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2. Computationally restoring the potency of a clinical antibody against Omicron

Author

Desautels, Thomas A., Arrildt, Kathryn T., Zemla, Adam T., Lau, Edmond Y., Zhu, Fangqiang, Ricci, Dante, Cronin, Stephanie, Zost, Seth J., Binshtein, Elad, Scheaffer, Suzanne M., Dadonaite, Bernadeta, Petersen, Brenden K., Engdahl, Taylor B., Chen, Elaine, Handal, Laura S., Hall, Lynn, Goforth, John W., Vashchenko, Denis, Nguyen, Sam, Weilhammer, Dina R., Lo, Jacky Kai-Yin, Rubinfeld, Bonnee, Saada, Edwin A., Weisenberger, Tracy, Lee, Tek-Hyung, Whitener, Bradley, Case, James B., Ladd, Alexander, Silva, Mary S., Haluska, Rebecca M., Grzesiak, Emilia A., Earnhart, Christopher G., Hopkins, Svetlana, Bates, Thomas W., Thackray, Larissa B., Segelke, Brent W., Lillo, Antonietta Maria, Sundaram, Shivshankar, Bloom, Jesse D., Diamond, Michael S., Crowe, Jr, James E., Carnahan, Robert H., and Faissol, Daniel M.

Published
2024
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3. Dynamics and durability of HIV-1 neutralization are determined by viral replication

Author

Schommers, Philipp, Kim, Dae Sung, Schlotz, Maike, Kreer, Christoph, Eggeling, Ralf, Hake, Anna, Stecher, Melanie, Park, Juyeon, Radford, Caelan E., Dingens, Adam S., Ercanoglu, Meryem S., Gruell, Henning, Odidika, Stanley, Dahlhaus, Marten, Gieselmann, Lutz, Ahmadov, Elvin, Lawong, Rene Y., Heger, Eva, Knops, Elena, Wyen, Christoph, Kümmerle, Tim, Römer, Katja, Scholten, Stefan, Wolf, Timo, Stephan, Christoph, Suárez, Isabelle, Raju, Nagarajan, Adhikari, Anurag, Esser, Stefan, Streeck, Hendrik, Duerr, Ralf, Nanfack, Aubin J., Zolla-Pazner, Susan, Geldmacher, Christof, Geisenberger, Otto, Kroidl, Arne, William, Wiston, Maganga, Lucas, Ntinginya, Nyanda Elias, Georgiev, Ivelin S., Vehreschild, Jörg J., Hoelscher, Michael, Fätkenheuer, Gerd, Lavinder, Jason J., Bloom, Jesse D., Seaman, Michael S., Lehmann, Clara, Pfeifer, Nico, Georgiou, George, and Klein, Florian

Published
2023
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5. Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination

Author

Voss, William N., Mallory, Michael L., Byrne, Patrick O., Marchioni, Jeffrey M., Knudson, Sean A., Powers, John M., Leist, Sarah R., Dadonaite, Bernadeta, Townsend, Douglas R., Kain, Jessica, Huang, Yimin, Satterwhite, Ed, Castillo, Izabella N., Mattocks, Melissa, Paresi, Chelsea, Munt, Jennifer E., Scobey, Trevor, Seeger, Allison, Premkumar, Lakshmanane, Bloom, Jesse D., Georgiou, George, McLellan, Jason S., Baric, Ralph S., Lavinder, Jason J., and Ippolito, Gregory C.

Published
2024
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6. Age-dependent heterogeneity in the antigenic effects of mutations to influenza hemagglutinin

Author

Welsh, Frances C., Eguia, Rachel T., Lee, Juhye M., Haddox, Hugh K., Galloway, Jared, Van Vinh Chau, Nguyen, Loes, Andrea N., Huddleston, John, Yu, Timothy C., Quynh Le, Mai, Nhat, Nguyen T.D., Thi Le Thanh, Nguyen, Greninger, Alexander L., Chu, Helen Y., Englund, Janet A., Bedford, Trevor, Matsen, Frederick A., IV, Boni, Maciej F., and Bloom, Jesse D.

