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4. Periphilin self-association underpins epigenetic silencing by the HUSH complex

Author

Prigozhin, Daniil M, Douse, Christopher H, Farleigh, Laura E, Albecka, Anna, Tchasovnikarova, Iva A, Timms, Richard T, Oda, Shun-ichiro, Adolf, Frank, Freund, Stefan MV, Maslen, Sarah, Lehner, Paul J, and Modis, Yorgo

Subjects
Genetics, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Antigens, Neoplasm, Crystallography, X-Ray, DNA Transposable Elements, Epigenesis, Genetic, Gene Silencing, Humans, Nuclear Proteins, Phosphoproteins, Protein Aggregates, Protein Binding, Protein Conformation, alpha-Helical, Protein Domains, RNA-Binding Proteins, Transcription, Genetic, Viruses, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Developmental Biology
Abstract

Transcription of integrated DNA from viruses or transposable elements is tightly regulated to prevent pathogenesis. The Human Silencing Hub (HUSH), composed of Periphilin, TASOR and MPP8, silences transcriptionally active viral and endogenous transgenes. HUSH recruits effectors that alter the epigenetic landscape and chromatin structure, but how HUSH recognizes target loci and represses their expression remains unclear. We identify the physicochemical properties of Periphilin necessary for HUSH assembly and silencing. A disordered N-terminal domain (NTD) and structured C-terminal domain are essential for silencing. A crystal structure of the Periphilin-TASOR minimal core complex shows Periphilin forms an α-helical homodimer, bound by a single TASOR molecule. The NTD forms insoluble aggregates through an arginine/tyrosine-rich sequence reminiscent of low-complexity regions from self-associating RNA-binding proteins. Residues required for TASOR binding and aggregation were required for HUSH-dependent silencing and genome-wide deposition of repressive mark H3K9me3. The NTD was functionally complemented by low-complexity regions from certain RNA-binding proteins and proteins that form condensates or fibrils. Our work suggests the associative properties of Periphilin promote HUSH aggregation at target loci.

Published
2020

5. TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control.

Author

Douse, Christopher H, Tchasovnikarova, Iva A, Timms, Richard T, Protasio, Anna V, Seczynska, Marta, Prigozhin, Daniil M, Albecka, Anna, Wagstaff, Jane, Williamson, James C, Freund, Stefan MV, Lehner, Paul J, and Modis, Yorgo

Subjects
Hela Cells, Humans, Multiprotein Complexes, NAD, Poly(ADP-ribose) Polymerases, Lysine, Nuclear Proteins, Histones, Phosphoproteins, DNA Transposable Elements, RNA, Antigens, Neoplasm, Magnetic Resonance Spectroscopy, Transcription, Genetic, Epigenesis, Genetic, RNA Processing, Post-Transcriptional, Binding Sites, Amino Acid Sequence, Protein Binding, Methylation, Genome, Exons, HEK293 Cells, Protein Domains, HeLa Cells, Antigens, Neoplasm, Transcription, Genetic, Epigenesis, RNA Processing, Post-Transcriptional
Abstract

The HUSH complex represses retroviruses, transposons and genes to maintain the integrity of vertebrate genomes. HUSH regulates deposition of the epigenetic mark H3K9me3, but how its three core subunits - TASOR, MPP8 and Periphilin - contribute to assembly and targeting of the complex remains unknown. Here, we define the biochemical basis of HUSH assembly and find that its modular architecture resembles the yeast RNA-induced transcriptional silencing complex. TASOR, the central HUSH subunit, associates with RNA processing components. TASOR is required for H3K9me3 deposition over LINE-1 repeats and repetitive exons in transcribed genes. In the context of previous studies, this suggests that an RNA intermediate is important for HUSH activity. We dissect the TASOR and MPP8 domains necessary for transgene repression. Structure-function analyses reveal TASOR bears a catalytically-inactive PARP domain necessary for targeted H3K9me3 deposition. We conclude that TASOR is a multifunctional pseudo-PARP that directs HUSH assembly and epigenetic regulation of repetitive genomic targets.

Published
2020

6. TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control

Author

Douse, Christopher, Tchasovnikarova, Iva, Timms, Richard, Protasio, Anna, Seczynska, Marta, Prigozhin, Daniil, Albecka, Anna, Wagstaff, Jane, Williamson, James, Freund, Stefan MV, Lehner, Paul, and Modis, Yorgo

Abstract

Summary The Human Silencing Hub (HUSH) complex epigenetically represses retroviruses, transposons and genes in vertebrates. HUSH therefore maintains genome integrity and is central in the interplay between intrinsic immunity, transposable elements and transcriptional regulation. Comprising three subunits – TASOR, MPP8 and Periphilin – HUSH regulates SETDB1-dependent deposition of the transcriptionally repressive epigenetic mark H3K9me3 and recruits MORC2 to modify local chromatin structure. However the mechanistic roles of each HUSH subunit remain undetermined. Here we show that TASOR lies at the heart of HUSH, providing a platform for assembling the other subunits. Targeted epigenomic profiling supports the model that TASOR binds and regulates H3K9me3 specifically over LINE-1 repeats and other repetitive exons in transcribed genes. We find TASOR associates with several components of the nuclear RNA processing machinery and its modular domain architecture bears striking similarities to that of Chp1, the central component of the yeast RNA-induced transcriptional silencing (RITS) complex. Together these observations suggest that an RNA intermediate may be important for HUSH activity. We identify the TASOR domains necessary for HUSH assembly and transgene repression. Structural and genomic analyses reveal that TASOR contains a poly-ADP ribose polymerase (PARP) domain dispensable for assembly and chromatin localization, but critical for epigenetic regulation of target elements. This domain contains a degenerated and obstructed active site and has hence lost catalytic activity. Together our data demonstrate that TASOR is a pseudo-PARP critical for HUSH complex assembly and H3K9me3 deposition over its genomic targets.

Published
2020

7. Periphilin self-association underpins epigenetic silencing by the HUSH complex

Author

Prigozhin, Daniil, Albecka, Anna, Douse, Christopher, Tchasovnikarova, Iva, Timms, Richard, Farleigh, Laura, Oda, Shun, Freund, Stefan, Maslen, Sarah, Lehner, Paul, and Modis, Yorgo

Abstract

Transcription of integrated DNA from viruses or transposable elements is tightly regulated to prevent pathogenesis. The Human Silencing Hub (HUSH), composed of Periphilin, TASOR and MPP8, silences transcriptionally active viral and endogenous transgenes. HUSH recruits effectors that alter the epigenetic landscape and chromatin structure, but how HUSH recognizes target loci and represses their expression remains unclear. We identify the physicochemical properties of Periphilin necessary for HUSH assembly and silencing. A disordered N-terminal domain (NTD) and structured C-terminal domain are essential for silencing. A crystal structure of the Periphilin-TASOR core complex shows Periphilin forms α -helical homodimers, which each bind a single TASOR molecule. The NTD binds RNA non-specifically and forms insoluble aggregates through an arginine/tyrosine-rich sequence reminiscent of low-complexity regions from self-associating RNA-binding proteins. Residues required for TASOR binding and aggregation were required for HUSH-dependent silencing and genome-wide deposition of repressive mark H3K9me3. The NTD was functionally complemented by low-complexity regions from certain RNA-binding proteins and proteins that form condensates or fibrils. Our work suggests the associative properties of Periphilin promote HUSH aggregation on nascent transcripts.

