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2. Potent and broad neutralization of SARS-CoV-2 variants of concern (VOCs) including omicron sub-lineages BA.1 and BA.2 by biparatopic human VH domains

Author

Chen, Chuan, Saville, James W., Marti, Michelle M., Schäfer, Alexandra, Cheng, Mary Hongying, Mannar, Dhiraj, Zhu, Xing, Berezuk, Alison M., Banerjee, Anupam, Sobolewski, Michele D., Kim, Andrew, Treat, Benjamin R., Da Silva Castanha, Priscila Mayrelle, Enick, Nathan, McCormick, Kevin D., Liu, Xianglei, Adams, Cynthia, Hines, Margaret Grace, Sun, Zehua, Chen, Weizao, Jacobs, Jana L., Barratt-Boyes, Simon M., Mellors, John W., Baric, Ralph S., Bahar, Ivet, Dimitrov, Dimiter S., Subramaniam, Sriram, Martinez, David R., and Li, Wei

Published
2022
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4. SARS-CoV-2 variants of concern: spike protein mutational analysis and epitope for broad neutralization

Author

Mannar, Dhiraj, Saville, James W., Sun, Zehua, Zhu, Xing, Marti, Michelle M., Srivastava, Shanti S., Berezuk, Alison M., Zhou, Steven, Tuttle, Katharine S., Sobolewski, Michele D., Kim, Andrew, Treat, Benjamin R., Da Silva Castanha, Priscila Mayrelle, Jacobs, Jana L., Barratt-Boyes, Simon M., Mellors, John W., Dimitrov, Dimiter S., Li, Wei, and Subramaniam, Sriram

Published
2022
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8. Therapeutic stem cell‐derived alveolar‐like macrophages display bactericidal effects and resolve Pseudomonas aeruginosa ‐induced lung injury

Author

Bouch, Sheena, primary, Litvack, Michael L., additional, Litman, Kymberly, additional, Luo, Lisha, additional, Post, Alex, additional, Williston, Emma, additional, Park, Amber J., additional, Roach, Elyse J., additional, Berezuk, Alison M., additional, Khursigara, Cezar M., additional, and Post, Martin, additional

Published
2022
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9. Potent Neutralization of Omicron and other SARS-CoV-2 Variants of Concern by Biparatopic Human VH Domains

Author

Chen, Chuan, primary, Martinez, David R, additional, Marti, Michelle M, additional, Schaefer, Alexandra, additional, Cheng, Mary Hongying, additional, Mannar, Dhiraj, additional, Zhu, Xing, additional, Berezuk, Alison M, additional, Banerjee, Anupam, additional, Sobolewski, Michele D, additional, Kim, Andrew, additional, Treat, Benjamin R, additional, Da Silva Castanha, Priscila Mayrelle, additional, Enick, Nathan, additional, McCormick, Kevin D, additional, Liu, Xianglei, additional, Adams, Cynthia, additional, Hines, Margaret Grace, additional, Sun, Zehua, additional, Chen, Weizao, additional, Jacobs, Jana L, additional, Barratt-Boyes, Simon M, additional, Mellors, John W., additional, Baric, Ralph S., additional, Bahar, Ivet, additional, Dimitrov, Dimiter S, additional, Subramaniam, Sriram, additional, Saville, James W, additional, and Li, Wei, additional

Published
2022
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11. The Pseudomonas aeruginosa homeostasis enzyme AlgL clears the periplasmic space of accumulated alginate during polymer biosynthesis

Author

Gheorghita, Andreea A., primary, Wolfram, Francis, additional, Whitfield, Gregory B., additional, Jacobs, Holly M., additional, Pfoh, Roland, additional, Wong, Steven S.Y., additional, Guitor, Allison K., additional, Goodyear, Mara C., additional, Berezuk, Alison M., additional, Khursigara, Cezar M., additional, Parsek, Matthew R., additional, and Howell, P. Lynne, additional

