المؤلفون: Florova, Marianna, Abreu-Mota, Tiago, Paesen, Guido C, Beetschen, Anna Sophia, Cornille, Karen, Marx, Anna-Friederike, Narr, Kerstin, Sahin, Mehmet, Dimitrova, Mirela, Swarnalekha, Nivedya, Beil-Wagner, Jane, Savic, Natasa, Pelczar, Pawel, Buch, Thorsten, King, Carolyn G, Bowden, Thomas A, Pinschewer, Daniel D

المصدر: Florova, Marianna; Abreu-Mota, Tiago; Paesen, Guido C; Beetschen, Anna Sophia; Cornille, Karen; Marx, Anna-Friederike; Narr, Kerstin; Sahin, Mehmet; Dimitrova, Mirela; Swarnalekha, Nivedya; Beil-Wagner, Jane; Savic, Natasa; Pelczar, Pawel; Buch, Thorsten; King, Carolyn G; Bowden, Thomas A; Pinschewer, Daniel D (2024). Central tolerance shapes the neutralizing B cell repertoire against a persisting virus in its natural host. Proceedings of the National Academy of Sciences of the United States of America, 121(11):e2318657121.

مصطلحات موضوعية: Institute of Laboratory Animal Science, 570 Life sciences, biology, 610 Medicine & health, 590 Animals (Zoology), Multidisciplinary

الوصف: Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus–host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV-neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgM $^{low}$ cells were not anergic but up-regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire.

وصف الملف: application/pdf

العلاقة: https://www.zora.uzh.ch/id/eprint/258363/1/Florova_2024_PNAS_eigene_paper_central_tolerance_shapes_the_neutralizing_b_cell_repertoire_against_a_persisting_virus_in_its.pdfTest; info:pmid/38446855; urn:issn:0027-8424

الإتاحة: https://doi.org/10.5167/uzh-258363Test
https://doi.org/10.1073/pnas.2318657121Test
https://www.zora.uzh.ch/id/eprint/258363Test/
https://www.zora.uzh.ch/id/eprint/258363/1/Florova_2024_PNAS_eigene_paper_central_tolerance_shapes_the_neutralizing_b_cell_repertoire_against_a_persisting_virus_in_its.pdfTest

المؤلفون: Stelfox, Alice J., Oguntuyo, Kasopefoluwa Y., Rissanen, Ilona, Harlos, Karl, Rambo, Robert, Lee, Benhur, Bowden, Thomas A.

المساهمون: Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE

مصطلحات موضوعية: Glycoprotein, Paramyxovirus, Structure, Viral attachment, Virus-host interactions, 1182 Biochemistry, cell and molecular biology

