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hanover, Germany; (D.L.L.); (J.T.M.)
| | - Julien Glanz
- Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, 30559 Hanover, Germany; (J.G.); (K.J.)
| | - Klaus Jung
- Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, 30559 Hanover, Germany; (J.G.); (K.J.)
| | - Stefanie C. Becker
- Institute for Parasitology & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hanover, Germany;
- Correspondence: (S.C.B.); (B.L.)
| | - Bernd Lepenies
- Institute for Immunology & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hanover, Germany; (D.L.L.); (J.T.M.)
- Correspondence: (S.C.B.); (B.L.)
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21
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Windhaber S, Xin Q, Uckeley ZM, Koch J, Obr M, Garnier C, Luengo-Guyonnot C, Duboeuf M, Schur FKM, Lozach PY. The Orthobunyavirus Germiston Enters Host Cells from Late Endosomes. J Virol 2022; 96:e0214621. [PMID: 35019710 PMCID: PMC8906410 DOI: 10.1128/jvi.02146-21] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 01/03/2022] [Indexed: 01/01/2023] Open
Abstract
With more than 80 members worldwide, the Orthobunyavirus genus in the Peribunyaviridae family is a large genus of enveloped RNA viruses, many of which are emerging pathogens in humans and livestock. How orthobunyaviruses (OBVs) penetrate and infect mammalian host cells remains poorly characterized. Here, we investigated the entry mechanisms of the OBV Germiston (GERV). Viral particles were visualized by cryo-electron microscopy and appeared roughly spherical with an average diameter of 98 nm. Labeling of the virus with fluorescent dyes did not adversely affect its infectivity and allowed the monitoring of single particles in fixed and live cells. Using this approach, we found that endocytic internalization of bound viruses was asynchronous and occurred within 30 to 40 min. The virus entered Rab5a-positive (Rab5a+) early endosomes and, subsequently, late endosomal vacuoles containing Rab7a but not LAMP-1. Infectious entry did not require proteolytic cleavage, and endosomal acidification was sufficient and necessary for viral fusion. Acid-activated penetration began 15 to 25 min after initiation of virus internalization and relied on maturation of early endosomes to late endosomes. The optimal pH for viral membrane fusion was slightly below 6.0, and penetration was hampered when the potassium influx was abolished. Overall, our study provides real-time visualization of GERV entry into host cells and demonstrates the importance of late endosomal maturation in facilitating OBV penetration. IMPORTANCE Orthobunyaviruses (OBVs), which include La Crosse, Oropouche, and Schmallenberg viruses, represent a growing threat to humans and domestic animals worldwide. Ideally, preventing OBV spread requires approaches that target early stages of infection, i.e., virus entry. However, little is known about the molecular and cellular mechanisms by which OBVs enter and infect host cells. Here, we developed accurate, sensitive tools and assays to investigate the penetration process of GERV. Our data emphasize the central role of late endosomal maturation in GERV entry, providing a comprehensive overview of the early stages of an OBV infection. Our study also brings a complete toolbox of innovative methods to study each step of the OBV entry program in fixed and living cells, from virus binding and endocytosis to fusion and penetration. The information gained herein lays the foundation for the development of antiviral strategies aiming to block OBV entry.
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Affiliation(s)
- Stefan Windhaber
- CellNetworks-Cluster of Excellence Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Qilin Xin
- University of Lyon, INRAE, EPHE, IVPC, Lyon, France
| | - Zina M. Uckeley
- CellNetworks-Cluster of Excellence Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jana Koch
- CellNetworks-Cluster of Excellence Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin Obr
- Institute of Science and Technology Austria, Klosterneuburg, Austria
| | | | | | | | | | - Pierre-Yves Lozach
- CellNetworks-Cluster of Excellence Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
- University of Lyon, INRAE, EPHE, IVPC, Lyon, France
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22
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Gonçalves Júnior J. COVID-19, liver dysfunction and pathophysiology: A conceptual discussion. World J Gastroenterol 2022; 28:683-688. [PMID: 35317425 PMCID: PMC8900549 DOI: 10.3748/wjg.v28.i6.683] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/21/2021] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open
Abstract
The intra and extracellular pathways of hepatic injury by coronavirus disease 2019 (COVID-19) are still being studied. Understanding them is important to treat this viral disease and other liver and biliary tract disorders. Thus, this paper aims to present three hypotheses about liver injury caused by COVID-19: (1) The interactions between severe acute respiratory syndrome coronavirus 2 spike protein and membrane receptors in the hepatocyte; (2) The dysbiosis and “gut-liver axis” disruption in patients with serious clinical presentations of COVID-19; and (3) The inflammatory response exacerbated through the production of interleukins such as interleukin-6. However, despite these new perspectives, the pathophysiological process of liver injury caused by COVID-19 is still complex and multifactorial. Thus, understanding all these variables is a challenge to science but also the key to propose individualized and effective patient therapies.
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Affiliation(s)
- Jucier Gonçalves Júnior
- Department of Internal Medicine, Division of Rheumatology, São Paulo University, São Paulo 01246-903, State, Brazil
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23
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Abstract
Arboviruses are medically important arthropod-borne viruses that cause a range of diseases in humans from febrile illness to arthritis, encephalitis and hemorrhagic fever. Given their transmission cycles, these viruses face the challenge of replicating in evolutionarily divergent organisms that can include ticks, flies, mosquitoes, birds, rodents, reptiles and primates. Furthermore, their cell attachment receptor utilization may be affected by the opposing needs for generating high and sustained serum viremia in vertebrates such that virus particles are efficiently collected during a hematophagous arthropod blood meal but they must also bind sufficiently to cellular structures on divergent organisms such that productive infection can be initiated and viremia generated. Sulfated polysaccharides of the glycosaminoglycan (GAG) groups, primarily heparan sulfate (HS), have been identified as cell attachment moieties for many arboviruses. Original identification of GAG binding as a phenotype of arboviruses appeared to involve this attribute arising solely as a consequence of adaptation of virus isolates to growth in cell culture. However, more recently, naturally circulating strains of at least one arbovirus, eastern equine encephalitis, have been shown to bind HS efficiently and the GAG binding phenotype continues to be associated with arbovirus infection in published studies. If GAGs are attachment receptors for many naturally circulating arboviruses, this could lead to development of broad-spectrum antiviral therapies through blocking of the virus-GAG interaction. This review summarizes the available data for GAG/HS binding as a phenotype of naturally circulating arbovirus strains emphasizing the importance of avoiding tissue culture amplification and artifactual phenotypes during their isolation.