Published
2022
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13. Emerging SARS-CoV-2 Variants of Concern: Spike Protein Mutational Analysis and Epitope for Broad Neutralization

Author

Mannar, Dhiraj, primary, Saville, James W., additional, Sun, Zehua, additional, Zhu, Xing, additional, Marti, Michelle M., additional, Srivastava, Shanti S., additional, Berezuk, Alison M., additional, Zhou, Steven, additional, Tuttle, Katharine S., additional, Sobolewski, Michele D., additional, Kim, Andrew, additional, Treat, Benjamin R., additional, Da Silva Castanha, Priscila Mayrelle, additional, Jacobs, Jana L., additional, Barratt-Boyes, Simon M., additional, Mellors, John W., additional, Dimitrov, Dimiter S., additional, Li, Wei, additional, and Subramaniam, Sriram, additional

Published
2021
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14. Structural analysis of receptor binding domain mutations in SARS-CoV-2 variants of concern that modulate ACE2 and antibody binding

Author

Mannar, Dhiraj, primary, Saville, James W., additional, Zhu, Xing, additional, Srivastava, Shanti S., additional, Berezuk, Alison M., additional, Zhou, Steven, additional, Tuttle, Katharine S., additional, Kim, Andrew, additional, Li, Wei, additional, Dimitrov, Dimiter S., additional, and Subramaniam, Sriram, additional

Published
2021
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16. Structural and Biochemical Rationale for Enhanced Spike Protein Fitness in Delta and Kappa SARS-CoV-2 Variants

Author

Saville, James W., primary, Mannar, Dhiraj, additional, Zhu, Xing, additional, Srivastava, Shanti S., additional, Berezuk, Alison M., additional, Demers, Jean-Philippe, additional, Zhou, Steven, additional, Tuttle, Katharine S., additional, Sekirov, Inna, additional, Kim, Andrew, additional, Li, Wei, additional, Dimitrov, Dimiter S., additional, and Subramaniam, Sriram, additional

Published
2021
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18. Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies

Author

Zhu, Xing, primary, Mannar, Dhiraj, additional, Srivastava, Shanti S., additional, Berezuk, Alison M., additional, Demers, Jean-Philippe, additional, Saville, James W., additional, Leopold, Karoline, additional, Li, Wei, additional, Dimitrov, Dimiter S., additional, Tuttle, Katharine S., additional, Zhou, Steven, additional, Chittori, Sagar, additional, and Subramaniam, Sriram, additional

Published
2021
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19. High Potency of a Bivalent Human VH Domain in SARS-CoV-2 Animal Models

Author

Berezuk, Alison, Ura, Marcin L., Chen, Chuan, Zhang, Liyong, Liu, Xianglei, Baric, Ralph S., Dimitrov, Dimiter S., Schäfer, Alexandra, Subramaniam, Sriram, Martinez, David R., Li, Wei, Chittori, Sagar, Kulkarni, Swarali S., Leopold, Karoline, Drelich, Aleksandra, Sun, Zehua, Leist, Sarah R., and Falzarano, Darryl

Abstract

Novel COVID-19 therapeutics are urgently needed. We generated a phage-displayed human antibody VH domain library from which we identified a high-affinity VH binder ab8. Bivalent VH, VH-Fc ab8, bound with high avidity to membrane-associated S glycoprotein and to mutants found in patients. It potently neutralized mouse-adapted SARS-CoV-2 in wild-type mice at a dose as low as 2 mg/kg and exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection, possibly enhanced by its relatively small size. Electron microscopy combined with scanning mutagenesis identified ab8 interactions with all three S protomers and showed how ab8 neutralized the virus by directly interfering with ACE2 binding. VHFc ab8 did not aggregate and did not bind to 5,300 human membrane-associated proteins. The potent neutralization activity of VH-Fc ab8 combined with good developability properties and cross-reactivity to SARS-CoV-2 mutants provide a strong rationale for its evaluation as a COVID-19 therapeutic.