الوصف: Increased viral surveillance has led to the isolation and identification of numerous uncharacterized paramyxoviruses, rapidly expanding our understanding of paramyxoviral diversity beyond the bounds of known genera. Despite this diversity, a key feature that unites paramyxoviruses is the presence of a receptor-binding protein (RBP), which facilitates host-cell attachment and plays a fundamental role in determining host range. Here, we study the RBP presented on the surface of rodent-borne paramyxoviruses Mossman and Nariva (MosV and NarV, respectively), viruses that constitute founding members of the recently defined Narmovirus genus within the Paramyxoviridae family. Crystallographic analysis of the C-terminal head region of the dimeric MosV and NarV RBPs demonstrates that while these glycoproteins retain the canonical six-bladed β-propeller fold found in other paramyxoviral RBPs, they lack the structural motifs associated with established paramyxovirus host-cell receptor entry pathways. Consistent with MosV-RBP and NarV-RBP undergoing a distinct entry pathway from other characterized paramyxoviruses, structure-based phylogenetic analysis demonstrates that these six-bladed β-propeller head domains form a singular structural class that is distinct from other paramyxoviral RBPs. Additionally, using an integrated crystallographic and small-angle X-ray scattering analysis, we confirm that MosV-RBP and NarV-RBP form homodimeric arrangements that are distinct from those adopted by other paramyxovirus RBPs. Altogether, this investigation provides a molecular-level blueprint of the narmovirus RBP that broadens our understanding of the structural space and functional diversity available to paramyxovirus RBPs. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: We are grateful to DLS for beamtime (proposals mx10627 and mx14744) and the staff of beamlines I02, I04, and B21 for assistance with data collection.r We thank the Medical Research Council (MR/L009528/1 and MR/S007555/1 to T.A.B., MR/V001329/1 to K.H.), Engineering and Physics Research Council (EP/K503113/1, EP/L505031/1, EP/M50659X/1, and EP/M508111/1 to A.J.S.), Academy of Finland (342988 and 309605 to I.R.), and NIH (NIAID AI123449, AI171403, and AI115226 to B.L.) for funding. B.L. also acknowledges the Ward Coleman estate for endowing the Ward-Coleman Chairs at the Icahn School of Medicine at Mount Sinai. The Wellcome Centre for Human Genetics is supported by Wellcome Centre (grant 203141/Z/16Z).; Stelfox , A J , Oguntuyo , K Y , Rissanen , I , Harlos , K , Rambo , R , Lee , B & Bowden , T A 2023 , ' Crystal structure and solution state of the C-terminal head region of the narmovirus receptor binding protein ' , mBio , vol. 14 , no. 5 , e0139123 . https://doi.org/10.1128/mbio.01391-23Test; 85176560746; c74b7d17-3fdb-4be4-ba12-fb38a6454e79; http://hdl.handle.net/10138/570912Test; 001071847700001

الإتاحة: http://hdl.handle.net/10138/570912Test

المؤلفون: Faria, Nuno R, Mellan, Thomas A, Whittaker, Charles, Claro, Ingra M, Candido, Darlan da S, Mishra, Swapnil, Crispim, Myuki AE, Sales, Flavia CS, Hawryluk, Iwona, McCrone, John T, Hulswit, Ruben JG, Franco, Lucas AM, Ramundo, Mariana S, de Jesus, Jaqueline G, Andrade, Pamela S, Coletti, Thais M, Ferreira, Giulia M, Silva, Camila AM, Manuli, Erika R, Pereira, Rafael HM, Peixoto, Pedro S, Kraemer, Moritz UG, Gaburo, Nelson, Camilo, Cecilia da C, Hoeltgebaum, Henrique, Souza, William M, Rocha, Esmenia C, de Souza, Leandro M, de Pinho, Mariana C, Araujo, Leonardo JT, Malta, Frederico SV, de Lima, Aline B, Silva, Joice do P, Zauli, Danielle AG, Ferreira, Alessandro C de S, Schnekenberg, Ricardo P, Laydon, Daniel J, Walker, Patrick GT, Schlüter, Hannah M, Dos Santos, Ana LP, Vidal, Maria S, Del Caro, Valentina S, Filho, Rosinaldo MF, Dos Santos, Helem M, Aguiar, Renato S, Proença-Modena, José L, Nelson, Bruce, Hay, James A, Monod, Mélodie, Miscouridou, Xenia, Coupland, Helen, Sonabend, Raphael, Vollmer, Michaela, Gandy, Axel, Prete, Carlos A, Nascimento, Vitor H, Suchard, Marc A, Bowden, Thomas A, Pond, Sergei LK, Wu, Chieh-Hsi, Ratmann, Oliver, Ferguson, Neil M, Dye, Christopher, Loman, Nick J, Lemey, Philippe, Rambaut, Andrew, Fraiji, Nelson A, Carvalho, Maria do PSS, Pybus, Oliver G, Flaxman, Seth, Bhatt, Samir, Sabino, Ester C

المصدر: Science. 372(6544)

مصطلحات موضوعية: Human Genome, Immunization, Pneumonia & Influenza, Lung, Prevention, Genetics, Vaccine Related, Biotechnology, Pneumonia, Emerging Infectious Diseases, Biodefense, Infectious Diseases, Infection, Good Health and Well Being, Angiotensin-Converting Enzyme 2, Brazil, COVID-19, Communicable Diseases, Emerging, Epidemiological Monitoring, Genome, Viral, Genomics, Humans, Models, Theoretical, Molecular Epidemiology, Mutation, Protein Binding, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Viral Load, General Science & Technology