Published
2019

9. Periphilin self-association underpins epigenetic silencing by the HUSH complex

Author

Prigozhin, Daniil M, Albecka, Anna, Douse, Christopher H, Tchasovnikarova, Iva A, Timms, Richard T, Farleigh, Laura E, Oda, Shun, Freund, Stefan MV, Maslen, Sarah, Lehner, Paul J, and Modis, Yorgo

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance
Abstract

Transcription of integrated DNA from viruses or transposable elements is tightly regulated to prevent pathogenesis. The Human Silencing Hub (HUSH), composed of Periphilin, TASOR and MPP8, silences transcriptionally active viral and endogenous transgenes. HUSH recruits effectors that alter the epigenetic landscape and chromatin structure, but how HUSH recognizes target loci and represses their expression remains unclear. We identify the physicochemical properties of Periphilin necessary for HUSH assembly and silencing. A disordered N-terminal domain (NTD) and structured C-terminal domain are essential for silencing. A crystal structure of the Periphilin-TASOR core complex shows Periphilin forms α -helical homodimers, which each bind a single TASOR molecule. The NTD binds RNA non-specifically and forms insoluble aggregates through an arginine/tyrosine-rich sequence reminiscent of low-complexity regions from self-associating RNA-binding proteins. Residues required for TASOR binding and aggregation were required for HUSH-dependent silencing and genome-wide deposition of repressive mark H3K9me3. The NTD was functionally complemented by low-complexity regions from certain RNA-binding proteins and proteins that form condensates or fibrils. Our work suggests the associative properties of Periphilin promote HUSH aggregation on nascent transcripts.

Published
2019

11. A pan-SARS-CoV-2 specific soluble ACE2-albumin fusion engineered for enhanced plasma half-life and needle-free mucosal delivery

Author

Benjakul, Sopisa, primary, Anthi, Aina Karen, additional, Kolderup, Anette, additional, Vaysburd, Marina, additional, Lode, Heidrun Elisabeth, additional, Mallery, Donna, additional, Fossum, Even, additional, Vikse, Elisabeth Lea, additional, Albecka, Anna, additional, Ianevski, Aleksandr, additional, Kainov, Denis, additional, Karlsen, Karine Flem, additional, Sakya, Siri Aastedatter, additional, Nyquist-Andersen, Mari, additional, Gjølberg, Torleif Tollefsrud, additional, Moe, Morten C, additional, Bjørås, Magnar, additional, Sandlie, Inger, additional, James, Leo C, additional, and Andersen, Jan Terje, additional

Published
2023
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12. Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2

Author

Gaynor, Katherine U., primary, Vaysburd, Marina, additional, Harman, Maximilian A. J., additional, Albecka, Anna, additional, Jeffrey, Phillip, additional, Beswick, Paul, additional, Papa, Guido, additional, Chen, Liuhong, additional, Mallery, Donna, additional, McGuinness, Brian, additional, Van Rietschoten, Katerine, additional, Stanway, Steven, additional, Brear, Paul, additional, Lulla, Aleksei, additional, Ciazynska, Katarzyna, additional, Chang, Veronica T., additional, Sharp, Jo, additional, Neary, Megan, additional, Box, Helen, additional, Herriott, Jo, additional, Kijak, Edyta, additional, Tatham, Lee, additional, Bentley, Eleanor G., additional, Sharma, Parul, additional, Kirby, Adam, additional, Han, Ximeng, additional, Stewart, James P., additional, Owen, Andrew, additional, Briggs, John A. G., additional, Hyvönen, Marko, additional, Skynner, Michael J., additional, and James, Leo C., additional

Published
2023
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13. Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2

Author

Gaynor, Katherine U, Vaysburd, Marina, Harman, Maximilian AJ, Albecka, Anna, Jeffrey, Phillip, Beswick, Paul, Papa, Guido, Chen, Liuhong, Mallery, Donna, McGuinness, Brian, Van Rietschoten, Katerine, Stanway, Steven, Brear, Paul, Lulla, Aleksei, Ciazynska, Katarzyna, Chang, Veronica T, Sharp, Jo, Neary, Megan, Box, Helen, Herriott, Jo, Kijak, Edyta, Tatham, Lee, Bentley, Eleanor G, Sharma, Parul, Kirby, Adam, Han, Ximeng, Stewart, James P, Owen, Andrew, Briggs, John AG, Hyvönen, Marko, Skynner, Michael J, James, Leo C, Gaynor, Katherine U [0000-0003-0461-810X], Harman, Maximilian AJ [0000-0002-3667-5929], Papa, Guido [0000-0002-5215-0014], Chen, Liuhong [0000-0003-1776-3146], Mallery, Donna [0000-0003-2713-5215], Brear, Paul [0000-0002-4045-0474], Ciazynska, Katarzyna [0000-0002-9899-2428], Chang, Veronica T [0000-0001-7047-9019], Sharp, Jo [0000-0001-8482-5736], Stewart, James P [0000-0002-8928-2037], Owen, Andrew [0000-0002-9819-7651], Briggs, John AG [0000-0003-3990-6910], Hyvönen, Marko [0000-0001-8683-4070], Skynner, Michael J [0000-0001-6586-9055], James, Leo C [0000-0003-2131-0334], and Apollo - University of Cambridge Repository

Subjects
Male, Mice, Mesocricetus, SARS-CoV-2, Cricetinae, Spike Glycoprotein, Coronavirus, Animals, COVID-19, Mice, Transgenic, Peptides, Antiviral Agents, Antibodies
Abstract

COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles' inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.