Published
2020
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20. Cryo-EM Structures of the N501Y SARS-CoV-2 Spike Protein in Complex with ACE2 and Two Potent Neutralizing Antibodies

Author

Zhu, Xing, primary, Mannar, Dhiraj, additional, Srivastava, Shanti S., additional, Berezuk, Alison M., additional, Demers, Jean-Philippe, additional, Saville, James W, additional, Leopold, Karoline, additional, Li, Wei, additional, Dimitrov, Dimiter S., additional, Tuttle, Katharine S., additional, Zhou, Steven, additional, Chittori, Sagar, additional, and Subramaniam, Sriram, additional

Published
2021
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21. High Potency of a Bivalent Human VH Domain in SARS-CoV-2 Animal Models

Author

Li, Wei, primary, Schäfer, Alexandra, additional, Kulkarni, Swarali S., additional, Liu, Xianglei, additional, Martinez, David R., additional, Chen, Chuan, additional, Sun, Zehua, additional, Leist, Sarah R., additional, Drelich, Aleksandra, additional, Zhang, Liyong, additional, Ura, Marcin L., additional, Berezuk, Alison, additional, Chittori, Sagar, additional, Leopold, Karoline, additional, Mannar, Dhiraj, additional, Srivastava, Shanti S., additional, Zhu, Xing, additional, Peterson, Eric C., additional, Tseng, Chien-Te, additional, Mellors, John W., additional, Falzarano, Darryl, additional, Subramaniam, Sriram, additional, Baric, Ralph S., additional, and Dimitrov, Dimiter S., additional

Published
2020
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24. Investigating the Role of Divisome Protein FtsK as an Essential Checkpoint During Bacterial Cell Division

Author

Berezuk, Alison and Khursigara, Cezar

Subjects
cell division, microbiology, Escherichia coli, microscopy, biochemistry, FtsK, protein interactions
Abstract

Bacterial cell division is an essential and fundamental process required to sustain life. In Escherichia coli, division requires the recruitment and assembly of approximately thirty soluble and membrane-bound proteins, ten of which are essential (FtsZ, FtsA, ZipA, FtsK, FtsQ/B/L, FtsW/I, FtsN). Complete assembly of this macromolecular complex relies on formation of a dynamic ring-like structure known as the Z-ring. Following initial formation and stabilization of the Z-ring, cells must complete segregation of the bacterial chromosome and remodel the cell envelope to allow septum formation. One key modulator linking early (Z-ring) and late (cell envelope remodeling) division complexes is the essential protein FtsK. FtsK is a bifunctional transmembrane protein that coordinates chromosome segregation with its C-terminus (FtsKC) and cell division with its membrane-anchored N-terminal domain (FtsKN). Although the structure and function of FtsKN during division is unclear, it is suggested that FtsK acts as a checkpoint to ensure DNA is properly segregated before septation can begin. In this capacity, we hypothesize that FtsK must modulate septum formation during division through the formation of dynamic and essential protein interactions with both the Z-ring and late stage division machinery. Drawing on advanced molecular techniques and imaging technologies, this thesis refines the membrane topology of FtsKN using site-directed fluorescence labeling, and elucidates several protein interaction partners that are critical for its role as an essential division checkpoint. Our revised topology revealed a novel functional periplasmic loop of FtsKN that, when mutated, produces cellular voids. We extensively characterized this novel cell division defect by fluorescence microscopy and high-resolution transmission electron microscopy, which exposed a novel role for FtsKN in linking cell envelope septation events. In addition, UV cross-linking and a genomic suppressor screen each uncovered potential interaction partners of FtsKN involved in both cell elongation and division. Two of these proteins, rare lipoprotein A (RlpA) and FtsA, were confirmed as direct FtsKN protein interactors by in vitro pull-down assays. Together, these findings provide critical evidence on how FtsKN may mediate the transition between cell elongation and septation in E. coli, and significantly advances our understanding of what is necessary for bacteria to replicate and survive. Natural Sciences and Engineering Research Council of Canada (NSERC), Cystic Fibrosis Canada, Government of Ontario

Published
2018

32. Bypassing the Need for the Transcriptional Activator EarA through a Spontaneous Deletion in the BRE Portion of the fla Operon Promoter in Methanococcus maripaludis.