Published
2024
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8. Defining the risk of SARS-CoV-2 variants on immune protection

Author

DeGrace, Marciela M, Ghedin, Elodie, Frieman, Matthew B, Krammer, Florian, Grifoni, Alba, Alisoltani, Arghavan, Alter, Galit, Amara, Rama R, Baric, Ralph S, Barouch, Dan H, Bloom, Jesse D, Bloyet, Louis-Marie, Bonenfant, Gaston, Boon, Adrianus CM, Boritz, Eli A, Bratt, Debbie L, Bricker, Traci L, Brown, Liliana, Buchser, William J, Carreño, Juan Manuel, Cohen-Lavi, Liel, Darling, Tamarand L, Davis-Gardner, Meredith E, Dearlove, Bethany L, Di, Han, Dittmann, Meike, Doria-Rose, Nicole A, Douek, Daniel C, Drosten, Christian, Edara, Venkata-Viswanadh, Ellebedy, Ali, Fabrizio, Thomas P, Ferrari, Guido, Fischer, Will M, Florence, William C, Fouchier, Ron AM, Franks, John, García-Sastre, Adolfo, Godzik, Adam, Gonzalez-Reiche, Ana Silvia, Gordon, Aubree, Haagmans, Bart L, Halfmann, Peter J, Ho, David D, Holbrook, Michael R, Huang, Yaoxing, James, Sarah L, Jaroszewski, Lukasz, Jeevan, Trushar, Johnson, Robert M, Jones, Terry C, Joshi, Astha, Kawaoka, Yoshihiro, Kercher, Lisa, Koopmans, Marion PG, Korber, Bette, Koren, Eilay, Koup, Richard A, LeGresley, Eric B, Lemieux, Jacob E, Liebeskind, Mariel J, Liu, Zhuoming, Livingston, Brandi, Logue, James P, Luo, Yang, McDermott, Adrian B, McElrath, Margaret J, Meliopoulos, Victoria A, Menachery, Vineet D, Montefiori, David C, Mühlemann, Barbara, Munster, Vincent J, Munt, Jenny E, Nair, Manoj S, Netzl, Antonia, Niewiadomska, Anna M, O’Dell, Sijy, Pekosz, Andrew, Perlman, Stanley, Pontelli, Marjorie C, Rockx, Barry, Rolland, Morgane, Rothlauf, Paul W, Sacharen, Sinai, Scheuermann, Richard H, Schmidt, Stephen D, Schotsaert, Michael, Schultz-Cherry, Stacey, Seder, Robert A, Sedova, Mayya, Sette, Alessandro, Shabman, Reed S, Shen, Xiaoying, Shi, Pei-Yong, Shukla, Maulik, Simon, Viviana, Stumpf, Spencer, Sullivan, Nancy J, Thackray, Larissa B, and Theiler, James

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Emerging Infectious Diseases, Pneumonia, Vaccine Related, Pneumonia & Influenza, Infectious Diseases, Biodefense, Immunization, Biotechnology, Prevention, Lung, Prevention of disease and conditions, and promotion of well-being, 2.1 Biological and endogenous factors, 3.4 Vaccines, Aetiology, Infection, Good Health and Well Being, Animals, Biological Evolution, COVID-19, COVID-19 Vaccines, Humans, National Institute of Allergy and Infectious Diseases (U.S.), Pandemics, Pharmacogenomic Variants, SARS-CoV-2, United States, Virulence, General Science & Technology
Abstract

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced after infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases within the National Institutes of Health established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants that could potentially affect the transmission, virulence, and resistance to infection- and vaccine-induced immunity. The SAVE programme is a critical data-generating component of the US Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines and therapeutics, and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models and notable findings facilitated by this collaborative approach and identify future challenges. This programme is a template for the response to rapidly evolving pathogens with pandemic potential by monitoring viral evolution in the human population to identify variants that could reduce the effectiveness of countermeasures.

Published
2022

9. Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice

Author

Hunt, Andrew C, Case, James Brett, Park, Young-Jun, Cao, Longxing, Wu, Kejia, Walls, Alexandra C, Liu, Zhuoming, Bowen, John E, Yeh, Hsien-Wei, Saini, Shally, Helms, Louisa, Zhao, Yan Ting, Hsiang, Tien-Ying, Starr, Tyler N, Goreshnik, Inna, Kozodoy, Lisa, Carter, Lauren, Ravichandran, Rashmi, Green, Lydia B, Matochko, Wadim L, Thomson, Christy A, Vögeli, Bastian, Krüger, Antje, VanBlargan, Laura A, Chen, Rita E, Ying, Baoling, Bailey, Adam L, Kafai, Natasha M, Boyken, Scott E, Ljubetič, Ajasja, Edman, Natasha, Ueda, George, Chow, Cameron M, Johnson, Max, Addetia, Amin, Navarro, Mary Jane, Panpradist, Nuttada, Gale, Michael, Freedman, Benjamin S, Bloom, Jesse D, Ruohola-Baker, Hannele, Whelan, Sean PJ, Stewart, Lance, Diamond, Michael S, Veesler, David, Jewett, Michael C, and Baker, David