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Affiliation(s)
- Maria D H Alcorn
- Center for Vaccine Research, Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - William B Klimstra
- Center for Vaccine Research, Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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24
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Highly adaptive
Phenuiviridae
with biomedical importance in multiple fields. J Med Virol 2022; 94:2388-2401. [DOI: 10.1002/jmv.27618] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/24/2021] [Accepted: 01/21/2022] [Indexed: 11/07/2022]
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25
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Jarahian M, Marofi F, Maashi MS, Ghaebi M, Khezri A, Berger MR. Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape. Cancers (Basel) 2021; 13:5203. [PMID: 34680351 PMCID: PMC8534074 DOI: 10.3390/cancers13205203] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/28/2022] Open
Abstract
Glycans linked to surface proteins are the most complex biological macromolecules that play an active role in various cellular mechanisms. This diversity is the basis of cell-cell interaction and communication, cell growth, cell migration, as well as co-stimulatory or inhibitory signaling. Our review describes the importance of neuraminic acid and its derivatives as recognition elements, which are located at the outermost positions of carbohydrate chains linked to specific glycoproteins or glycolipids. Tumor cells, especially from solid tumors, mask themselves by re-expression of hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) in order to protect themselves against the cytotoxic attack of the also highly sialylated immune effector cells. More particularly, we focus on α-2,8-linked polysialic acid chains, which characterize carrier glycoproteins such as NCAM, NRP-2, or SynCam-1. This characteristic property correlates with an aggressive clinical phenotype and endows them with multiple roles in biological processes that underlie all steps of cancer progression, including regulation of cell-cell and/or cell-extracellular matrix interactions, as well as increased proliferation, migration, reduced apoptosis rate of tumor cells, angiogenesis, and metastasis. Specifically, re-expression of poly/oligo-sialylated adhesion molecules on the surface of tumor cells disrupts their interaction with immune-effector cells and contributes to pathophysiological immune escape. Further, sialylated glycoproteins induce immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. We describe the processes, which modulate the interaction between sialylated carrier glycoproteins and their ligands, and illustrate that sialic acids could be targets of novel therapeutic strategies for treatment of cancer and immune diseases.
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Affiliation(s)
- Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit Heidelberg, 69120 Heidelberg, Germany;
| | - Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5165665931, Iran;
| | - Marwah Suliman Maashi
- Stem Cells and Regenerative Medicine Unit at King Fahad Medical Research Centre, Jeddah 11211, Saudi Arabia;
| | - Mahnaz Ghaebi
- Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan 4513956184, Iran;
| | - Abdolrahman Khezri
- Department of Biotechnology, Inland Norway University of Applied Sciences, 2418 Hamar, Norway;
| | - Martin R. Berger
- German Cancer Research Center, Toxicology and Chemotherapy Unit Heidelberg, 69120 Heidelberg, Germany;
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26
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Ganaie SS, Schwarz MM, McMillen CM, Price DA, Feng AX, Albe JR, Wang W, Miersch S, Orvedahl A, Cole AR, Sentmanat MF, Mishra N, Boyles DA, Koenig ZT, Kujawa MR, Demers MA, Hoehl RM, Moyle AB, Wagner ND, Stubbs SH, Cardarelli L, Teyra J, McElroy A, Gross ML, Whelan SPJ, Doench J, Cui X, Brett TJ, Sidhu SS, Virgin HW, Egawa T, Leung DW, Amarasinghe GK, Hartman AL. Lrp1 is a host entry factor for Rift Valley fever virus. Cell 2021; 184:5163-5178.e24. [PMID: 34559985 DOI: 10.1016/j.cell.2021.09.001] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 04/29/2021] [Accepted: 09/01/2021] [Indexed: 12/26/2022]
Abstract
Rift Valley fever virus (RVFV) is a zoonotic pathogen with pandemic potential. RVFV entry is mediated by the viral glycoprotein (Gn), but host entry factors remain poorly defined. Our genome-wide CRISPR screen identified low-density lipoprotein receptor-related protein 1 (mouse Lrp1/human LRP1), heat shock protein (Grp94), and receptor-associated protein (RAP) as critical host factors for RVFV infection. RVFV Gn directly binds to specific Lrp1 clusters and is glycosylation independent. Exogenous addition of murine RAP domain 3 (mRAPD3) and anti-Lrp1 antibodies neutralizes RVFV infection in taxonomically diverse cell lines. Mice treated with mRAPD3 and infected with pathogenic RVFV are protected from disease and death. A mutant mRAPD3 that binds Lrp1 weakly failed to protect from RVFV infection. Together, these data support Lrp1 as a host entry factor for RVFV infection and define a new target to limit RVFV infections.
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Affiliation(s)
- Safder S Ganaie
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Madeline M Schwarz
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Cynthia M McMillen
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - David A Price
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Annie X Feng
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Joseph R Albe
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Wenjie Wang
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Shane Miersch
- The Donnelly Centre, University of Toronto, Toronto, ON, Canada
| | - Anthony Orvedahl
- Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Aidan R Cole
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Monica F Sentmanat
- Genome Engineering and iPSC Center (GEiC), Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Nawneet Mishra
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Devin A Boyles
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Zachary T Koenig
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michael R Kujawa
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Matthew A Demers
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ryan M Hoehl
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Austin B Moyle
- Department of Chemistry, Washington University in St. Louis, St. Louis, MO, USA
| | - Nicole D Wagner
- Department of Chemistry, Washington University in St. Louis, St. Louis, MO, USA
| | - Sarah H Stubbs
- Department of Microbiology, Harvard Medical School, Boston, MA, USA
| | - Lia Cardarelli
- The Donnelly Centre, University of Toronto, Toronto, ON, Canada
| | - Joan Teyra
- The Donnelly Centre, University of Toronto, Toronto, ON, Canada
| | - Anita McElroy
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pediatrics, Division of Pediatric Infectious Disease, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michael L Gross
- Department of Chemistry, Washington University in St. Louis, St. Louis, MO, USA
| | - Sean P J Whelan
- Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO, USA
| | - John Doench
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Xiaoxia Cui
- Genome Engineering and iPSC Center (GEiC), Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Tom J Brett
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Sachdev S Sidhu
- The Donnelly Centre, University of Toronto, Toronto, ON, Canada
| | - Herbert W Virgin
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA; Current address: Vir Biotechnology, San Francisco, CA, USA
| | - Takeshi Egawa
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Daisy W Leung
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Gaya K Amarasinghe
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
| | - Amy L Hartman
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
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27
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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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28
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Léger P, Lozach PY. [Rift Valley fever virus and the amazing NSs protein]. Med Sci (Paris) 2021; 37:601-608. [PMID: 34180819 DOI: 10.1051/medsci/2021090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Rift Valley Fever Virus (RVFV) is an emerging zoonotic pathogen transmitted to humans and livestock through mosquito bites, which was first isolated in Kenya in 1930. The virus is classified by the WHO among the pathogens for which there is an urgent need to develop research, diagnostics, and therapies. However, the efforts developed to control the virus remain limited, and the virus is not well characterized. In this article, we will introduce RVFV and then focus on its virulence factor, the nonstructural protein NSs. We will mainly discuss the ability of this viral protein to form amyloid-like fibrils and its implication in the neurotoxicity associated with RVFV infection.