Author

Yan Ding, Berezuk, Alison, Khursigara, Cezar M., and Jarrell, Ken F.

Subjects
METHANOCOCCUS maripaludis, PROMOTERS (Genetics), GENETIC transcription
Abstract

In Methanococcus maripaludis, the euryarchaeal archaellum regulator A (EarA) is required for the transcription of the fla operon, which is comprised of a series of genes which encode most of the proteins needed for the formation of the archaeal swimming organelle, the archaellum. In mutants deleted for earA (1earA), there is almost undetectable transcription of the fla operon, Fla proteins are not synthesized and the cells are non-archaellated. In this study, we have isolated a spontaneous mutant of a 1earA mutant in which the restoration of the transcription and translation of the fla operon (using flaB2, the second gene of the operon, as a reporter), archaella formation and swarming motility were all restored even in the absence of EarA. Analysis of the DNA sequence from the fla promoter of this spontaneous mutant revealed a deletion of three adenines within a string of seven adenines in the transcription factor B recognition element (BRE). When the three adenine deletion in the BRE was regenerated in a stock culture of the 1earA mutant, very similar phenotypes to that of the spontaneous mutant were observed. Deletion of the three adenines in the fla promoter BRE resulted in the mutant BRE having high sequence identity to BREs from promoters that have strong basal transcription level in Mc. maripaludis and Methanocaldococcus jannaschii. These data suggest that EarA may help recruit transcription factor B to a weak BRE in the fla promoter of wild-type cells but is not required for transcription from the fla promoter with a strong BRE, as in the three adenine deletion version in the spontaneous mutant. [ABSTRACT FROM AUTHOR]

Published
2017
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35. Potent Neutralization of Omicron and other SARS-CoV-2 Variants of Concern by Biparatopic Human VH Domains.

Author

Chen C, Saville JW, Marti MM, Schäfer A, Cheng MH, Mannar D, Zhu X, Berezuk AM, Banerjee A, Sobolewski MD, Kim A, Treat BR, Da Silva Castanha PM, Enick N, McCormick KD, Liu X, Adams C, Hines MG, Sun Z, Chen W, Jacobs JL, Barratt-Boyes SM, Mellors JW, Baric RS, Bahar I, Dimitrov DS, Subramaniam S, Martinez DR, and Li W

Abstract

The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics that are effective against a variety of strains of the virus. Herein, we characterize a human V H domain, F6, which we generated by sequentially panning large phage displayed V H libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized V H domain, resulted in a construct (F6-ab8-Fc) that neutralized Omicron pseudoviruses with a half-maximal neutralizing concentration (IC 50 ) of 4.8 nM in vitro . Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 VOCs - including the recently emerged Omicron variant - and highlight a vulnerable epitope within the spike protein RBD that may be exploited to achieve broad protection against circulating variants.

Published
2022
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36. High Potency of a Bivalent Human V H Domain in SARS-CoV-2 Animal Models.