الوصف: Cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Manaus, Brazil, resurged in late 2020 despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1 acquired 17 mutations, including a trio in the spike protein (K417T, E484K, and N501Y) associated with increased binding to the human ACE2 (angiotensin-converting enzyme 2) receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7- to 2.4-fold more transmissible and that previous (non-P.1) infection provides 54 to 79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5z75x4xxTest

المؤلفون: El Omari, Kamel, Duman, Ramona, Mykhaylyk, Vitaliy, Orr, Christian M., Latimer-Smith, Merlyn, Winter, Graeme, Grama, Vinay, Qu, Feng, Bountra, Kiran, Kwong, Hok Sau, Romano, Maria, Reis, Rosana I., Vogeley, Lutz, Vecchia, Luca, Owen, C. David, Wittmann, Sina, Renner, Max, Senda, Miki, Matsugaki, Naohiro, Kawano, Yoshiaki, Bowden, Thomas A., Moraes, Isabel, Grimes, Jonathan M., Mancini, Erika J., Walsh, Martin A., Guzzo, Cristiane R., Owens, Raymond J., Jones, E. Yvonne, Brown, David G., Stuart, Dave I., Beis, Konstantinos, Wagner, Armin

المصدر: Communications Chemistry. 6(1)

الوصف: Despite recent advances in cryo-electron microscopy and artificial intelligence-based model predictions, a significant fraction of structure determinations by macromolecular crystallography still requires experimental phasing, usually by means of single-wavelength anomalous diffraction (SAD) techniques. Most synchrotron beamlines provide highly brilliant beams of X-rays of between 0.7 and 2 Å wavelength. Use of longer wavelengths to access the absorption edges of biologically important lighter atoms such as calcium, potassium, chlorine, sulfur and phosphorus for native-SAD phasing is attractive but technically highly challenging. The long-wavelength beamline I23 at Diamond Light Source overcomes these limitations and extends the accessible wavelength range to λ = 5.9 Å. Here we report 22 macromolecular structures solved in this extended wavelength range, using anomalous scattering from a range of elements which demonstrate the routine feasibility of lighter atom phasing. We suggest that, in light of its advantages, long-wavelength crystallography is a compelling option for experimental phasing.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-215721Test
https://doi.org/10.1038/s42004-023-01014-0Test
https://umu.diva-portal.org/smash/get/diva2:1809904/FULLTEXT01.pdfTest

المؤلفون: Escalera-Zamudio, Marina, Kosakovsky Pond, Sergei L, Martínez de la Viña, Natalia, Gutiérrez, Bernardo, Inward, Rhys P D, Thézé, Julien, van Dorp, Lucy, Castelán-Sánchez, Hugo G, Bowden, Thomas A, Pybus, Oliver G, Hulswit, Ruben J G

المساهمون: Virologie

مصطلحات موضوعية: Animals, Humans, SARS-CoV-2/genetics, COVID-19/genetics, Phylogeny, Middle East Respiratory Syndrome Coronavirus/genetics, Mutation

الوصف: Comparing the evolution of distantly related viruses can provide insights into common adaptive processes related to shared ecological niches. Phylogenetic approaches, coupled with other molecular evolution tools, can help identify mutations informative on adaptation, although the structural contextualization of these to functional sites of proteins may help gain insight into their biological properties. Two zoonotic betacoronaviruses capable of sustained human-to-human transmission have caused pandemics in recent times (SARS-CoV-1 and SARS-CoV-2), although a third virus (MERS-CoV) is responsible for sporadic outbreaks linked to animal infections. Moreover, two other betacoronaviruses have circulated endemically in humans for decades (HKU1 and OC43). To search for evidence of adaptive convergence between established and emerging betacoronaviruses capable of sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1, and SARS-CoV-2), we developed a methodological pipeline to classify shared nonsynonymous mutations as putatively denoting homoplasy (repeated mutations that do not share direct common ancestry) or stepwise evolution (sequential mutations leading towards a novel genotype). In parallel, we look for evidence of positive selection and draw upon protein structure data to identify potential biological implications. We find 30 candidate mutations, from which 4 (codon sites 18121 [nsp14/residue 28], 21623 [spike/21], 21635 [spike/25], and 23948 [spike/796]; SARS-CoV-2 genome numbering) further display evolution under positive selection and proximity to functional protein regions. Our findings shed light on potential mechanisms underlying betacoronavirus adaptation to the human host and pinpoint common mutational pathways that may occur during establishment of human endemicity.