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Affiliation(s)
- Psylvia Léger
- CellNetworks, CIID (Cluster of Excellence and Center for Integrative Infectious Disease Research), Virology, University hospital Heidelberg, Im Neuenheimer Feld 344, 69120 Heidelberg, Allemagne
| | - Pierre-Yves Lozach
- CellNetworks, CIID (Cluster of Excellence and Center for Integrative Infectious Disease Research), Virology, University hospital Heidelberg, Im Neuenheimer Feld 344, 69120 Heidelberg, Allemagne - Univ. Lyon, INRAe, EPHE, IVPC (Infections virales et pathologie comparée), 50 avenue Tony Garnier, 69007 Lyon, France
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29
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Orthobunyaviruses: From Virus Binding to Penetration into Mammalian Host Cells. Viruses 2021; 13:v13050872. [PMID: 34068494 PMCID: PMC8151349 DOI: 10.3390/v13050872] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/05/2021] [Accepted: 05/07/2021] [Indexed: 12/04/2022] Open
Abstract
With over 80 members worldwide, Orthobunyavirus is the largest genus in the Peribunyaviridae family. Orthobunyaviruses (OBVs) are arthropod-borne viruses that are structurally simple, with a trisegmented, negative-sense RNA genome and only four structural proteins. OBVs are potential agents of emerging and re-emerging diseases and overall represent a global threat to both public and veterinary health. The focus of this review is on the very first steps of OBV infection in mammalian hosts, from virus binding to penetration and release of the viral genome into the cytosol. Here, we address the most current knowledge and advances regarding OBV receptors, endocytosis, and fusion.
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30
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Odendaal L, Davis AS, Venter EH. Insights into the Pathogenesis of Viral Haemorrhagic Fever Based on Virus Tropism and Tissue Lesions of Natural Rift Valley Fever. Viruses 2021; 13:v13040709. [PMID: 33923863 PMCID: PMC8073615 DOI: 10.3390/v13040709] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/26/2021] [Accepted: 04/02/2021] [Indexed: 12/20/2022] Open
Abstract
Rift Valley fever phlebovirus (RVFV) infects humans and a wide range of ungulates and historically has caused devastating epidemics in Africa and the Arabian Peninsula. Lesions of naturally infected cases of Rift Valley fever (RVF) have only been described in detail in sheep with a few reports concerning cattle and humans. The most frequently observed lesion in both ruminants and humans is randomly distributed necrosis, particularly in the liver. Lesions supportive of vascular endothelial injury are also present and include mild hydropericardium, hydrothorax and ascites; marked pulmonary congestion and oedema; lymph node congestion and oedema; and haemorrhages in many tissues. Although a complete understanding of RVF pathogenesis is still lacking, antigen-presenting cells in the skin are likely the early targets of the virus. Following suppression of type I IFN production and necrosis of dermal cells, RVFV spreads systemically, resulting in infection and necrosis of other cells in a variety of organs. Failure of both the innate and adaptive immune responses to control infection is exacerbated by apoptosis of lymphocytes. An excessive pro-inflammatory cytokine and chemokine response leads to microcirculatory dysfunction. Additionally, impairment of the coagulation system results in widespread haemorrhages. Fatal outcomes result from multiorgan failure, oedema in many organs (including the lungs and brain), hypotension, and circulatory shock. Here, we summarize current understanding of RVF cellular tropism as informed by lesions caused by natural infections. We specifically examine how extant knowledge informs current understanding regarding pathogenesis of the haemorrhagic fever form of RVF, identifying opportunities for future research.
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Affiliation(s)
- Lieza Odendaal
- Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, Pretoria 0002, South Africa
- Correspondence: (L.O.); (A.S.D.)
| | - A Sally Davis
- Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, Pretoria 0002, South Africa
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
- Correspondence: (L.O.); (A.S.D.)
| | - Estelle H Venter
- Department of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of Pretoria, Pretoria 0002, South Africa;
- College of Public Health Medical and Veterinary Sciences, Discipline Veterinary Science, James Cook University, Townsville, QLD 4811, Australia
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31
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Hulswit RJG, Paesen GC, Bowden TA, Shi X. Recent Advances in Bunyavirus Glycoprotein Research: Precursor Processing, Receptor Binding and Structure. Viruses 2021; 13:353. [PMID: 33672327 PMCID: PMC7926653 DOI: 10.3390/v13020353] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/13/2021] [Accepted: 02/15/2021] [Indexed: 01/04/2023] Open
Abstract
The Bunyavirales order accommodates related viruses (bunyaviruses) with segmented, linear, single-stranded, negative- or ambi-sense RNA genomes. Their glycoproteins form capsomeric projections or spikes on the virion surface and play a crucial role in virus entry, assembly, morphogenesis. Bunyavirus glycoproteins are encoded by a single RNA segment as a polyprotein precursor that is co- and post-translationally cleaved by host cell enzymes to yield two mature glycoproteins, Gn and Gc (or GP1 and GP2 in arenaviruses). These glycoproteins undergo extensive N-linked glycosylation and despite their cleavage, remain associated to the virion to form an integral transmembrane glycoprotein complex. This review summarizes recent advances in our understanding of the molecular biology of bunyavirus glycoproteins, including their processing, structure, and known interactions with host factors that facilitate cell entry.
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Affiliation(s)
- Ruben J. G. Hulswit
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; (R.J.G.H.); (G.C.P.)
| | - Guido C. Paesen
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; (R.J.G.H.); (G.C.P.)
| | - Thomas A. Bowden
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; (R.J.G.H.); (G.C.P.)
| | - Xiaohong Shi
- MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G61 1QH, UK
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32
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Entry of Phenuiviruses into Mammalian Host Cells. Viruses 2021; 13:v13020299. [PMID: 33672975 PMCID: PMC7918600 DOI: 10.3390/v13020299] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 12/22/2022] Open
Abstract
Phenuiviridae is a large family of arthropod-borne viruses with over 100 species worldwide. Several cause severe diseases in both humans and livestock. Global warming and the apparent geographical expansion of arthropod vectors are good reasons to seriously consider these viruses potential agents of emerging diseases. With an increasing frequency and number of epidemics, some phenuiviruses represent a global threat to public and veterinary health. This review focuses on the early stage of phenuivirus infection in mammalian host cells. We address current knowledge on each step of the cell entry process, from virus binding to penetration into the cytosol. Virus receptors, endocytosis, and fusion mechanisms are discussed in light of the most recent progress on the entry of banda-, phlebo-, and uukuviruses, which together constitute the three prominent genera in the Phenuiviridae family.