Published
2023

16. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Author

Mlcochova, Petra, Kemp, Steven A., Dhar, Mahesh Shanker, Papa, Guido, Meng, Bo, Ferreira, Isabella A. T. M., Datir, Rawlings, Collier, Dami A., Albecka, Anna, Singh, Sujeet, Pandey, Rajesh, Brown, Jonathan, Zhou, Jie, Goonawardane, Niluka, Mishra, Swapnil, Whittaker, Charles, Mellan, Thomas, Marwal, Robin, Datta, Meena, Sengupta, Shantanu, Ponnusamy, Kalaiarasan, Radhakrishnan, Venkatraman Srinivasan, Abdullahi, Adam, Charles, Oscar, Chattopadhyay, Partha, Devi, Priti, Caputo, Daniela, Peacock, Tom, Wattal, Chand, Goel, Neeraj, Satwik, Ambrish, Vaishya, Raju, Agarwal, Meenakshi, Chauhan, Himanshu, Dikid, Tanzin, Gogia, Hema, Lall, Hemlata, Verma, Kaptan, Singh, Manoj K., Soni, Namita, Meena, Namonarayan, Madan, Preeti, Singh, Priyanka, Sharma, Ramesh, Sharma, Rajeev, Kabra, Sandhya, Kumar, Sattender, Kumari, Swati, Sharma, Uma, Chaudhary, Urmila, Sivasubbu, Sridhar, Scaria, Vinod, Oberoi, J. K., Raveendran, Reena, Datta, S., Das, Saumitra, Maitra, Arindam, Chinnaswamy, Sreedhar, Biswas, Nidhan Kumar, Parida, Ajay, Raghav, Sunil K., Prasad, Punit, Sarin, Apurva, Mayor, Satyajit, Ramakrishnan, Uma, Palakodeti, Dasaradhi, Seshasayee, Aswin Sai Narain, Thangaraj, K., Bashyam, Murali Dharan, Dalal, Ashwin, Bhat, Manoj, Shouche, Yogesh, Pillai, Ajay, Abraham, Priya, Potdar, Varsha Atul, Cherian, Sarah S., Desai, Anita Sudhir, Pattabiraman, Chitra, Manjunatha, M. V., Mani, Reeta S., Udupi, Gautam Arunachal, Nandicoori, Vinay, Tallapaka, Karthik Bharadwaj, Sowpati, Divya Tej, Kawabata, Ryoko, Morizako, Nanami, Sadamasu, Kenji, Asakura, Hiroyuki, Nagashima, Mami, Yoshimura, Kazuhisa, Ito, Jumpei, Kimura, Izumi, Uriu, Keiya, Kosugi, Yusuke, Suganami, Mai, Oide, Akiko, Yokoyama, Miyabishara, Chiba, Mika, Saito, Akatsuki, Butlertanaka, Erika P., Tanaka, Yuri L., Ikeda, Terumasa, Motozono, Chihiro, Nasser, Hesham, Shimizu, Ryo, Yuan, Yue, Kitazato, Kazuko, Hasebe, Haruyo, Nakagawa, So, Wu, Jiaqi, Takahashi, Miyoko, Fukuhara, Takasuke, Shimizu, Kenta, Tsushima, Kana, Kubo, Haruko, Shirakawa, Kotaro, Kazuma, Yasuhiro, Nomura, Ryosuke, Horisawa, Yoshihito, Takaori-Kondo, Akifumi, Tokunaga, Kenzo, Ozono, Seiya, Baker, Stephen, Dougan, Gordon, Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Lyons, Paul A., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Summers, Charlotte, Thaventhiran, James E. D., Toshner, Mark, Weekes, Michael P., Maxwell, Patrick, Shaw, Ashley, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O'Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Graf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O'Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Bergamaschi, Laura, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Krishna, Ben, Lewis, Daniel, Marsden, Joe, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Potts, Martin, Richoz, Nathan, Romashova, Veronika, Yarkoni, Natalia Savinykh, Sharma, Rahul, Stefanucci, Luca, Stephens, Jonathan, Strezlecki, Mateusz, Turner, Lori, De Bie, Eckart M. D. D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Allison, John, Butcher, Helen, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Kasanicki, Mary, Le Gresley, Emma, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Scholtes, Ingrid, Hein, Sabine, King, Rebecca, Mavousian, Antranik, Lee, Joo Hyeon, Bassi, Jessica, Silacci-Fegni, Chiara, Saliba, Christian, Pinto, Dora, Irie, Takashi, Yoshida, Isao, Hamilton, William L., Sato, Kei, Bhatt, Samir, Flaxman, Seth, James, Leo C., Corti, Davide, Piccoli, Luca, Barclay, Wendy S., Rakshit, Partha, Agrawal, Anurag, Gupta, Ravindra K., (INSACOG), Indian SARS-CoV-2 Genomics Consortium, Consortium, Genotype to Phenotype Japan (G2P-Japan), Collaboration, CITIID-NIHR BioResource COVID-19, Gupta, Ravindra K [0000-0001-9751-1808], Apollo - University of Cambridge Repository, and Gupta, Ravindra K. [0000-0001-9751-1808]

Subjects
Male, COVID-19 Vaccines, medicine.drug_class, Health Personnel, India, Monoclonal antibody, Virus Replication, Antibodies, Cell Line, Cell Fusion, Immune system, 13/100, medicine, Humans, Neutralizing antibody, Antibodies, Neutralizing, Female, Kinetics, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Vaccination, Immune Evasion, Neutralizing, 631/326/596/4130, Syncytium, Multidisciplinary, Cell fusion, biology, article, Vaccine efficacy, 631/250/254, Virology, Spike Glycoprotein, Coronavirus, 13/31, biology.protein, Antibody, Infection
Abstract

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era., A study of SARS-CoV-2 variants examining their transmission, infectivity, and potential resistance to therapies provides insights into the biology of the Delta variant and its role in the global pandemic.

Published
2022
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17. Single‐dose immunisation with a multimerised SARS‐CoV‐2 receptor binding domain (RBD) induces an enhanced and protective response in mice

Author

Salzer, Ralf, Clark, Jordan J, Vaysburd, Marina, Chang, Veronica T, Albecka, Anna, Kiss, Leo, Sharma, Parul, Gonzalez Llamazares, Andres, Kipar, Anja, Hiscox, Julian A, Owen, Andrew, Aricescu, A Radu, Stewart, James P, James, Leo C, Löwe, Jan, University of Zurich, James, Leo C, and Löwe, Jan

Subjects
1303 Biochemistry, Biophysics, 10184 Institute of Veterinary Pathology, Cell Biology, Biochemistry, 1307 Cell Biology, 1315 Structural Biology, 1311 Genetics, Structural Biology, 1312 Molecular Biology, Genetics, 570 Life sciences, biology, Molecular Biology, 1304 Biophysics
Published
2021

19. Analysis of Serological Biomarkers of SARS-CoV-2 Infection in Convalescent Samples From Severe, Moderate and Mild COVID-19 Cases

Author

Castillo-Olivares, Javier, primary, Wells, David A., additional, Ferrari, Matteo, additional, Chan, Andrew C. Y., additional, Smith, Peter, additional, Nadesalingam, Angalee, additional, Paloniemi, Minna, additional, Carnell, George W., additional, Ohlendorf, Luis, additional, Cantoni, Diego, additional, Mayora-Neto, Martin, additional, Palmer, Phil, additional, Tonks, Paul, additional, Temperton, Nigel J., additional, Peterhoff, David, additional, Neckermann, Patrick, additional, Wagner, Ralf, additional, Doffinger, Rainer, additional, Kempster, Sarah, additional, Otter, Ashley D., additional, Semper, Amanda, additional, Brooks, Tim, additional, Albecka, Anna, additional, James, Leo C., additional, Page, Mark, additional, Schwaeble, Wilhelm, additional, Baxendale, Helen, additional, and Heeney, Jonathan L., additional

Published
2021
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21. Single‐dose immunisation with a multimerised SARS‐CoV‐2 receptor binding domain (RBD) induces an enhanced and protective response in mice

Author

Salzer, Ralf, primary, Clark, Jordan J., additional, Vaysburd, Marina, additional, Chang, Veronica T., additional, Albecka, Anna, additional, Kiss, Leo, additional, Sharma, Parul, additional, Gonzalez Llamazares, Andres, additional, Kipar, Anja, additional, Hiscox, Julian A., additional, Owen, Andrew, additional, Aricescu, A. Radu, additional, Stewart, James P., additional, James, Leo C., additional, and Löwe, Jan, additional