وصف الملف: application/pdf

العلاقة: https://dspace.library.uu.nl/handle/1874/429642Test

الإتاحة: https://dspace.library.uu.nl/handle/1874/429642Test

المؤلفون: Chapman, Nathaniel S., Hulswit, Ruben J. G., Westover, Jonna L. B., Stass, Robert, Paesen, Guido C., Binshtein, Elad, Reidy, Joseph X., Engdahl, Taylor B., Handal, Laura S., Flores, Alejandra, Gowen, Brian B., Bowden, Thomas A., Crowe, James E.

المساهمون: U.S. Department of Health & Human Services | National Institutes of Health, RCUK | Medical Research Council, Wellcome Trust

المصدر: Nature Communications ; volume 14, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic.

الإتاحة: https://doi.org/10.1038/s41467-023-41171-3Test
https://www.nature.com/articles/s41467-023-41171-3.pdfTest
https://www.nature.com/articles/s41467-023-41171-3Test

المؤلفون: Stass, Robert, Engdahl, Taylor B., Chapman, Nathaniel S., Wolters, Rachael M., Handal, Laura S., Diaz, Summer M., Crowe, James E., Bowden, Thomas A.

المساهمون: RCUK | Medical Research Council, Wellcome Trust, Foundation for the National Institutes of Health, Merck KGaA

المصدر: Nature Microbiology ; volume 8, issue 7, page 1293-1303 ; ISSN 2058-5276

مصطلحات موضوعية: Cell Biology, Microbiology (medical), Genetics, Applied Microbiology and Biotechnology, Immunology, Microbiology

الوصف: Rodent-borne hantaviruses are prevalent worldwide and upon spillover to human populations, cause severe disease for which no specific treatment is available. A potent antibody response is key for recovery from hantavirus infection. Here we study a highly neutralizing human monoclonal antibody, termed SNV-42, which was derived from a memory B cell isolated from an individual with previous Sin Nombre virus (SNV) infection. Crystallographic analysis demonstrates that SNV-42 targets the Gn subcomponent of the tetrameric (Gn−Gc) 4 glycoprotein assembly that is relevant for viral entry. Integration of our 1.8 Å structure with the (Gn−Gc) 4 ultrastructure arrangement indicates that SNV-42 targets the membrane-distal region of the virus envelope. Comparison of the SNV-42 paratope encoding variable genes with inferred germline gene segments reveals high sequence conservation, suggesting that germline-encoded antibodies inhibit SNV. Furthermore, mechanistic assays reveal that SNV-42 interferes with both receptor recognition and fusion during host-cell entry. This work provides a molecular-level blueprint for understanding the human neutralizing antibody response to hantavirus infection.

الإتاحة: https://doi.org/10.1038/s41564-023-01413-yTest
https://www.nature.com/articles/s41564-023-01413-y.pdfTest
https://www.nature.com/articles/s41564-023-01413-yTest

المؤلفون: Jenkin, Daniel, Wright, Daniel, Folegatti, Pedro M, Platt, Abigail, Poulton, Ian, Lawrie, Alison, Tran, Nguyen, Boyd, Amy, Turner, Cheryl, Gitonga, John N, Karanja, Henry K, Mugo, Daisy, Ewer, Katie J, Bowden, Thomas A, Gilbert, Sarah C, Charleston, Bryan, Kaleebu, Pontiano, Hill, Adrian V S, Warimwe, George M