Author

Li W, Schäfer A, Kulkarni SS, Liu X, Martinez DR, Chen C, Sun Z, Leist SR, Drelich A, Zhang L, Ura ML, Berezuk A, Chittori S, Leopold K, Mannar D, Srivastava SS, Zhu X, Peterson EC, Tseng CT, Mellors JW, Falzarano D, Subramaniam S, Baric RS, and Dimitrov DS

Subjects
Angiotensin-Converting Enzyme 2, Animals, Antibodies, Neutralizing immunology, Antibodies, Neutralizing ultrastructure, Antibodies, Viral administration & dosage, Antibodies, Viral chemistry, Antibodies, Viral immunology, Antibodies, Viral ultrastructure, Antibody Affinity, COVID-19, Cricetinae, Female, Humans, Immunoglobulin Fc Fragments immunology, Immunoglobulin Heavy Chains chemistry, Immunoglobulin Heavy Chains immunology, Immunoglobulin Heavy Chains ultrastructure, Immunoglobulin Variable Region chemistry, Immunoglobulin Variable Region immunology, Immunoglobulin Variable Region ultrastructure, Mice, Mice, Inbred BALB C, Mutation, Pandemics, Peptidyl-Dipeptidase A metabolism, Protein Domains, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus metabolism, Spike Glycoprotein, Coronavirus ultrastructure, COVID-19 Drug Treatment, Coronavirus Infections drug therapy, Immunoglobulin Heavy Chains administration & dosage, Immunoglobulin Variable Region administration & dosage, Peptide Library, Pneumonia, Viral drug therapy
Abstract

Novel COVID-19 therapeutics are urgently needed. We generated a phage-displayed human antibody V H domain library from which we identified a high-affinity V H binder ab8. Bivalent V H , V H -Fc ab8, bound with high avidity to membrane-associated S glycoprotein and to mutants found in patients. It potently neutralized mouse-adapted SARS-CoV-2 in wild-type mice at a dose as low as 2 mg/kg and exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection, possibly enhanced by its relatively small size. Electron microscopy combined with scanning mutagenesis identified ab8 interactions with all three S protomers and showed how ab8 neutralized the virus by directly interfering with ACE2 binding. V H -Fc ab8 did not aggregate and did not bind to 5,300 human membrane-associated proteins. The potent neutralization activity of V H -Fc ab8 combined with good developability properties and cross-reactivity to SARS-CoV-2 mutants provide a strong rationale for its evaluation as a COVID-19 therapeutic., Competing Interests: Declaration of Interests W.L., C.C., Z.S., J.W.M., and D.S.D. are co-inventors of a patent, filed on March 12 by the University of Pittsburgh, related to ab8 described in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Published
2020
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37. Phylogenetic distribution of the euryarchaeal archaellum regulator EarA and complementation of a Methanococcus maripaludis ∆earA mutant with heterologous earA homologues.

Author

Ding Y, Berezuk A, Khursigara CM, and Jarrell KF

Abstract

Archaella are the swimming organelles in the Archaea. Recently, the first archaellum regulator in the Euryarchaeota, EarA Mma , was identified in Methanococcus maripaludis , one of the model organisms used for archaellum studies. EarA Mma binds to 6 bp consensus sequences upstream of the fla promoter to activate the transcription of the fla operon, which encodes most of the proteins required for archaella synthesis. In this study, synteny analysis showed that earA homologues are widely distributed in the phylum of Euryarchaeota, with the notable exception of extreme halophiles. We classified Euryarchaeota species containing earA homologues into five classes based on the genomic location of the earA genes relative to fla and chemotaxis operons. EarA homologues from Methanococcus vannielii , Methanothermococcus thermolithotrophicus and Methanocaldococcus jannaschii successfully complemented the function of EarA Mma in a ΔearAMma mutant, demonstrated by the restoration of FlaB2 expression in Western blot analysis and the appearance of archaella on the cell surface in complemented cells. Furthermore, the 6 bp consensus sequence was also found in the fla promoter region in these methanogens, indicating that the EarA homologues ly use a similar mechanism to activate transcription of the fla operons in their own hosts. Attempts to demonstrate complementation of the function of EarA Mma in a ΔearAMma mutant by the EarA homologue of Pyrococcus furiosus were unsuccessful, despite the presence of a copy of the 6 bp consensus EarA-binding sequence upstream of the fla promoter in the P. furiosus genome.

Published
2017
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