Published
2021
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22. Analysis of Serological Biomarkers of SARS-CoV-2 Infection in Convalescent Samples From Severe, Moderate and Mild COVID-19 Cases

Author

Castillo-Olivares, Javier, Wells, David A., Ferrari, Matteo, Chan, Andrew C. Y., Smith, Peter, Nadesalingam, Angalee, Paloniemi, Minna, Carnell, George W., Ohlendorf, Luis, Cantoni, Diego, Mayora-Neto, Martin, Palmer, Phil, Tonks, Paul, Temperton, Nigel J., Peterhoff, David, Neckermann, Patrick, Wagner, Ralf, Doffinger, Rainer, Kempster, Sarah, Otter, Ashley D., Semper, Amanda, Brooks, Tim, Albecka, Anna, James, Leo C., Page, Mark, Schwaeble, Wilhelm, Baxendale, Helen, Heeney, Jonathan L., Castillo-Olivares, Javier, Wells, David A., Ferrari, Matteo, Chan, Andrew C. Y., Smith, Peter, Nadesalingam, Angalee, Paloniemi, Minna, Carnell, George W., Ohlendorf, Luis, Cantoni, Diego, Mayora-Neto, Martin, Palmer, Phil, Tonks, Paul, Temperton, Nigel J., Peterhoff, David, Neckermann, Patrick, Wagner, Ralf, Doffinger, Rainer, Kempster, Sarah, Otter, Ashley D., Semper, Amanda, Brooks, Tim, Albecka, Anna, James, Leo C., Page, Mark, Schwaeble, Wilhelm, Baxendale, Helen, and Heeney, Jonathan L.

Abstract

Precision monitoring of antibody responses during the COVID-19 pandemic is increasingly important during large scale vaccine rollout and rise in prevalence of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2) variants of concern (VOC). Equally important is defining Correlates of Protection (CoP) for SARS-CoV-2 infection and COVID-19 disease. Data from epidemiological studies and vaccine trials identified virus neutralising antibodies (Nab) and SARS-CoV-2 antigen-specific (notably RBD and S) binding antibodies as candidate CoP. In this study, we used the World Health Organisation (WHO) international standard to benchmark neutralising antibody responses and a large panel of binding antibody assays to compare convalescent sera obtained from: a) COVID-19 patients; b) SARS-CoV-2 seropositive healthcare workers (HCW) and c) seronegative HCW. The ultimate aim of this study is to identify biomarkers of humoral immunity that could be used to differentiate severe from mild or asymptomatic SARS-CoV-2 infections. Some of these biomarkers could be used to define CoP in further serological studies using samples from vaccination breakthrough and/or re-infection cases. Whenever suitable, the antibody levels of the samples studied were expressed in International Units (IU) for virus neutralisation assays or in Binding Antibody Units (BAU) for ELISA tests. In this work we used commercial and non-commercial antibody binding assays; a lateral flow test for detection of SARS-CoV-2-specific IgG/IgM; a high throughput multiplexed particle flow cytometry assay for SARS-CoV-2 Spike (S), Nucleocapsid (N) and Receptor Binding Domain (RBD) proteins); a multiplex antigen semi-automated immuno-blotting assay measuring IgM, IgA and IgG; a pseudotyped microneutralisation test (pMN) and an electroporation-dependent neutralisation assay (EDNA). Our results indicate that overall, severe COVID-19 patients showed statistically significantly higher levels of SARS-CoV-2-specific neutra