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Zhu L, Yan C, Duan G. Prediction of Virus-Receptor Interactions Based on Improving Similarities. J Comput Biol 2021; 28:650-659. [PMID: 33481654 DOI: 10.1089/cmb.2020.0544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Viral infectious diseases have been seriously threatening human health. The receptor binding is the first step of viral infection. Predicting virus-receptor interactions will be helpful for the interaction mechanism of viruses and receptors, and further find some effective ways of preventing and treating viral infectious diseases so as to reduce the morbidity and mortality caused by viruses. Some computation algorithms have been proposed for identifying potential virus-receptor interactions. However, a common problem in those methods is the presence of noise in the similarity network. A new computational model (Network Enhancement and the Regularized Least Squares [NERLS]) is proposed to predict virus-receptor interactions based on improving similarities by Network Enhancement (NE). NERLS integrates the virus sequence similarity, the receptor sequence similarity and known virus-receptor interactions. We compute the virus sequence similarity and known virus-receptor interactions to construct the virus similarity network. The receptor similarity network is constructed by the Gaussian interaction profile kernel similarity and the receptor sequence similarity. To obtain the final virus similarity network and the final receptor similarity network, NE is, respectively, applied for reducing the noise of the virus similarity network and the receptor similarity network. Finally, NERLS employs the regularized least squares to predict interactions of viruses and receptors. The experiment results show that NERLS achieves the area under curve value of 0.893 and 0.921 in 10-fold cross-validation and leave-one-out cross-validation, respectively, which is consistently superior to four related methods [which include Initial interaction scores method via the neighbors and the Laplacian regularized Least Square (IILLS), Bi-random walk on a heterogeneous network (BRWH), Laplacian regularized least squares classifier (LapRLS), and Collaborative matrix factorization (CMF)]. Furthermore, a case study also demonstrates that NERLS effectively predicts potential virus-receptor interactions.
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Affiliation(s)
- Lingzhi Zhu
- School of Computer Science and Engineering, Central South University, Changsha, China.,School of Computer and Information Science, Hunan Institute of Technology, Hengyang, China
| | - Cheng Yan
- School of Computer Science and Engineering, Central South University, Changsha, China.,School of Computer and Information, Qiannan Normal University for Nationalities, Duyun, China
| | - Guihua Duan
- School of Computer Science and Engineering, Central South University, Changsha, China
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34
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Abdouni Y, Ter Huurne GM, Yilmaz G, Monaco A, Redondo-Gómez C, Meijer EW, Palmans ARA, Becer CR. Self-Assembled Multi- and Single-Chain Glyconanoparticles and Their Lectin Recognition. Biomacromolecules 2020; 22:661-670. [PMID: 33373527 DOI: 10.1021/acs.biomac.0c01486] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In this work, we describe the physicochemical characterization of amphiphilic glycopolymers synthesized via copper(0)-mediated reversible-deactivation radical polymerization (Cu-RDRP). Depending on the chemical composition of the polymer, these glycopolymers are able to form multi-chain or single-chain polymeric nanoparticles. The folding of these polymers is first of all driven by the amphiphilicity of the glycopolymers and furthermore by the supramolecular formation of helical supramolecular stacks of benzene-1,3,5-tricarboxamides (BTAs) stabilized by threefold hydrogen bonding. The obtained polymeric nanoparticles were subsequently evaluated for their lectin-binding affinity toward a series of mannose- and galactose-binding lectins via surface plasmon resonance. We found that addition of 2-ethylhexyl acrylate to the polymer composition results in compact particles, which translates to a reduction in binding affinity, whereas with the addition of BTAs, the relation between the nature of the particle and the binding ability system becomes more unpredictable.
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Affiliation(s)
- Yamin Abdouni
- School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, U.K
| | - Gijs M Ter Huurne
- Institute for Complex Molecular Systems, Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, Eindhoven 5600 MB, The Netherlands
| | - Gokhan Yilmaz
- School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, U.K.,Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K
| | - Alessandra Monaco
- School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, U.K.,Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K
| | - Carlos Redondo-Gómez
- School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, U.K
| | - E W Meijer
- Institute for Complex Molecular Systems, Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, Eindhoven 5600 MB, The Netherlands
| | - Anja R A Palmans
- Institute for Complex Molecular Systems, Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, Eindhoven 5600 MB, The Netherlands
| | - C Remzi Becer
- School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, U.K.,Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K
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35
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Valverde P, Martínez JD, Cañada FJ, Ardá A, Jiménez-Barbero J. Molecular Recognition in C-Type Lectins: The Cases of DC-SIGN, Langerin, MGL, and L-Sectin. Chembiochem 2020; 21:2999-3025. [PMID: 32426893 PMCID: PMC7276794 DOI: 10.1002/cbic.202000238] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 05/19/2020] [Indexed: 12/16/2022]
Abstract
Carbohydrates play a pivotal role in intercellular communication processes. In particular, glycan antigens are key for sustaining homeostasis, helping leukocytes to distinguish damaged tissues and invading pathogens from healthy tissues. From a structural perspective, this cross-talk is fairly complex, and multiple membrane proteins guide these recognition processes, including lectins and Toll-like receptors. Since the beginning of this century, lectins have become potential targets for therapeutics for controlling and/or avoiding the progression of pathologies derived from an incorrect immune outcome, including infectious processes, cancer, or autoimmune diseases. Therefore, a detailed knowledge of these receptors is mandatory for the development of specific treatments. In this review, we summarize the current knowledge about four key C-type lectins whose importance has been steadily growing in recent years, focusing in particular on how glycan recognition takes place at the molecular level, but also looking at recent progresses in the quest for therapeutics.