Subjects
Medical Biotechnology, Engineering, Biomedical and Clinical Sciences, Biomedical Engineering, Vaccine Related, Lung, Emerging Infectious Diseases, Biodefense, Pneumonia, Autoimmune Disease, Infectious Diseases, Pneumonia & Influenza, Prevention, Biotechnology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Animals, Antibodies, Neutralizing, Antibodies, Viral, COVID-19, Cryoelectron Microscopy, Humans, Mice, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression workflow to rapidly screen and optimize constructs containing multiple computationally designed miniprotein inhibitors of SARS-CoV-2. We found the broadest efficacy was achieved with a homotrimeric version of the 75-residue angiotensin-converting enzyme 2 (ACE2) mimic AHB2 (TRI2-2) designed to geometrically match the trimeric spike architecture. Consistent with the design model, in the cryo-electron microscopy structure TRI2-2 forms a tripod at the apex of the spike protein that engaged all three receptor binding domains simultaneously. TRI2-2 neutralized Omicron (B.1.1.529), Delta (B.1.617.2), and all other variants tested with greater potency than the monoclonal antibodies used clinically for the treatment of COVID-19. TRI2-2 also conferred prophylactic and therapeutic protection against SARS-CoV-2 challenge when administered intranasally in mice. Designed miniprotein receptor mimics geometrically arrayed to match pathogen receptor binding sites could be a widely applicable antiviral therapeutic strategy with advantages over antibodies in greater resistance to viral escape and antigenic drift, and advantages over native receptor traps in lower chances of autoimmune responses.

Published
2022

11. SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape

Author

Starr, Tyler N, Czudnochowski, Nadine, Liu, Zhuoming, Zatta, Fabrizia, Park, Young-Jun, Addetia, Amin, Pinto, Dora, Beltramello, Martina, Hernandez, Patrick, Greaney, Allison J, Marzi, Roberta, Glass, William G, Zhang, Ivy, Dingens, Adam S, Bowen, John E, Tortorici, M Alejandra, Walls, Alexandra C, Wojcechowskyj, Jason A, De Marco, Anna, Rosen, Laura E, Zhou, Jiayi, Montiel-Ruiz, Martin, Kaiser, Hannah, Dillen, Josh R, Tucker, Heather, Bassi, Jessica, Silacci-Fregni, Chiara, Housley, Michael P, di Iulio, Julia, Lombardo, Gloria, Agostini, Maria, Sprugasci, Nicole, Culap, Katja, Jaconi, Stefano, Meury, Marcel, Dellota Jr, Exequiel, Abdelnabi, Rana, Foo, Shi-Yan Caroline, Cameroni, Elisabetta, Stumpf, Spencer, Croll, Tristan I, Nix, Jay C, Havenar-Daughton, Colin, Piccoli, Luca, Benigni, Fabio, Neyts, Johan, Telenti, Amalio, Lempp, Florian A, Pizzuto, Matteo S, Chodera, John D, Hebner, Christy M, Virgin, Herbert W, Whelan, Sean PJ, Veesler, David, Corti, Davide, Bloom, Jesse D, and Snell, Gyorgy

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Vaccine Related, Lung, Prevention, Biodefense, Pneumonia & Influenza, Emerging Infectious Diseases, Immunization, Pneumonia, Biotechnology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Adult, Aged, Animals, Antibodies, Monoclonal, Antibodies, Viral, Antibody Affinity, Broadly Neutralizing Antibodies, COVID-19, COVID-19 Vaccines, Cell Line, Cricetinae, Cross Reactions, Epitopes, B-Lymphocyte, Female, Humans, Immune Evasion, Male, Mesocricetus, Middle Aged, Models, Molecular, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Vaccinology, COVID-19 Drug Treatment, General Science & Technology
Abstract

An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape1-3, have activity against diverse sarbecoviruses4-7, and be highly protective through viral neutralization8-11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.

Published
2021

13. Investigate the origins of COVID-19

Author

Bloom, Jesse D, Chan, Yujia Alina, Baric, Ralph S, Bjorkman, Pamela J, Cobey, Sarah, Deverman, Benjamin E, Fisman, David N, Gupta, Ravindra, Iwasaki, Akiko, Lipsitch, Marc, Medzhitov, Ruslan, Neher, Richard A, Nielsen, Rasmus, Patterson, Nick, Stearns, Tim, van Nimwegen, Erik, Worobey, Michael, and Relman, David A

Subjects
Animals, Biohazard Release, COVID-19, China, Humans, Pandemics, SARS-CoV-2, Viral Zoonoses, World Health Organization, General Science & Technology
Published
2021

14. Antibodies targeting a quaternary site on SARS-CoV-2 spike glycoprotein prevent viral receptor engagement by conformational locking

Author

Liu, Lihong, Casner, Ryan G., Guo, Yicheng, Wang, Qian, Iketani, Sho, Chan, Jasper Fuk-Woo., Yu, Jian, Dadonaite, Bernadeta, Nair, Manoj S., Mohri, Hiroshi, Reddem, Eswar R., Yuan, Shuofeng, Poon, Vincent Kwok-Man, Chan, Chris Chung-Sing, Yuen, Kwok-Yung, Sheng, Zizhang, Huang, Yaoxing, Bloom, Jesse D., Shapiro, Lawrence, and Ho, David D.