Published
2021

23. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Author

Mlcochova, Petra, Kemp, Steven A., Dhar, Mahesh Shanker, Papa, Guido, Meng, Bo, Ferreira, Isabella A. T. M., Datir, Rawlings, Collier, Dami A., Albecka, Anna, Singh, Sujeet, Pandey, Rajesh, Brown, Jonathan, Zhou, Jie, Goonawardane, Niluka, Mishra, Swapnil, Whittaker, Charles, Mellan, Thomas, Marwal, Robin, Datta, Meena, Sengupta, Shantanu, Ponnusamy, Kalaiarasan, Radhakrishnan, Venkatraman Srinivasan, Abdullahi, Adam, Charles, Oscar, Chattopadhyay, Partha, Devi, Priti, Caputo, Daniela, Peacock, Tom, Wattal, Chand, Goel, Neeraj, Satwik, Ambrish, Vaishya, Raju, Agarwal, Meenakshi, Chauhan, Himanshu, Dikid, Tanzin, Gogia, Hema, Lall, Hemlata, Verma, Kaptan, Singh, Manoj K., Soni, Namita, Meena, Namonarayan, Madan, Preeti, Singh, Priyanka, Sharma, Ramesh, Sharma, Rajeev, Kabra, Sandhya, Kumar, Sattender, Kumari, Swati, Sharma, Uma, Chaudhary, Urmila, Sivasubbu, Sridhar, Scaria, Vinod, Oberoi, J. K., Raveendran, Reena, Datta, S., Das, Saumitra, Maitra, Arindam, Chinnaswamy, Sreedhar, Biswas, Nidhan Kumar, Parida, Ajay, Raghav, Sunil K., Prasad, Punit, Sarin, Apurva, Mayor, Satyajit, Ramakrishnan, Uma, Palakodeti, Dasaradhi, Seshasayee, Aswin Sai Narain, Thangaraj, K., Bashyam, Murali Dharan, Dalal, Ashwin, Bhat, Manoj, Shouche, Yogesh, Pillai, Ajay, Abraham, Priya, Potdar, Varsha Atul, Cherian, Sarah S., Desai, Anita Sudhir, Pattabiraman, Chitra, Manjunatha, M. V., Mani, Reeta S., Udupi, Gautam Arunachal, Nandicoori, Vinay, Tallapaka, Karthik Bharadwaj, Sowpati, Divya Tej, Kawabata, Ryoko, Morizako, Nanami, Sadamasu, Kenji, Asakura, Hiroyuki, Nagashima, Mami, Yoshimura, Kazuhisa, Ito, Jumpei, Kimura, Izumi, Uriu, Keiya, Kosugi, Yusuke, Suganami, Mai, Oide, Akiko, Yokoyama, Miyabishara, Chiba, Mika, Saito, Akatsuki, Butlertanaka, Erika P., Tanaka, Yuri L., Ikeda, Terumasa, Motozono, Chihiro, Nasser, Hesham, Shimizu, Ryo, Yuan, Yue, Kitazato, Kazuko, Hasebe, Haruyo, Nakagawa, So, Wu, Jiaqi, Takahashi, Miyoko, Fukuhara, Takasuke, Shimizu, Kenta, Tsushima, Kana, Kubo, Haruko, Shirakawa, Kotaro, Kazuma, Yasuhiro, Nomura, Ryosuke, Horisawa, Yoshihito, Takaori-Kondo, Akifumi, Tokunaga, Kenzo, Ozono, Seiya, Baker, Stephen, Dougan, Gordon, Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Lyons, Paul A., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Summers, Charlotte, Thaventhiran, James E. D., Toshner, Mark, Weekes, Michael P., Maxwell, Patrick, Shaw, Ashley, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O'Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Graf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O'Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Bergamaschi, Laura, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Krishna, Ben, Lewis, Daniel, Marsden, Joe, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Potts, Martin, Richoz, Nathan, Romashova, Veronika, Yarkoni, Natalia Savinykh, Sharma, Rahul, Stefanucci, Luca, Stephens, Jonathan, Strezlecki, Mateusz, Turner, Lori, De Bie, Eckart M. D. D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Allison, John, Butcher, Helen, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Kasanicki, Mary, Le Gresley, Emma, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Scholtes, Ingrid, Hein, Sabine, King, Rebecca, Mavousian, Antranik, Lee, Joo Hyeon, Bassi, Jessica, Silacci-Fegni, Chiara, Saliba, Christian, Pinto, Dora, Irie, Takashi, Yoshida, Isao, Hamilton, William L., Sato, Kei, Bhatt, Samir, Flaxman, Seth, James, Leo C., Corti, Davide, Piccoli, Luca, Barclay, Wendy S., Rakshit, Partha, Agrawal, Anurag, Gupta, Ravindra K., Mlcochova, Petra, Kemp, Steven A., Dhar, Mahesh Shanker, Papa, Guido, Meng, Bo, Ferreira, Isabella A. T. M., Datir, Rawlings, Collier, Dami A., Albecka, Anna, Singh, Sujeet, Pandey, Rajesh, Brown, Jonathan, Zhou, Jie, Goonawardane, Niluka, Mishra, Swapnil, Whittaker, Charles, Mellan, Thomas, Marwal, Robin, Datta, Meena, Sengupta, Shantanu, Ponnusamy, Kalaiarasan, Radhakrishnan, Venkatraman Srinivasan, Abdullahi, Adam, Charles, Oscar, Chattopadhyay, Partha, Devi, Priti, Caputo, Daniela, Peacock, Tom, Wattal, Chand, Goel, Neeraj, Satwik, Ambrish, Vaishya, Raju, Agarwal, Meenakshi, Chauhan, Himanshu, Dikid, Tanzin, Gogia, Hema, Lall, Hemlata, Verma, Kaptan, Singh, Manoj K., Soni, Namita, Meena, Namonarayan, Madan, Preeti, Singh, Priyanka, Sharma, Ramesh, Sharma, Rajeev, Kabra, Sandhya, Kumar, Sattender, Kumari, Swati, Sharma, Uma, Chaudhary, Urmila, Sivasubbu, Sridhar, Scaria, Vinod, Oberoi, J. K., Raveendran, Reena, Datta, S., Das, Saumitra, Maitra, Arindam, Chinnaswamy, Sreedhar, Biswas, Nidhan Kumar, Parida, Ajay, Raghav, Sunil K., Prasad, Punit, Sarin, Apurva, Mayor, Satyajit, Ramakrishnan, Uma, Palakodeti, Dasaradhi, Seshasayee, Aswin Sai Narain, Thangaraj, K., Bashyam, Murali Dharan, Dalal, Ashwin, Bhat, Manoj, Shouche, Yogesh, Pillai, Ajay, Abraham, Priya, Potdar, Varsha Atul, Cherian, Sarah S., Desai, Anita Sudhir, Pattabiraman, Chitra, Manjunatha, M. V., Mani, Reeta S., Udupi, Gautam Arunachal, Nandicoori, Vinay, Tallapaka, Karthik Bharadwaj, Sowpati, Divya Tej, Kawabata, Ryoko, Morizako, Nanami, Sadamasu, Kenji, Asakura, Hiroyuki, Nagashima, Mami, Yoshimura, Kazuhisa, Ito, Jumpei, Kimura, Izumi, Uriu, Keiya, Kosugi, Yusuke, Suganami, Mai, Oide, Akiko, Yokoyama, Miyabishara, Chiba, Mika, Saito, Akatsuki, Butlertanaka, Erika P., Tanaka, Yuri L., Ikeda, Terumasa, Motozono, Chihiro, Nasser, Hesham, Shimizu, Ryo, Yuan, Yue, Kitazato, Kazuko, Hasebe, Haruyo, Nakagawa, So, Wu, Jiaqi, Takahashi, Miyoko, Fukuhara, Takasuke, Shimizu, Kenta, Tsushima, Kana, Kubo, Haruko, Shirakawa, Kotaro, Kazuma, Yasuhiro, Nomura, Ryosuke, Horisawa, Yoshihito, Takaori-Kondo, Akifumi, Tokunaga, Kenzo, Ozono, Seiya, Baker, Stephen, Dougan, Gordon, Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Lyons, Paul A., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Summers, Charlotte, Thaventhiran, James E. D., Toshner, Mark, Weekes, Michael P., Maxwell, Patrick, Shaw, Ashley, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O'Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Graf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O'Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Bergamaschi, Laura, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Krishna, Ben, Lewis, Daniel, Marsden, Joe, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Potts, Martin, Richoz, Nathan, Romashova, Veronika, Yarkoni, Natalia Savinykh, Sharma, Rahul, Stefanucci, Luca, Stephens, Jonathan, Strezlecki, Mateusz, Turner, Lori, De Bie, Eckart M. D. D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Allison, John, Butcher, Helen, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Kasanicki, Mary, Le Gresley, Emma, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Scholtes, Ingrid, Hein, Sabine, King, Rebecca, Mavousian, Antranik, Lee, Joo Hyeon, Bassi, Jessica, Silacci-Fegni, Chiara, Saliba, Christian, Pinto, Dora, Irie, Takashi, Yoshida, Isao, Hamilton, William L., Sato, Kei, Bhatt, Samir, Flaxman, Seth, James, Leo C., Corti, Davide, Piccoli, Luca, Barclay, Wendy S., Rakshit, Partha, Agrawal, Anurag, and Gupta, Ravindra K.

Published
2021

24. Single‐dose immunisation with a multimerised SARS‐CoV‐2 receptor binding domain (RBD) induces an enhanced and protective response in mice