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Affiliation(s)
- Pablo Valverde
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
| | - J Daniel Martínez
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
| | - F Javier Cañada
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040, Madrid, Spain
- CIBER de Enfermedades Respiratorias (CIBERES), Avda Monforte de Lemos 3-5, 28029, Madrid, Spain
| | - Ana Ardá
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
| | - Jesús Jiménez-Barbero
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
- Ikerbasque, Basque Foundation for Science, 48009, Bilbao, Spain
- Department of Organic Chemistry II, Faculty of Science and Technology, UPV-EHU, 48940, Leioa, Spain
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36
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Abdouni Y, Yilmaz G, Monaco A, Aksakal R, Becer CR. Effect of Arm Number and Length of Star-Shaped Glycopolymers on Binding to Dendritic and Langerhans Cell Lectins. Biomacromolecules 2020; 21:3756-3764. [DOI: 10.1021/acs.biomac.0c00856] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Yamin Abdouni
- School of Engineering and Materials Science, Queen Mary University of London, London, E1 4NS, United Kingdom
| | - Gokhan Yilmaz
- School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, United Kingdom
| | - Alessandra Monaco
- School of Engineering and Materials Science, Queen Mary University of London, London, E1 4NS, United Kingdom
| | - Resat Aksakal
- School of Engineering and Materials Science, Queen Mary University of London, London, E1 4NS, United Kingdom
| | - C. Remzi Becer
- School of Engineering and Materials Science, Queen Mary University of London, London, E1 4NS, United Kingdom
- Department of Chemistry, University of Warwick, Coventry, CV4 7AL, United Kingdom
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37
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Efficient functional screening of a cellular cDNA library to identify severe fever with thrombocytopenia syndrome virus entry factors. Sci Rep 2020; 10:5996. [PMID: 32265454 PMCID: PMC7138800 DOI: 10.1038/s41598-020-62876-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 03/18/2020] [Indexed: 01/15/2023] Open
Abstract
The identification of host cell factors for virus entry is useful for the molecular explanation of viral tropisms and often leads to a more profound understanding of virus-induced diseases. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by SFTS virus. No countermeasures against the disease exist. In this report, we show an efficient method using virus-like particles for the functional screening of a cellular cDNA library to identify SFTS virus entry factors. Two variants encoding dendritic cell-specific ICAM-3 grabbing non-integrin related (DC-SIGNR), a calcium-dependent lectin known to enhance SFTS virus infection, were successfully identified from a human liver cDNA library. We will discuss applications for yet unidentified factor(s) for SFTS virus entry and for entry factor(s) for other viruses related to SFTS virus.
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Woelfl F, Léger P, Oreshkova N, Pahmeier F, Windhaber S, Koch J, Stanifer M, Roman Sosa G, Uckeley ZM, Rey FA, Boulant S, Kortekaas J, Wichgers Schreur PJ, Lozach PY. Novel Toscana Virus Reverse Genetics System Establishes NSs as an Antagonist of Type I Interferon Responses. Viruses 2020; 12:v12040400. [PMID: 32260371 PMCID: PMC7232479 DOI: 10.3390/v12040400] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 03/30/2020] [Accepted: 04/03/2020] [Indexed: 12/13/2022] Open
Abstract
The sand fly-borne Toscana virus (TOSV) is the major cause of human meningoencephalitis in the Mediterranean basin during the summer season. In this work, we have developed a T7 RNA polymerase-driven reverse genetics system to recover infectious particles of a lineage B strain of TOSV. The viral protein pattern and growth properties of the rescued virus (rTOSV) were found to be similar to those of the corresponding wild-type (wt) virus. Using this system, we genetically engineered a TOSV mutant lacking expression of the non-structural protein NSs (rTOSVɸNSs). Unlike rTOSV and the wt virus, rTOSVɸNSs was unable to (i) suppress interferon (IFN)-b messenger RNA induction; and (ii) grow efficiently in cells producing IFN-b. Together, our results highlight the importance of NSs for TOSV in evading the IFN response and provide a comprehensive toolbox to investigate the TOSV life cycle in mammalian and insect host cells, including several novel polyclonal antibodies.
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Affiliation(s)
- Franziska Woelfl
- CellNetworks Cluster of Excellence, University Hospital Heidelberg, 69120 Heidelberg, Germany; (F.W.); (P.L.); (F.P.); (S.W.); (J.K.); (Z.M.U.)
- Center for Integrative Infectious Diseases Research (CIID), Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Psylvia Léger
- CellNetworks Cluster of Excellence, University Hospital Heidelberg, 69120 Heidelberg, Germany; (F.W.); (P.L.); (F.P.); (S.W.); (J.K.); (Z.M.U.)
- Center for Integrative Infectious Diseases Research (CIID), Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Nadia Oreshkova
- Wageningen Bioveterinary Research, Department of Virology, 8221 RA Lelystad, The Netherlands; (N.O.); (J.K.)
| | - Felix Pahmeier
- CellNetworks Cluster of Excellence, University Hospital Heidelberg, 69120 Heidelberg, Germany; (F.W.); (P.L.); (F.P.); (S.W.); (J.K.); (Z.M.U.)
- Center for Integrative Infectious Diseases Research (CIID), Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Stefan Windhaber
- CellNetworks Cluster of Excellence, University Hospital Heidelberg, 69120 Heidelberg, Germany; (F.W.); (P.L.); (F.P.); (S.W.); (J.K.); (Z.M.U.)
- Center for Integrative Infectious Diseases Research (CIID), Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Jana Koch
- CellNetworks Cluster of Excellence, University Hospital Heidelberg, 69120 Heidelberg, Germany; (F.W.); (P.L.); (F.P.); (S.W.); (J.K.); (Z.M.U.)
- Center for Integrative Infectious Diseases Research (CIID), Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Megan Stanifer
- Center for Integrative Infectious Diseases Research (CIID), Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Gleyder Roman Sosa
- Structural Virology Unit, Pasteur Institute, 75015 Paris, France; (G.R.S.); (F.A.R.)
| | - Zina M. Uckeley
- CellNetworks Cluster of Excellence, University Hospital Heidelberg, 69120 Heidelberg, Germany; (F.W.); (P.L.); (F.P.); (S.W.); (J.K.); (Z.M.U.)
- Center for Integrative Infectious Diseases Research (CIID), Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Felix A. Rey
- Structural Virology Unit, Pasteur Institute, 75015 Paris, France; (G.R.S.); (F.A.R.)
| | - Steeve Boulant
- Center for Integrative Infectious Diseases Research (CIID), Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Jeroen Kortekaas
- Wageningen Bioveterinary Research, Department of Virology, 8221 RA Lelystad, The Netherlands; (N.O.); (J.K.)
- Laboratory of Virology, Wageningen University, 6708 PB Wageningen, The Netherlands
| | - Paul J. Wichgers Schreur
- Wageningen Bioveterinary Research, Department of Virology, 8221 RA Lelystad, The Netherlands; (N.O.); (J.K.)
- Correspondence: (P.J.W.S.); (P.-Y.L.)
| | - Pierre-Yves Lozach
- CellNetworks Cluster of Excellence, University Hospital Heidelberg, 69120 Heidelberg, Germany; (F.W.); (P.L.); (F.P.); (S.W.); (J.K.); (Z.M.U.)
- Center for Integrative Infectious Diseases Research (CIID), Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
- INRAE, EPHE, Viral Infections and Comparative Pathology (IVPC), University Claude Bernard Lyon1, University of Lyon, UMR754, 69007 Lyon, France
- Correspondence: (P.J.W.S.); (P.-Y.L.)