المساهمون: Wellcome Trust, United Kingdom Department of Health and Social Care

المصدر: The Lancet Infectious Diseases ; volume 23, issue 8, page 956-964 ; ISSN 1473-3099

مصطلحات موضوعية: Infectious Diseases

الإتاحة: https://doi.org/10.1016/s1473-3099Test(23)00068-3
https://api.elsevier.com/content/article/PII:S1473309923000683?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1473309923000683?httpAccept=text/plainTest

المؤلفون: Stelfox, Alice J., Oguntuyo, Kasopefoluwa Y., Rissanen, Ilona, Harlos, Karl, Rambo, Robert, Lee, Benhur, Bowden, Thomas A.

المساهمون: Reese, Michael L., UKRI | Medical Research Council, UKRI | Engineering and Physical Sciences Research Council, Academy of Finland, HHS | National Institutes of Health, Wellcome Trust

المصدر: mBio ; volume 14, issue 5 ; ISSN 2150-7511

الوصف: Increased viral surveillance has led to the isolation and identification of numerous uncharacterized paramyxoviruses, rapidly expanding our understanding of paramyxoviral diversity beyond the bounds of known genera. Despite this diversity, a key feature that unites paramyxoviruses is the presence of a receptor-binding protein (RBP), which facilitates host-cell attachment and plays a fundamental role in determining host range. Here, we study the RBP presented on the surface of rodent-borne paramyxoviruses Mossman and Nariva (MosV and NarV, respectively), viruses that constitute founding members of the recently defined Narmovirus genus within the Paramyxoviridae family. Crystallographic analysis of the C-terminal head region of the dimeric MosV and NarV RBPs demonstrates that while these glycoproteins retain the canonical six-bladed β-propeller fold found in other paramyxoviral RBPs, they lack the structural motifs associated with established paramyxovirus host-cell receptor entry pathways. Consistent with MosV-RBP and NarV-RBP undergoing a distinct entry pathway from other characterized paramyxoviruses, structure-based phylogenetic analysis demonstrates that these six-bladed β-propeller head domains form a singular structural class that is distinct from other paramyxoviral RBPs. Additionally, using an integrated crystallographic and small-angle X-ray scattering analysis, we confirm that MosV-RBP and NarV-RBP form homodimeric arrangements that are distinct from those adopted by other paramyxovirus RBPs. Altogether, this investigation provides a molecular-level blueprint of the narmovirus RBP that broadens our understanding of the structural space and functional diversity available to paramyxovirus RBPs. IMPORTANCE Genetically diverse paramyxoviruses are united in their presentation of a receptor-binding protein (RBP), which works in concert with the fusion protein to facilitate host-cell entry. The C-terminal head region of the paramyxoviral RBP, a primary determinant of host-cell tropism and ...

الإتاحة: https://doi.org/10.1128/mbio.01391-23Test

المؤلفون: Kingston, Natalie J., Grehan, Keith, Snowden, Joseph S., Hassall, Mark, Alzahrani, Jehad, Paesen, Guido C., Sherry, Lee, Hayward, Connor, Roe, Amy, Stephen, Sam, Tomlinson, Darren, Zeltina, Antra, Doores, Katie J., Ranson, Neil A., Stacey, Martin, Page, Mark, Rose, Nicola J., Bowden, Thomas A., Rowlands, David J., Stonehouse, Nicola J.

المساهمون: Pasetti, Marcela F., HHS | NIH | OSC | Common Fund, UKRI | Medical Research Council, Wellcome Trust

المصدر: mSphere ; volume 8, issue 1 ; ISSN 2379-5042

الوصف: The hepatitis B core protein (HBc) forms noninfectious virus-like particles, which can be modified to present a capturing molecule, allowing suitably tagged antigens to be bound on their surface. This system can be adapted and provides the foundation for a universal “bolt-on” vaccine platform (termed VelcroVax) that can be easily and rapidly modified to generate nanoparticle vaccine candidates.

الإتاحة: https://doi.org/10.1128/msphere.00568-22Test