Published
2023
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15. When Two are Better than One: Modeling the Mechanisms of Antibody Mixtures

Author

Einav, Tal and Bloom, Jesse D

Subjects
Quantitative Biology - Cell Behavior, Physics - Biological Physics
Abstract

It is difficult to predict how antibodies will behave when mixed together, even after each has been independently characterized. Here, we present a statistical mechanical model for the activity of antibody mixtures that accounts for whether pairs of antibodies bind to distinct or overlapping epitopes. This model requires measuring $n$ individual antibodies and their $n(n-1)/2$ pairwise interactions to predict the $2^n$ potential combinations. We apply this model to epidermal growth factor receptor (EGFR) antibodies and find that the activity of antibody mixtures can be predicted without positing synergy at the molecular level. In addition, we demonstrate how the model can be used in reverse, where straightforward experiments measuring the activity of antibody mixtures can be used to infer the molecular interactions between antibodies. Lastly, we generalize this model to analyze engineered multidomain antibodies, where components of different antibodies are tethered together to form novel amalgams, and characterize how well it predicts recently designed influenza antibodies.

Published
2019
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17. Deep mutational scanning of H5 hemagglutinin to inform influenza virus surveillance

Author

Dadonaite, Bernadeta, primary, Ahn, Jenny J, additional, Ort, Jordan T, additional, Yu, Jin, additional, Furey, Colleen, additional, Dosey, Annie, additional, Hannon, William W, additional, Baker, Amy Vincent, additional, Webby, Richard J, additional, King, Neil P, additional, Liu, Yan, additional, Hensley, Scott E, additional, Peacock, Thomas P, additional, Moncla, Louise H, additional, and Bloom, Jesse D, additional

Published
2024
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18. Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern

Author

Rubio, Adonis A., primary, Baharani, Viren A., additional, Dadonaite, Bernadeta, additional, Parada, Megan, additional, Abernathy, Morgan E., additional, Wang, Zijun, additional, Lee, Yu E., additional, Eso, Michael, additional, Phung, Jennie, additional, Ramos, Israel, additional, Chen, Teresia, additional, El Nesr, Gina, additional, Bloom, Jesse D, additional, Bieniasz, Paul D, additional, Nussenzweig, Michel C., additional, and Barnes, Christopher O, additional

Published
2024
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20. Broadly neutralizing antibodies target a haemagglutinin anchor epitope

Author

Guthmiller, Jenna J., Han, Julianna, Utset, Henry A., Li, Lei, Lan, Linda Yu-Ling, Henry, Carole, Stamper, Christopher T., McMahon, Meagan, O’Dell, George, Fernández-Quintero, Monica L., Freyn, Alec W., Amanat, Fatima, Stovicek, Olivia, Gentles, Lauren, Richey, Sara T., de la Peña, Alba Torrents, Rosado, Victoria, Dugan, Haley L., Zheng, Nai-Ying, Tepora, Micah E., Bitar, Dalia J., Changrob, Siriruk, Strohmeier, Shirin, Huang, Min, García-Sastre, Adolfo, Liedl, Klaus R., Bloom, Jesse D., Nachbagauer, Raffael, Palese, Peter, Krammer, Florian, Coughlan, Lynda, Ward, Andrew B., and Wilson, Patrick C.

Published
2022
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23. Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail

Author

Dong, Jinhui, Zost, Seth J., Greaney, Allison J., Starr, Tyler N., Dingens, Adam S., Chen, Elaine C., Chen, Rita E., Case, James Brett, Sutton, Rachel E., Gilchuk, Pavlo, Rodriguez, Jessica, Armstrong, Erica, Gainza, Christopher, Nargi, Rachel S., Binshtein, Elad, Xie, Xuping, Zhang, Xianwen, Shi, Pei-Yong, Logue, James, Weston, Stuart, McGrath, Marisa E., Frieman, Matthew B., Brady, Tyler, Tuffy, Kevin M., Bright, Helen, Loo, Yueh-Ming, McTamney, Patrick M., Esser, Mark T., Carnahan, Robert H., Diamond, Michael S., Bloom, Jesse D., and Crowe, Jr, James E.