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39
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Identification of Virus-Receptor Interactions Based on Network Enhancement and Similarity. BIOINFORMATICS RESEARCH AND APPLICATIONS 2020. [DOI: 10.1007/978-3-030-57821-3_33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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40
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Yan C, Duan G, Wu FX, Wang J. IILLS: predicting virus-receptor interactions based on similarity and semi-supervised learning. BMC Bioinformatics 2019; 20:651. [PMID: 31881820 PMCID: PMC6933616 DOI: 10.1186/s12859-019-3278-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background Viral infectious diseases are the serious threat for human health. The receptor-binding is the first step for the viral infection of hosts. To more effectively treat human viral infectious diseases, the hidden virus-receptor interactions must be discovered. However, current computational methods for predicting virus-receptor interactions are limited. Result In this study, we propose a new computational method (IILLS) to predict virus-receptor interactions based on Initial Interaction scores method via the neighbors and the Laplacian regularized Least Square algorithm. IILLS integrates the known virus-receptor interactions and amino acid sequences of receptors. The similarity of viruses is calculated by the Gaussian Interaction Profile (GIP) kernel. On the other hand, we also compute the receptor GIP similarity and the receptor sequence similarity. Then the sequence similarity is used as the final similarity of receptors according to the prediction results. The 10-fold cross validation (10CV) and leave one out cross validation (LOOCV) are used to assess the prediction performance of our method. We also compare our method with other three competing methods (BRWH, LapRLS, CMF). Conlusion The experiment results show that IILLS achieves the AUC values of 0.8675 and 0.9061 with the 10-fold cross validation and leave-one-out cross validation (LOOCV), respectively, which illustrates that IILLS is superior to the competing methods. In addition, the case studies also further indicate that the IILLS method is effective for the virus-receptor interaction prediction.
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Affiliation(s)
- Cheng Yan
- School of Computer Science and Engineering, Central South University, 932 South Lushan Rd, ChangSha, 410083, China.,School of Computer and Information,Qiannan Normal University for Nationalities, Longshan Road, DuYun, 558000, China
| | - Guihua Duan
- School of Computer Science and Engineering, Central South University, 932 South Lushan Rd, ChangSha, 410083, China.
| | - Fang-Xiang Wu
- Biomedical Engineering and Department of Mechanical Engineering, University of Saskatchewan, Saskatoon, SKS7N5A9, Canada
| | - Jianxin Wang
- School of Computer Science and Engineering, Central South University, 932 South Lushan Rd, ChangSha, 410083, China
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41
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Uckeley ZM, Moeller R, Kühn LI, Nilsson E, Robens C, Lasswitz L, Lindqvist R, Lenman A, Passos V, Voss Y, Sommerauer C, Kampmann M, Goffinet C, Meissner F, Överby AK, Lozach PY, Gerold G. Quantitative Proteomics of Uukuniemi Virus-host Cell Interactions Reveals GBF1 as Proviral Host Factor for Phleboviruses. Mol Cell Proteomics 2019; 18:2401-2417. [PMID: 31570497 PMCID: PMC6885706 DOI: 10.1074/mcp.ra119.001631] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 09/15/2019] [Indexed: 12/20/2022] Open
Abstract
Novel tick-borne phleboviruses in the Phenuiviridae family, which are highly pathogenic in humans and all closely related to Uukuniemi virus (UUKV), have recently emerged on different continents. How phleboviruses assemble, bud, and exit cells remains largely elusive. Here, we performed high-resolution, label-free mass spectrometry analysis of UUKV immunoprecipitated from cell lysates and identified 39 cellular partners interacting with the viral envelope glycoproteins. The importance of these host factors for UUKV infection was validated by silencing each host factor by RNA interference. This revealed Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1), a guanine nucleotide exchange factor resident in the Golgi, as a critical host factor required for the UUKV life cycle. An inhibitor of GBF1, Golgicide A, confirmed the role of the cellular factor in UUKV infection. We could pinpoint the GBF1 requirement to UUKV replication and particle assembly. When the investigation was extended to viruses from various positive and negative RNA viral families, we found that not only phleboviruses rely on GBF1 for infection, but also Flavi-, Corona-, Rhabdo-, and Togaviridae In contrast, silencing or blocking GBF1 did not abrogate infection by the human adenovirus serotype 5 and immunodeficiency retrovirus type 1, the replication of both requires nuclear steps. Together our results indicate that UUKV relies on GBF1 for viral replication, assembly and egress. This study also highlights the proviral activity of GBF1 in the infection by a broad range of important zoonotic RNA viruses.
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Affiliation(s)
- Zina M Uckeley
- CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany; CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Rebecca Moeller
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Lars I Kühn
- Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Emma Nilsson
- Division of Virology, Department of Clinical Microbiology, and Laboratory for Molecular Infection Medicine Sweden, Umeå University, Umeå, Sweden
| | - Claudia Robens
- CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Lisa Lasswitz
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Richard Lindqvist
- Division of Virology, Department of Clinical Microbiology, and Laboratory for Molecular Infection Medicine Sweden, Umeå University, Umeå, Sweden
| | - Annasara Lenman
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Vania Passos
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Instituto De Ciências Biomédicas Abel Salazar, Universidade Do Porto, Porto, Portugal
| | - Yannik Voss
- CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Sommerauer
- CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin Kampmann
- CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christine Goffinet
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Institute of Virology, Charité, Universitätsmedizin Berlin, Berlin, Germany and Berlin Institute of Health (BIH), Berlin, Germany
| | - Felix Meissner
- Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Anna K Överby
- Division of Virology, Department of Clinical Microbiology, and Laboratory for Molecular Infection Medicine Sweden, Umeå University, Umeå, Sweden
| | - Pierre-Yves Lozach
- CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany; IVPC UMR754, INRA, Univ. Lyon, EPHE, 50 Av. Tony Garnier, 69007 Lyon, France.
| | - Gisa Gerold
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Clinical Microbiology, Virology & Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, SE-90185 Umeå, Sweden.
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42
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Watanabe Y, Bowden TA, Wilson IA, Crispin M. Exploitation of glycosylation in enveloped virus pathobiology. Biochim Biophys Acta Gen Subj 2019; 1863:1480-1497. [PMID: 31121217 PMCID: PMC6686077 DOI: 10.1016/j.bbagen.2019.05.012] [Citation(s) in RCA: 346] [Impact Index Per Article: 57.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 05/13/2019] [Accepted: 05/17/2019] [Indexed: 12/12/2022]
Abstract
Glycosylation is a ubiquitous post-translational modification responsible for a multitude of crucial biological roles. As obligate parasites, viruses exploit host-cell machinery to glycosylate their own proteins during replication. Viral envelope proteins from a variety of human pathogens including HIV-1, influenza virus, Lassa virus, SARS, Zika virus, dengue virus, and Ebola virus have evolved to be extensively glycosylated. These host-cell derived glycans facilitate diverse structural and functional roles during the viral life-cycle, ranging from immune evasion by glycan shielding to enhancement of immune cell infection. In this review, we highlight the imperative and auxiliary roles glycans play, and how specific oligosaccharide structures facilitate these functions during viral pathogenesis. We discuss the growing efforts to exploit viral glycobiology in the development of anti-viral vaccines and therapies.