Author

Salzer, Ralf; https://orcid.org/0000-0002-6334-7453, Clark, Jordan J; https://orcid.org/0000-0003-1790-7883, Vaysburd, Marina; https://orcid.org/0000-0001-7236-678X, Chang, Veronica T; https://orcid.org/0000-0001-7047-9019, Albecka, Anna; https://orcid.org/0000-0002-3672-5498, Kiss, Leo; https://orcid.org/0000-0001-8735-1118, Sharma, Parul; https://orcid.org/0000-0002-9090-7540, Gonzalez Llamazares, Andres; https://orcid.org/0000-0001-5404-6360, Kipar, Anja; https://orcid.org/0000-0001-7289-3459, Hiscox, Julian A; https://orcid.org/0000-0002-6582-0275, Owen, Andrew; https://orcid.org/0000-0002-9819-7651, Aricescu, A Radu; https://orcid.org/0000-0003-3783-1388, Stewart, James P; https://orcid.org/0000-0002-8928-2037, James, Leo C; https://orcid.org/0000-0003-2131-0334, Löwe, Jan; https://orcid.org/0000-0002-5218-6615, Salzer, Ralf; https://orcid.org/0000-0002-6334-7453, Clark, Jordan J; https://orcid.org/0000-0003-1790-7883, Vaysburd, Marina; https://orcid.org/0000-0001-7236-678X, Chang, Veronica T; https://orcid.org/0000-0001-7047-9019, Albecka, Anna; https://orcid.org/0000-0002-3672-5498, Kiss, Leo; https://orcid.org/0000-0001-8735-1118, Sharma, Parul; https://orcid.org/0000-0002-9090-7540, Gonzalez Llamazares, Andres; https://orcid.org/0000-0001-5404-6360, Kipar, Anja; https://orcid.org/0000-0001-7289-3459, Hiscox, Julian A; https://orcid.org/0000-0002-6582-0275, Owen, Andrew; https://orcid.org/0000-0002-9819-7651, Aricescu, A Radu; https://orcid.org/0000-0003-3783-1388, Stewart, James P; https://orcid.org/0000-0002-8928-2037, James, Leo C; https://orcid.org/0000-0003-2131-0334, and Löwe, Jan; https://orcid.org/0000-0002-5218-6615

Abstract

The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has triggered a worldwide health emergency. Here, we show that ferritin-like Dps from hyperthermophilic Sulfolobus islandicus, covalently coupled with SARS-CoV-2 antigens via the SpyCatcher system, forms stable multivalent dodecameric vaccine nanoparticles that remain intact even after lyophilisation. Immunisation experiments in mice demonstrated that the SARS-CoV-2 receptor binding domain (RBD) coupled to Dps (RBD-S-Dps) elicited a higher antibody titre and an enhanced neutralising antibody response compared to monomeric RBD. A single immunisation with RBD-S-Dps completely protected hACE2-expressing mice from serious illness and led to viral clearance from the lungs upon SARS-CoV-2 infection. Our data highlight that multimerised SARS-CoV-2 subunit vaccines are a highly efficacious modality, particularly when combined with an ultra-stable scaffold.

Published
2021

25. Towards Internationally standardised humoral Immune Correlates of Protection from SARS-CoV-2 infection and COVID-19 disease

Author

Castillo-Olivares, Javier, primary, Wells, David A., additional, Ferrari, Matteo, additional, Chan, Andrew, additional, Smith, Peter, additional, Nadesalingam, Angalee, additional, Paloniemi, Minna, additional, Carnell, George, additional, Ohlendorf, Luis, additional, Cantoni, Diego, additional, Mayora-Neto, Martin, additional, Palmer, Phil, additional, Tonks, Paul, additional, Temperton, Nigel, additional, Wagner, Ralf, additional, Neckermann, Patrick, additional, Peterhoff, David, additional, Doffinger, Rainer, additional, Kempster, Sarah, additional, Otter, Ashley, additional, Semper, Amanda, additional, Brooks, Tim, additional, Page, Mark, additional, Albecka, Anna, additional, James, Leo C., additional, Briggs, John, additional, Schwaeble, Wilhelm, additional, Baxendale, Helen, additional, and Heeney, Jonathan, additional

Published
2021
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28. Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion

Author

Papa, Guido, primary, Mallery, Donna L., additional, Albecka, Anna, additional, Welch, Lawrence G., additional, Cattin-Ortolá, Jérôme, additional, Luptak, Jakub, additional, Paul, David, additional, McMahon, Harvey T., additional, Goodfellow, Ian G., additional, Carter, Andrew, additional, Munro, Sean, additional, and James, Leo C., additional

Published
2021
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30. Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion

Author

Papa, Guido, primary, Mallery, Donna L., additional, Albecka, Anna, additional, Welch, Lawrence, additional, Cattin-Ortolá, Jérôme, additional, Luptak, Jakub, additional, Paul, David, additional, McMahon, Harvey T., additional, Goodfellow, Ian G., additional, Carter, Andrew, additional, Munro, Sean, additional, and James, Leo C., additional

Published
2020
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31. TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control

Author

Douse, Christopher H., primary, Tchasovnikarova, Iva A., additional, Timms, Richard T., additional, Protasio, Anna V., additional, Seczynska, Marta, additional, Prigozhin, Daniil M., additional, Albecka, Anna, additional, Wagstaff, Jane, additional, Williamson, James C., additional, Freund, Stefan M.V., additional, Lehner, Paul J., additional, and Modis, Yorgo, additional

Published
2020
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35. Structural analysis of herpes simplex virus by optical super-resolution imaging

Author

Laine, Romain F., Albecka, Anna, van de Linde, Sebastian, Rees, Eric J., Crump, Colin M., Kaminski, Clemens F., Rees, Eric [0000-0001-7478-5961], Crump, Colin [0000-0001-9918-9998], Kaminski, Clemens [0000-0002-5194-0962], and Apollo - University of Cambridge Repository

Subjects
Keratinocytes, Simplexvirus, viruses, General Physics and Astronomy, Herpesvirus 1, Human, medicine.disease_cause, Mice, Viral Envelope Proteins, Microscopy, Image Processing, Computer-Assisted, chemistry.chemical_classification, 0303 health sciences, Mice, Inbred BALB C, Multidisciplinary, 030302 biochemistry & molecular biology, Optical Imaging, Antibodies, Monoclonal, Viral tegument, Recombinant Proteins, 3. Good health, Female, food.ingredient, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Virus, Cell Line, 03 medical and health sciences, Viral Proteins, food, ddc:570, medicine, Animals, Humans, 030304 developmental biology, Viral Structural Proteins, Cryoelectron Microscopy, Virion, General Chemistry, biochemical phenomena, metabolism, and nutrition, Superresolution, Molecular biology, Optical reconstruction, QR, Herpes simplex virus, chemistry, Microscopy, Fluorescence, Biophysics, Glycoprotein
Abstract

Herpes simplex virus type-1 (HSV-1) is one of the most widespread pathogens among humans. Although the structure of HSV-1 has been extensively investigated, the precise organization of tegument and envelope proteins remains elusive. Here we use super-resolution imaging by direct stochastic optical reconstruction microscopy (dSTORM) in combination with a model-based analysis of single-molecule localization data, to determine the position of protein layers within virus particles. We resolve different protein layers within individual HSV-1 particles using multi-colour dSTORM imaging and discriminate envelope-anchored glycoproteins from tegument proteins, both in purified virions and in virions present in infected cells. Precise characterization of HSV-1 structure was achieved by particle averaging of purified viruses and model-based analysis of the radial distribution of the tegument proteins VP16, VP1/2 and pUL37, and envelope protein gD. From this data, we propose a model of the protein organization inside the tegument., Herpes simplex virus type-1 (HSV-1) is a widespread human pathogen, the structure of which is not yet fully characterized. Here, the authors apply dSTORM super-resolution microscopy in combination with advanced data analysis tools to locate the position of four key protein layers in HSV-1 with unprecedented precision.