Published
2021
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24. Broad sarbecovirus neutralization by a human monoclonal antibody

Author

Tortorici, M. Alejandra, Czudnochowski, Nadine, Starr, Tyler N., Marzi, Roberta, Walls, Alexandra C., Zatta, Fabrizia, Bowen, John E., Jaconi, Stefano, Di Iulio, Julia, Wang, Zhaoqian, De Marco, Anna, Zepeda, Samantha K., Pinto, Dora, Liu, Zhuoming, Beltramello, Martina, Bartha, Istvan, Housley, Michael P., Lempp, Florian A., Rosen, Laura E., Dellota, Jr, Exequiel, Kaiser, Hannah, Montiel-Ruiz, Martin, Zhou, Jiayi, Addetia, Amin, Guarino, Barbara, Culap, Katja, Sprugasci, Nicole, Saliba, Christian, Vetti, Eneida, Giacchetto-Sasselli, Isabella, Fregni, Chiara Silacci, Abdelnabi, Rana, Foo, Shi-Yan Caroline, Havenar-Daughton, Colin, Schmid, Michael A., Benigni, Fabio, Cameroni, Elisabetta, Neyts, Johan, Telenti, Amalio, Virgin, Herbert W., Whelan, Sean P. J., Snell, Gyorgy, Bloom, Jesse D., Corti, Davide, Veesler, David, and Pizzuto, Matteo Samuele

Published
2021
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27. Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination

Author

Voss, William N, primary, Mallory, Michael A., additional, Byrne, Patrick O., additional, Marchioni, Jeffrey M., additional, Knudson, Sean A., additional, Powers, John M., additional, Leist, Sarah R., additional, Dadonaite, Bernadeta, additional, Townsend, Douglas R., additional, Kain, Jessica, additional, Huang, Yimin, additional, Satterwhite, Ed, additional, Castillo, Izabella N., additional, Mattocks, Melissa, additional, Paresi, Chelsea, additional, Munt, Jennifer E., additional, Scobey, Trevor, additional, Seeger, Allison, additional, Premkumar, Lakshmanane, additional, Bloom, Jesse D., additional, Georgiou, George, additional, McLellan, Jason S., additional, Baric, Ralph S., additional, Lavinder, Jason J., additional, and Ippolito, Gregory C., additional

Published
2024
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28. Age-dependent heterogeneity in the antigenic effects of mutations to influenza hemagglutinin

Author

Welsh, Frances C., primary, Eguia, Rachel T., additional, Lee, Juhye M., additional, Haddox, Hugh K., additional, Galloway, Jared, additional, Chau, Nguyen Van Vinh, additional, Loes, Andrea N., additional, Huddleston, John, additional, Yu, Timothy C., additional, Le, Mai Quynh, additional, Nhat, Nguyen T.D., additional, Thanh, Nguyen Thi Le, additional, Greninger, Alexander L., additional, Chu, Helen Y., additional, Englund, Janet A., additional, Bedford, Trevor, additional, Matsen, Frederick A., additional, Boni, Maciej F., additional, and Bloom, Jesse D., additional

Published
2023
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33. Positive Selection in CD8+ T-Cell Epitopes of Influenza Virus Nucleoprotein Revealed by a Comparative Analysis of Human and Swine Viral Lineages

Author

Machkovech, Heather M, Bedford, Trevor, Suchard, Marc A, and Bloom, Jesse D

Subjects
Emerging Infectious Diseases, Vaccine Related, Influenza, Infectious Diseases, Biodefense, Prevention, Pneumonia & Influenza, 2.2 Factors relating to the physical environment, Aetiology, Infection, Animals, CD8-Positive T-Lymphocytes, Epitopes, T-Lymphocyte, Humans, Influenza A Virus, H1N1 Subtype, Influenza A Virus, H1N2 Subtype, Influenza A Virus, H3N2 Subtype, Influenza, Human, Nucleocapsid Proteins, Orthomyxoviridae Infections, RNA-Binding Proteins, Selection, Genetic, Swine, Viral Core Proteins, Viral Matrix Proteins, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Virology
Abstract