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Affiliation(s)
- Yasunori Watanabe
- School of Biological Sciences and Institute of Life Sciences, University of Southampton, Southampton SO17 1BJ, UK; Division of Structural Biology, University of Oxford, Wellcome Centre for Human Genetics, Oxford OX3 7BN, UK; Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
| | - Thomas A Bowden
- Division of Structural Biology, University of Oxford, Wellcome Centre for Human Genetics, Oxford OX3 7BN, UK
| | - Ian A Wilson
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Max Crispin
- School of Biological Sciences and Institute of Life Sciences, University of Southampton, Southampton SO17 1BJ, UK.
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Abstract
Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that was first discovered in Kenya in 1930 and is now endemic throughout multiple African countries and the Arabian Peninsula. RVF virus primarily infects domestic livestock (sheep, goats, cattle) causing high rates of neonatal mortality and abortion, with human infection resulting in a wide variety of clinical outcomes, ranging from self-limiting febrile illness to life-threatening haemorrhagic diatheses, and miscarriage in pregnant women. Since its discovery, RVF has caused many outbreaks in Africa and the Arabian Peninsula with major impacts on human and animal health. However, options for the control of RVF outbreaks are limited by the lack of licensed human vaccines or therapeutics. For this reason, RVF is prioritized by the World Health Organization for urgent research and development of countermeasures for the prevention and control of future outbreaks. In this review, we highlight the current understanding of RVF, including its epidemiology, pathogenesis, clinical manifestations and status of vaccine development.
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Affiliation(s)
- Daniel Wright
- KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
- The Jenner Institute, University of Oxford, Oxford OX1 2JD, UK
| | - Jeroen Kortekaas
- Wageningen Bioveterinary Research, Lelystad, The Netherlands
- Laboratory of Virology, Wageningen University, Wageningen, The Netherlands
| | - Thomas A. Bowden
- Wellcome Centre for Human Genetics, Division of Structural Biology, University of Oxford, Oxford OX1 2JD, UK
| | - George M. Warimwe
- KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
- Centre for Tropical Medicine and Global Health, University of Oxford, Oxford OX1 2JD, UK
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Jagdale SS, Ghosh A. In silico analyses of molecular interactions between groundnut bud necrosis virus and its vector, Thrips palmi. Virusdisease 2019; 30:245-251. [PMID: 31179363 DOI: 10.1007/s13337-019-00521-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 03/13/2019] [Indexed: 12/17/2022] Open
Abstract
Groundnut bud necrosis virus (GBNV) is an economically important tospovirus transmitted by Thrips palmi (Thysanoptera: Thripidae). The current understanding of thrips-tospovirus interactions is largely based on the tomato spotted wilt virus-Frankliniella occidentalis relationship. Only limited information is available for the GBNV-T. palmi system. In the present study, available genome data of T. palmi and GBNV were used to predict the protein partners that may play a crucial role in the internalization of GBNV virions into thrips cells. Computational analyses showed that the GBNV precursor glycoprotein bears a signal peptide of 24 amino acids and a secondary cleavage site at position 434-435 separates the amino-terminal mature glycoprotein (GN) from the carboxyl-terminal glycoprotein (GC). Potential interactions of GBNV glycoproteins were predicted with T. palmi enolase, cathepsin, C-type lectin, clathrin and vacuolar ATP synthase subunit E. The in silico analyses suggested that C-type lectin is the primary cellular receptor to interact with GBNV-GN. After receptor binding, virus particles probably enter vector cells by clathrin-mediated endocytosis. This is the first in silico evidence of GBNV-T. palmi protein interaction.
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Affiliation(s)
- Shounak S Jagdale
- 1Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 India
| | - Amalendu Ghosh
- 2Insect Vector Laboratory, Advanced Centre for Plant Virology, ICAR-Indian Agricultural Research Institute, New Delhi, 110012 India
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Hoffmann AB, Mazelier M, Léger P, Lozach PY. Deciphering Virus Entry with Fluorescently Labeled Viral Particles. Methods Mol Biol 2019; 1836:159-183. [PMID: 30151573 DOI: 10.1007/978-1-4939-8678-1_8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
To infect host cells, viruses have to gain access to the intracellular compartment. The infection process starts with the attachment of viruses to the cell surface. Then a complex series of events, highly dynamic, tightly intricate, and often hard to investigate, follows. This includes virus displacement at the plasma membrane, binding to receptors, signaling, internalization, and release of the viral genome and material into the cytosol. In the past decades, the emergence of sensitive, accurate fluorescence-based technologies has opened new perspectives of investigations in the field. Visualization of single viral particles in fixed and living cells as well as quantification of each virus entry step has been made possible. Here we describe the procedure to fluorescently label viral particles. We also illustrate how to use this powerful tool to decipher the entry of viruses with the most recent fluorescence-based techniques such as high-speed confocal and total internal reflection microscopy, flow cytometry, and fluorimetry.
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Affiliation(s)
- Anja B Hoffmann
- From CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Magalie Mazelier
- From CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Psylvia Léger
- From CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Pierre-Yves Lozach
- From CellNetworks Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
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46
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Monteiro JT, Schön K, Ebbecke T, Goethe R, Ruland J, Baumgärtner W, Becker SC, Lepenies B. The CARD9-Associated C-Type Lectin, Mincle, Recognizes La Crosse Virus (LACV) but Plays a Limited Role in Early Antiviral Responses against LACV. Viruses 2019; 11:v11030303. [PMID: 30917612 PMCID: PMC6466035 DOI: 10.3390/v11030303] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 03/22/2019] [Accepted: 03/25/2019] [Indexed: 12/12/2022] Open
Abstract
La Crosse virus (LACV) is a mosquito-transmitted arbovirus and the main cause of virus-mediated neurological diseases in children. To date, little is known about the role of C-type lectin receptors (CLRs)—an important class of pattern recognition receptors—in LACV recognition. DC-SIGN remains the only well-described CLR that recognizes LACV. In this study, we investigated the role of additional CLR/LACV interactions. To this end, we applied a flow-through chromatography method for the purification of LACV to perform an unbiased high-throughput screening of LACV with a CLR-hFc fusion protein library. Interestingly, the CARD9-associated CLRs Mincle, Dectin-1, and Dectin-2 were identified to strongly interact with LACV. Since CARD9 is a common adaptor protein for signaling via Mincle, Dectin-1, and Dectin-2, we performed LACV infection of Mincle−/− and CARD9−/− DCs. Mincle−/− and CARD9−/− DCs produced less amounts of proinflammatory cytokines, namely IL-6 and TNF-α, albeit no reduction of the LACV titer was observed. Together, novel CLR/LACV interactions were identified; however, the Mincle/CARD9 axis plays a limited role in early antiviral responses against LACV.