Published
2015

38. Analysis of Serine Codon Conservation Reveals Diverse Phenotypic Constraints on Hepatitis C Virus Glycoprotein Evolution

Author

Brown, Richard J. P., primary, Koutsoudakis, George, additional, Urbanowicz, Richard A., additional, Mirza, Deeman, additional, Ginkel, Corinne, additional, Riebesehl, Nina, additional, Calland, Noémie, additional, Albecka, Anna, additional, Price, Louisa, additional, Hudson, Natalia, additional, Descamps, Véronique, additional, Backx, Matthijs, additional, McClure, C. Patrick, additional, Duverlie, Gilles, additional, Pecheur, Eve-Isabelle, additional, Dubuisson, Jean, additional, Perez-del-Pulgar, Sofia, additional, Forns, Xavier, additional, Steinmann, Eike, additional, Tarr, Alexander W., additional, Pietschmann, Thomas, additional, and Ball, Jonathan K., additional

Published
2014
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39. Griffithsin Has Antiviral Activity against Hepatitis C Virus

Author

Meuleman, Philip, primary, Albecka, Anna, additional, Belouzard, Sandrine, additional, Vercauteren, Koen, additional, Verhoye, Lieven, additional, Wychowski, Czeslaw, additional, Leroux-Roels, Geert, additional, Palmer, Kenneth E., additional, and Dubuisson, Jean, additional

Published
2011
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40. Hepatitis C Patient-Derived Glycoproteins Exhibit Marked Differences in Susceptibility to Serum Neutralizing Antibodies: Genetic Subtype Defines Antigenic but Not Neutralization Serotype

Author

Tarr, Alexander W., primary, Urbanowicz, Richard A., additional, Hamed, Mohamed R., additional, Albecka, Anna, additional, McClure, C. Patrick, additional, Brown, Richard J. P., additional, Irving, William L., additional, Dubuisson, Jean, additional, and Ball, Jonathan K., additional

Published
2011
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42. Single-dose immunisation with a multimerised SARS-CoV-2 receptor binding domain (RBD) induces an enhanced and protective response in mice

Author

Jordan J. Clark, Parul Sharma, Anja Kipar, Andrew Owen, Jan Löwe, Marina Vaysburd, James P. Stewart, Veronica T. Chang, Leo Kiss, Julian A. Hiscox, Anna Albecka, A. Radu Aricescu, Andres Gonzalez Llamazares, Ralf Salzer, Leo C. James, Salzer, Ralf [0000-0002-6334-7453], Clark, Jordan J [0000-0003-1790-7883], Vaysburd, Marina [0000-0001-7236-678X], Chang, Veronica T [0000-0001-7047-9019], Albecka, Anna [0000-0002-3672-5498], Kiss, Leo [0000-0001-8735-1118], Sharma, Parul [0000-0002-9090-7540], Gonzalez Llamazares, Andres [0000-0001-5404-6360], Kipar, Anja [0000-0001-7289-3459], Hiscox, Julian A [0000-0002-6582-0275], Owen, Andrew [0000-0002-9819-7651], Aricescu, A Radu [0000-0003-3783-1388], Stewart, James P [0000-0002-8928-2037], James, Leo C [0000-0003-2131-0334], Löwe, Jan [0000-0002-5218-6615], and Apollo - University of Cambridge Repository

Subjects
COVID-19 Vaccines, viruses, Protein domain, Biophysics, coronavirus, medicine.disease_cause, Antibodies, Viral, Biochemistry, DNA-binding protein, SARS‐CoV‐2, RBD, Sulfolobus, Mice, Antigen, Bacterial Proteins, Protein Domains, COVID‐19, Structural Biology, Research Letter, Genetics, medicine, Animals, Humans, Molecular Biology, Coronavirus, biology, Chemistry, SARS-CoV-2, COVID-19, Cell Biology, Virology, Antibodies, Neutralizing, Research Letters, DNA-Binding Proteins, Titer, Structural biology, Immunization, Ferritins, Spike Glycoprotein, Coronavirus, biology.protein, Nanoparticles, Receptors, Virus, Dps, subunit vaccine, Angiotensin-Converting Enzyme 2, Antibody, Protein Multimerization
Abstract

The COVID‐19 pandemic, caused by the SARS‐CoV‐2 coronavirus, has triggered a worldwide health emergency. Here, we show that ferritin‐like Dps from hyperthermophilic Sulfolobus islandicus, covalently coupled with SARS‐CoV‐2 antigens via the SpyCatcher system, forms stable multivalent dodecameric vaccine nanoparticles that remain intact even after lyophilisation. Immunisation experiments in mice demonstrated that the SARS‐CoV‐2 receptor binding domain (RBD) coupled to Dps (RBD‐S‐Dps) elicited a higher antibody titre and an enhanced neutralising antibody response compared to monomeric RBD. A single immunisation with RBD‐S‐Dps completely protected hACE2‐expressing mice from serious illness and led to viral clearance from the lungs upon SARS‐CoV‐2 infection. Our data highlight that multimerised SARS‐CoV‐2 subunit vaccines are a highly efficacious modality, particularly when combined with an ultra‐stable scaffold., Preparation and quality control of coupled antigen–Dps complexes (Ag‐S‐Dps). (A) SDS/PAGE of the three expressed and purified antigens as introduced in Fig. 1C, Coomassie stained. Glycosylation of Spike leads to a fuzzy appearance of its band. RBD‐SpyT2 and Spike‐SpyT2 were expressed in mammalian cells, and SpyT2‐NP was expressed in bacteria, as was the SpyC‐Dps scaffold. (B) Size exclusion chromatography to separate excess antigens after the SpyCatcher/Spytag2 coupling reactions; Superose 6 Increase in PBS. (C) SDS/PAGE of the coupled and purified Ag‐S‐Dps complexes. ‘RT’, no heating; ‘99’, heated to 99 °C. The SpyC‐Dps scaffold alone, as well as all the three coupled complexes show high‐molecular weight complexes, presumably dodecameric, that disappear only after heating of the samples in SDS loading buffer (Coomassie stained). (D) Negative‐stain electron microscopy analyses of the three multimeric Ag‐S‐Dps complexes, showing that all samples form defined and monodisperse spheres that display the antigens on their surface, leading to particles of different sizes for the three differently sized antigens.