UnlabelledNumerous experimental studies have demonstrated that CD8(+) T cells contribute to immunity against influenza by limiting viral replication. It is therefore surprising that rigorous statistical tests have failed to find evidence of positive selection in the epitopes targeted by CD8(+) T cells. Here we use a novel computational approach to test for selection in CD8(+) T-cell epitopes. We define all epitopes in the nucleoprotein (NP) and matrix protein (M1) with experimentally identified human CD8(+) T-cell responses and then compare the evolution of these epitopes in parallel lineages of human and swine influenza viruses that have been diverging since roughly 1918. We find a significant enrichment of substitutions that alter human CD8(+) T-cell epitopes in NP of human versus swine influenza virus, consistent with the idea that these epitopes are under positive selection. Furthermore, we show that epitope-altering substitutions in human influenza virus NP are enriched on the trunk versus the branches of the phylogenetic tree, indicating that viruses that acquire these mutations have a selective advantage. However, even in human influenza virus NP, sites in T-cell epitopes evolve more slowly than do nonepitope sites, presumably because these epitopes are under stronger inherent functional constraint. Overall, our work demonstrates that there is clear selection from CD8(+) T cells in human influenza virus NP and illustrates how comparative analyses of viral lineages from different hosts can identify positive selection that is otherwise obscured by strong functional constraint.ImportanceThere is a strong interest in correlates of anti-influenza immunity that are protective against diverse virus strains. CD8(+) T cells provide such broad immunity, since they target conserved viral proteins. An important question is whether T-cell immunity is sufficiently strong to drive influenza virus evolution. Although many studies have shown that T cells limit viral replication in animal models and are associated with decreased symptoms in humans, no studies have proven with statistical significance that influenza virus evolves under positive selection to escape T cells. Here we use comparisons of human and swine influenza viruses to rigorously demonstrate that human influenza virus evolves under pressure to fix mutations in the nucleoprotein that promote escape from T cells. We further show that viruses with these mutations have a selective advantage since they are preferentially located on the "trunk" of the phylogenetic tree. Overall, our results show that CD8(+) T cells targeting nucleoprotein play an important role in shaping influenza virus evolution.

Published
2015

34. Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies

Author

Greaney, Allison J., Starr, Tyler N., Barnes, Christopher O., Weisblum, Yiska, Schmidt, Fabian, Caskey, Marina, Gaebler, Christian, Cho, Alice, Agudelo, Marianna, Finkin, Shlomo, Wang, Zijun, Poston, Daniel, Muecksch, Frauke, Hatziioannou, Theodora, Bieniasz, Paul D., Robbiani, Davide F., Nussenzweig, Michel C., Bjorkman, Pamela J., and Bloom, Jesse D.

Published
2021
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35. Improving pandemic influenza risk assessment.

Author

Russell, Colin A, Kasson, Peter M, Donis, Ruben O, Riley, Steven, Dunbar, John, Rambaut, Andrew, Asher, Jason, Burke, Stephen, Davis, C Todd, Garten, Rebecca J, Gnanakaran, Sandrasegaram, Hay, Simon I, Herfst, Sander, Lewis, Nicola S, Lloyd-Smith, James O, Macken, Catherine A, Maurer-Stroh, Sebastian, Neuhaus, Elizabeth, Parrish, Colin R, Pepin, Kim M, Shepard, Samuel S, Smith, David L, Suarez, David L, Trock, Susan C, Widdowson, Marc-Alain, George, Dylan B, Lipsitch, Marc, and Bloom, Jesse D

Subjects
Humans, Influenza A virus, Risk Assessment, Public Health, Base Sequence, Geography, Models, Biological, Influenza, Human, Biological Evolution, Pandemics, Epidemiological Monitoring, emergence, evolutionary biology, genomics, human, infectious disease, influenza, microbiology, pandemic, viruses, Models, Biological, Influenza, Human, Biochemistry and Cell Biology
Abstract

Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response.

Published
2014

39. Neutral genetic drift can aid functional protein evolution

Author

Bloom, Jesse D, Romero, Philip A, Lu, Zhongyi, and Arnold, Frances H

Subjects
Quantitative Biology - Populations and Evolution, Quantitative Biology - Biomolecules
Abstract

BACKGROUND: Many of the mutations accumulated by naturally evolving proteins are neutral in the sense that they do not significantly alter a protein's ability to perform its primary biological function. However, new protein functions evolve when selection begins to favor other, "promiscuous" functions that are incidental to a protein's biological role. If mutations that are neutral with respect to a protein's primary biological function cause substantial changes in promiscuous functions, these mutations could enable future functional evolution. RESULTS: Here we investigate this possibility experimentally by examining how cytochrome P450 enzymes that have evolved neutrally with respect to activity on a single substrate have changed in their abilities to catalyze reactions on five other substrates. We find that the enzymes have sometimes changed as much as four-fold in the promiscuous activities. The changes in promiscuous activities tend to increase with the number of mutations, and can be largely rationalized in terms of the chemical structures of the substrates. The activities on chemically similar substrates tend to change in a coordinated fashion, potentially providing a route for systematically predicting the change in one function based on the measurement of several others. CONCLUSIONS: Our work suggests that initially neutral genetic drift can lead to substantial changes in protein functions that are not currently under selection, in effect poising the proteins to more readily undergo functional evolution should selection "ask new questions" in the future.

Published
2007
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40. Evolution favors protein mutational robustness in sufficiently large populations

Author

Bloom, Jesse D., Lu, Zhongyi, Chen, David, Raval, Alpan, Venturelli, Ophelia S., and Arnold, Frances H.