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Affiliation(s)
- João T Monteiro
- Immunology Unit & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
| | - Kathleen Schön
- Immunology Unit & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
- Institute for Parasitology and & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
| | - Tim Ebbecke
- Immunology Unit & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
| | - Ralph Goethe
- Institute for Microbiology, University of Veterinary Medicine Hannover, 30173 Hannover, Germany.
| | - Jürgen Ruland
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, 81675 Munich, Germany.
| | - Wolfgang Baumgärtner
- Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
| | - Stefanie C Becker
- Institute for Parasitology and & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
| | - Bernd Lepenies
- Immunology Unit & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
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Ter Horst S, Conceição-Neto N, Neyts J, Rocha-Pereira J. Structural and functional similarities in bunyaviruses: Perspectives for pan-bunya antivirals. Rev Med Virol 2019; 29:e2039. [PMID: 30746831 PMCID: PMC7169261 DOI: 10.1002/rmv.2039] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 11/29/2018] [Accepted: 01/17/2019] [Indexed: 01/03/2023]
Abstract
The order of Bunyavirales includes numerous (re)emerging viruses that collectively have a major impact on human and animal health worldwide. There are no vaccines for human use or antiviral drugs available to prevent or treat infections with any of these viruses. The development of efficacious and safe drugs and vaccines is a pressing matter. Ideally, such antivirals possess pan‐bunyavirus antiviral activity, allowing the containment of every bunya‐related threat. The fact that many bunyaviruses need to be handled in laboratories with biosafety level 3 or 4, the great variety of species and the frequent emergence of novel species complicate such efforts. We here examined the potential druggable targets of bunyaviruses, together with the level of conservation of their biological functions, structure, and genetic similarity by means of heatmap analysis. In the light of this, we revised the available models and tools currently available, pointing out directions for antiviral drug discovery.
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Affiliation(s)
- Sebastiaan Ter Horst
- Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium
| | - Nádia Conceição-Neto
- Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Clinical and Epidemiological Virology, KU Leuven, Leuven, Belgium
| | - Johan Neyts
- Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium
| | - Joana Rocha-Pereira
- Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium
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Loureiro ME, D'Antuono A, López N. Virus⁻Host Interactions Involved in Lassa Virus Entry and Genome Replication. Pathogens 2019; 8:pathogens8010017. [PMID: 30699976 PMCID: PMC6470645 DOI: 10.3390/pathogens8010017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 01/25/2019] [Accepted: 01/26/2019] [Indexed: 01/08/2023] Open
Abstract
Lassa virus (LASV) is the causative agent of Lassa fever, a human hemorrhagic disease associated with high mortality and morbidity rates, particularly prevalent in West Africa. Over the past few years, a significant amount of novel information has been provided on cellular factors that are determinant elements playing a role in arenavirus multiplication. In this review, we focus on host proteins that intersect with the initial steps of the LASV replication cycle: virus entry and genome replication. A better understanding of relevant virus⁻host interactions essential for sustaining these critical steps may help to identify possible targets for the rational design of novel therapeutic approaches against LASV and other arenaviruses that cause severe human disease.
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Affiliation(s)
- María Eugenia Loureiro
- Centro de Virología Animal (CEVAN), CONICET-SENASA, Av Sir Alexander Fleming 1653, Martínez, Provincia de Buenos Aires B1640CSI, Argentina.
| | - Alejandra D'Antuono
- Centro de Virología Animal (CEVAN), CONICET-SENASA, Av Sir Alexander Fleming 1653, Martínez, Provincia de Buenos Aires B1640CSI, Argentina.
| | - Nora López
- Centro de Virología Animal (CEVAN), CONICET-SENASA, Av Sir Alexander Fleming 1653, Martínez, Provincia de Buenos Aires B1640CSI, Argentina.
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Structures of phlebovirus glycoprotein Gn and identification of a neutralizing antibody epitope. Proc Natl Acad Sci U S A 2017; 114:E7564-E7573. [PMID: 28827346 DOI: 10.1073/pnas.1705176114] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) and Rift Valley fever virus (RVFV) are two arthropod-borne phleboviruses in the Bunyaviridae family, which cause severe illness in humans and animals. Glycoprotein N (Gn) is one of the envelope proteins on the virus surface and is a major antigenic component. Despite its importance for virus entry and fusion, the molecular features of the phleboviruse Gn were unknown. Here, we present the crystal structures of the Gn head domain from both SFTSV and RVFV, which display a similar compact triangular shape overall, while the three subdomains (domains I, II, and III) making up the Gn head display different arrangements. Ten cysteines in the Gn stem region are conserved among phleboviruses, four of which are responsible for Gn dimerization, as revealed in this study, and they are highly conserved for all members in Bunyaviridae Therefore, we propose an anchoring mode on the viral surface. The complex structure of the SFTSV Gn head and human neutralizing antibody MAb 4-5 reveals that helices α6 in subdomain III is the key component for neutralization. Importantly, the structure indicates that domain III is an ideal region recognized by specific neutralizing antibodies, while domain II is probably recognized by broadly neutralizing antibodies. Collectively, Gn is a desirable vaccine target, and our data provide a molecular basis for the rational design of vaccines against the diseases caused by phleboviruses and a model for bunyavirus Gn embedding on the viral surface.
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Abstract
The Bunyavirales Order encompasses nine families of enveloped viruses containing a single-stranded negative-sense RNA genome divided into three segments. The small (S) and large (L) segments encode proteins participating in genome replication in the infected cell cytoplasm. The middle (M) segment encodes the viral glycoproteins Gn and Gc, which are derived from a precursor polyprotein by host cell proteases. Entry studies are available only for a few viruses in the Order, and in each case they were shown to enter cells via receptor-mediated endocytosis. The acidic endosomal pH triggers the fusion of the viral envelope with the membrane of an endosome. Structural studies on two members of this Order, the phleboviruses and the hantaviruses, have shown that the membrane fusion protein Gc displays a class II fusion protein fold and is homologous to its counterparts in flaviviruses and alphaviruses, which are positive-sense, single-stranded RNA viruses. We analyze here recent data on the structure and function of the structure of the phlebovirus Gc and hantavirus Gn and Gc glycoproteins, and extrapolate common features identified in the amino acid sequences to understand also the structure and function of their counterparts in other families of the Bunyavirales Order. Our analysis also identified clear structural homology between the hantavirus Gn and alphavirus E2 glycoproteins, which make a heterodimer with the corresponding fusion proteins Gc and E1, respectively, revealing that not only the fusion protein has been conserved across viral families.
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Affiliation(s)
- Pablo Guardado-Calvo
- Institut Pasteur, Unité de Virologie Structurale, Paris Cedex 15, France; CNRS UMR 3569 Virologie, Paris Cedex 15, France
| | - Félix A Rey
- Institut Pasteur, Unité de Virologie Structurale, Paris Cedex 15, France; CNRS UMR 3569 Virologie, Paris Cedex 15, France.
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