Published
2021

43. A functional assay for serum detection of antibodies against SARS‐CoV‐2 nucleoprotein

Author

Tyler Rhinesmith, Anna Albecka, Leo C. James, Marina Vaysburd, Dean Clift, David M Favara, Sarah L Caddy, Helen Baxendale, Albecka, Anna [0000-0002-3672-5498], Clift, Dean [0000-0001-8141-7817], Caddy, Sarah L [0000-0002-9790-7420], James, Leo C [0000-0003-2131-0334], and Apollo - University of Cambridge Repository

Subjects
Resource, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Antigen presentation, Fc receptor, Antibodies, Viral, EMBO23, General Biochemistry, Genetics and Molecular Biology, Neutralization, SARS‐CoV‐2, Immune system, antibodies, Humans, Molecular Biology, nucleoprotein, General Immunology and Microbiology, biology, SARS-CoV-2, General Neuroscience, COVID-19, neutralization, Virology, Antibodies, Neutralizing, Resources, Microbiology, Virology & Host Pathogen Interaction, Nucleoprotein, Cytosol, Nucleoproteins, biology.protein, Antibody, TRIM21
Abstract

The humoral immune response to SARS‐CoV‐2 results in antibodies against spike (S) and nucleoprotein (N). However, whilst there are widely available neutralization assays for S antibodies, there is no assay for N‐antibody activity. Here, we present a simple in vitro method called EDNA (electroporated‐antibody‐dependent neutralization assay) that provides a quantitative measure of N‐antibody activity in unpurified serum from SARS‐CoV‐2 convalescents. We show that N antibodies neutralize SARS‐CoV‐2 intracellularly and cell‐autonomously but require the cytosolic Fc receptor TRIM21. Using EDNA, we show that low N‐antibody titres can be neutralizing, whilst some convalescents possess serum with high titres but weak activity. N‐antibody and N‐specific T‐cell activity correlates within individuals, suggesting N antibodies may protect against SARS‐CoV‐2 by promoting antigen presentation. This work highlights the potential benefits of N‐based vaccines and provides an in vitro assay to allow the antibodies they induce to be tested., A new in vitro assay, EDNA, measures neutralizing activities of patient antibodies against coronaviral N protein, complementing available methods for evaluating antiviral activities of anti‐spike (S) protein antibodies.

Published
2021

44. A pan-SARS-CoV-2-specific soluble angiotensin-converting enzyme 2-albumin fusion engineered for enhanced plasma half-life and needle-free mucosal delivery.

Author

Benjakul S, Anthi AK, Kolderup A, Vaysburd M, Lode HE, Mallery D, Fossum E, Vikse EL, Albecka A, Ianevski A, Kainov D, Karlsen KF, Sakya SA, Nyquist-Andersen M, Gjølberg TT, Moe MC, Bjørås M, Sandlie I, James LC, and Andersen JT

Abstract

Immunocompromised patients often fail to raise protective vaccine-induced immunity against the global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Although monoclonal antibodies have been authorized for clinical use, most have lost their ability to potently neutralize the evolving Omicron subvariants. Thus, there is an urgent need for treatment strategies that can provide protection against these and emerging SARS-CoV-2 variants to prevent the development of severe coronavirus disease 2019. Here, we report on the design and characterization of a long-acting viral entry-blocking angiotensin-converting enzyme 2 (ACE2) dimeric fusion molecule. Specifically, a soluble truncated human dimeric ACE2 variant, engineered for improved binding to the receptor-binding domain of SARS-CoV-2, was fused with human albumin tailored for favorable engagement of the neonatal fragment crystallizable receptor (FcRn), which resulted in enhanced plasma half-life and allowed for needle-free transmucosal delivery upon nasal administration in human FcRn-expressing transgenic mice. Importantly, the dimeric ACE2-fused albumin demonstrated potent neutralization of SARS-CoV-2 immune escape variants., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Published
2023
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45. Structural analysis of herpes simplex virus by optical super-resolution imaging.

Author

Laine RF, Albecka A, van de Linde S, Rees EJ, Crump CM, and Kaminski CF

Subjects
Animals, Antibodies, Monoclonal chemistry, Cell Line, Cryoelectron Microscopy, Female, Herpesvirus 1, Human, Humans, Image Processing, Computer-Assisted, Keratinocytes virology, Mice, Mice, Inbred BALB C, Microscopy, Fluorescence, Recombinant Proteins chemistry, Viral Envelope Proteins chemistry, Viral Proteins chemistry, Viral Structural Proteins chemistry, Virion metabolism, Microscopy methods, Optical Imaging methods, Simplexvirus ultrastructure
Abstract

Herpes simplex virus type-1 (HSV-1) is one of the most widespread pathogens among humans. Although the structure of HSV-1 has been extensively investigated, the precise organization of tegument and envelope proteins remains elusive. Here we use super-resolution imaging by direct stochastic optical reconstruction microscopy (dSTORM) in combination with a model-based analysis of single-molecule localization data, to determine the position of protein layers within virus particles. We resolve different protein layers within individual HSV-1 particles using multi-colour dSTORM imaging and discriminate envelope-anchored glycoproteins from tegument proteins, both in purified virions and in virions present in infected cells. Precise characterization of HSV-1 structure was achieved by particle averaging of purified viruses and model-based analysis of the radial distribution of the tegument proteins VP16, VP1/2 and pUL37, and envelope protein gD. From this data, we propose a model of the protein organization inside the tegument.

Published
2015
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46. (-)-Epigallocatechin-3-gallate is a new inhibitor of hepatitis C virus entry.

Author

Calland N, Albecka A, Belouzard S, Wychowski C, Duverlie G, Descamps V, Hober D, Dubuisson J, Rouillé Y, and Séron K

Subjects
Animals, Catechin pharmacology, Cattle, Cell Line, Chlorocebus aethiops, Dose-Response Relationship, Drug, Hepacivirus pathogenicity, Hepacivirus physiology, Hepatitis C pathology, Hepatitis C physiopathology, Hepatocytes drug effects, Hepatocytes pathology, Humans, Kidney drug effects, Kidney pathology, Kidney virology, Lipid Metabolism drug effects, Models, Animal, Vero Cells, Virus Replication drug effects, Virus Replication physiology, Antiviral Agents pharmacology, Catechin analogs & derivatives, Hepacivirus drug effects, Hepatocytes virology, Plant Extracts pharmacology, Tea, Virus Internalization drug effects
Abstract

Unlabelled: Here, we identify (-)-epigallocatechin-3-gallate (EGCG) as a new inhibitor of hepatitis C virus (HCV) entry. EGCG is a flavonoid present in green tea extract belonging to the subclass of catechins, which has many properties. Particularly, EGCG possesses antiviral activity and impairs cellular lipid metabolism. Because of close links between HCV life cycle and lipid metabolism, we postulated that EGCG may interfere with HCV infection. We demonstrate that a concentration of 50 μM of EGCG inhibits HCV infectivity by more than 90% at an early step of the viral life cycle, most likely the entry step. This inhibition was not observed with other members of the Flaviviridae family tested. The antiviral activity of EGCG on HCV entry was confirmed with pseudoparticles expressing HCV envelope glycoproteins E1 and E2 from six different genotypes. In addition, using binding assays at 4°C, we demonstrate that EGCG prevents attachment of the virus to the cell surface, probably by acting directly on the particle. We also show that EGCG has no effect on viral replication and virion secretion. By inhibiting cell-free virus transmission using agarose or neutralizing antibodies, we show that EGCG inhibits HCV cell-to-cell spread. Finally, by successive inoculation of naïve cells with supernatant of HCV-infected cells in the presence of EGCG, we observed that EGCG leads to undetectable levels of infection after four passages., Conclusion: EGCG is a new, interesting anti-HCV molecule that could be used in combination with other direct-acting antivirals. Furthermore, it is a novel tool to further dissect the mechanisms of HCV entry into the hepatocyte., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Published
2012
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