Subjects
Quantitative Biology - Populations and Evolution, Quantitative Biology - Biomolecules
Abstract

BACKGROUND: An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual, but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. RESULTS: Here we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by existing mathematical theories, and can be quantitatively related to the way that the proteins occupy their neutral network. CONCLUSIONS: Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon may contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations.

Published
2007
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41. Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies

Author

Sheward, Daniel J., Pushparaj, Pradeepa, Das, Hrishikesh, Greaney, Allison J., Kim, Changil, Kim, Sungyong, Hanke, Leo, Hyllner, Erik, Dyrdak, Robert, Lee, Jimin, Dopico, Xaquin Castro, Dosenovic, Pia, Peacock, Thomas P., McInerney, Gerald M., Albert, Jan, Corcoran, Martin, Bloom, Jesse D., Murrell, Ben, Karlsson Hedestam, Gunilla B., and Hällberg, B. Martin

Published
2024
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42. Thermodynamics of Neutral Protein Evolution

Author

Bloom, Jesse D, Raval, Alpan, and Wilke, Claus O

Subjects
Quantitative Biology - Populations and Evolution, Quantitative Biology - Biomolecules
Abstract

Naturally evolving proteins gradually accumulate mutations while continuing to fold to thermodynamically stable native structures. This process of neutral protein evolution is an important mode of genetic change, and forms the basis for the molecular clock. Here we present a mathematical theory that predicts the number of accumulated mutations, the index of dispersion, and the distribution of stabilities in an evolving protein population from knowledge of the stability effects (ddG values) for single mutations. Our theory quantitatively describes how neutral evolution leads to marginally stable proteins, and provides formulae for calculating how fluctuations in stability cause an overdispersion of the molecular clock. It also shows that the structural influences on the rate of sequence evolution that have been observed in earlier simulations can be calculated using only the single-mutation ddG values. We consider both the case when the product of the population size and mutation rate is small and the case when this product is large, and show that in the latter case proteins evolve excess mutational robustness that is manifested by extra stability and increases the rate of sequence evolution. Our basic method is to treat protein evolution as a Markov process constrained by a minimal requirement for stable folding, enabling an evolutionary description of the proteins solely in terms of the experimentally measureable ddG values. All of our theoretical predictions are confirmed by simulations with model lattice proteins. Our work provides a mathematical foundation for understanding how protein biophysics helps shape the process of evolution.

Published
2006
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43. Why highly expressed proteins evolve slowly

Author

Drummond, D. Allan, Bloom, Jesse D., Adami, Christoph, Wilke, Claus O., and Arnold, Frances H.

Subjects
Quantitative Biology - Populations and Evolution, Quantitative Biology - Genomics
Abstract

Much recent work has explored molecular and population-genetic constraints on the rate of protein sequence evolution. The best predictor of evolutionary rate is expression level, for reasons which have remained unexplained. Here, we hypothesize that selection to reduce the burden of protein misfolding will favor protein sequences with increased robustness to translational missense errors. Pressure for translational robustness increases with expression level and constrains sequence evolution. Using several sequenced yeast genomes, global expression and protein abundance data, and sets of paralogs traceable to an ancient whole-genome duplication in yeast, we rule out several confounding effects and show that expression level explains roughly half the variation in Saccharomyces cerevisiae protein evolutionary rates. We examine causes for expression's dominant role and find that genome-wide tests favor the translational robustness explanation over existing hypotheses that invoke constraints on function or translational efficiency. Our results suggest that proteins evolve at rates largely unrelated to their functions, and can explain why highly expressed proteins evolve slowly across the tree of life., Comment: 40 pages, 3 figures, with supporting information

Published
2005
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44. Inferring interactions from combinatorial protein libraries

Author

Endelman, Jeffrey B., Bloom, Jesse D., Otey, Christopher R., Landwehr, Marco, and Arnold, Frances H.

Subjects
Quantitative Biology - Biomolecules
Abstract

Proteins created by combinatorial methods in vitro are an important source of information for understanding sequence-structure-function relationships. Alignments of folded proteins from combinatorial libraries can be analyzed using methods developed for naturally occurring proteins, but this neglects the information contained in the unfolded sequences of the library. We introduce two algorithms, logistic regression and excess information analysis, that use both the folded and unfolded sequences and compare them against contingency table and statistical coupling analysis, which only use the former. The test set for this benchmark study is a library of fictitious proteins that fold according to a hypothetical energy model. Of the four methods studied, only logistic regression is able to correctly recapitulate the energy model from the sequence alignment. The other algorithms predict spurious interactions between alignment positions with strong but individual influences on protein stability. When present in the same protein, stabilizing amino acids tend to lower the energy below the threshold needed for folding. As a result, their frequencies in the alignment can be correlated even if the positions do not interact. We believe any algorithm that neglects the nonlinear relationship between folding and energy is susceptible to this error., Comment: 21 pages, 2 figures

Published
2005

46. Thermodynamic Prediction of Protein Neutrality

Author

Bloom, Jesse D., Silberg, Jonathan J., Wilke, Claus O., Drummond, D. Allan, Adami, Christoph, and Arnold, Frances H.

Subjects
Quantitative Biology - Biomolecules, Quantitative Biology - Populations and Evolution
Abstract

We present a simple theory that uses thermodynamic parameters to predict the probability that a protein retains the wildtype structure after one or more random amino acid substitutions. Our theory predicts that for large numbers of substitutions the probability that a protein retains its structure will decline exponentially with the number of substitutions, with the severity of this decline determined by properties of the structure. Our theory also predicts that a protein can gain extra robustness to the first few substitutions by increasing its thermodynamic stability. We validate our theory with simulations on lattice protein models and by showing that it quantitatively predicts previously published experimental measurements on subtilisin and our own measurements on variants of TEM1 beta-lactamase. Our work unifies observations about the clustering of functional proteins in sequence space, and provides a basis for interpreting the response of proteins to substitutions in protein engineering applications.

Published
2004
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47. Stability and the Evolvability of Function in a Model Protein

Author

Bloom, Jesse D, Wilke, Claus O, Arnold, Frances H, and Adami, Christoph

Subjects
Quantitative Biology - Biomolecules
Abstract

Functional proteins must fold with some minimal stability to a structure that can perform a biochemical task. Here we use a simple model to investigate the relationship between the stability requirement and the capacity of a protein to evolve the function of binding to a ligand. Although our model contains no built-in tradeoff between stability and function, proteins evolved function more efficiently when the stability requirement was relaxed. Proteins with both high stability and high function evolved more efficiently when the stability requirement was gradually increased than when there was constant selection for high stability. These results show that in our model, the evolution of function is enhanced by allowing proteins to explore sequences corresponding to marginally stable structures, and that it is easier to improve stability while maintaining high function than to improve function while maintaining high stability. Our model also demonstrates that even in the absence of a fundamental biophysical tradeoff between stability and function, the speed with which function can evolve is limited by the stability requirement imposed on the protein., Comment: Biophysical Journal in press

Published
2004
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48. Stability-mediated epistasis constrains the evolution of an influenza protein.

Author

Gong, Lizhi Ian, Suchard, Marc A, and Bloom, Jesse D

Subjects
Humans, Orthomyxoviridae, Viral Proteins, Evolution, Molecular, Epistasis, Genetic, Mutation, Viruses, epistasis, influenza, protein evolution, protein stability, Evolution, Molecular, Epistasis, Genetic, Biochemistry and Cell Biology
Abstract

John Maynard Smith compared protein evolution to the game where one word is converted into another a single letter at a time, with the constraint that all intermediates are words: WORD→WORE→GORE→GONE→GENE. In this analogy, epistasis constrains evolution, with some mutations tolerated only after the occurrence of others. To test whether epistasis similarly constrains actual protein evolution, we created all intermediates along a 39-mutation evolutionary trajectory of influenza nucleoprotein, and also introduced each mutation individually into the parent. Several mutations were deleterious to the parent despite becoming fixed during evolution without negative impact. These mutations were destabilizing, and were preceded or accompanied by stabilizing mutations that alleviated their adverse effects. The constrained mutations occurred at sites enriched in T-cell epitopes, suggesting they promote viral immune escape. Our results paint a coherent portrait of epistasis during nucleoprotein evolution, with stabilizing mutations permitting otherwise inaccessible destabilizing mutations which are sometimes of adaptive value. DOI:http://dx.doi.org/10.7554/eLife.00631.001.

Published
2013

50. Determinants of Zika virus host tropism uncovered by deep mutational scanning

Author

Setoh, Yin Xiang, Amarilla, Alberto A., Peng, Nias Y. G., Griffiths, Rebecca E., Carrera, Julio, Freney, Morgan E., Nakayama, Eri, Ogawa, Shinya, Watterson, Daniel, Modhiran, Naphak, Nanyonga, Faith Elizabeth, Torres, Francisco J., Slonchak, Andrii, Periasamy, Parthiban, Prow, Natalie A., Tang, Bing, Harrison, Jessica, Hobson-Peters, Jody, Cuddihy, Thom, Cooper-White, Justin, Hall, Roy A., Young, Paul R., Mackenzie, Jason M., Wolvetang, Ernst, Bloom, Jesse D., Suhrbier, Andreas, and Khromykh, Alexander A.

Published
2019
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