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1. Imprinting of serum neutralizing antibodies by Wuhan-1 mRNA vaccines

Author

Liang, Chieh-Yu, Raju, Saravanan, Liu, Zhuoming, Li, Yuhao, Asthagiri Arunkumar, Guha, Case, James Brett, Scheaffer, Suzanne M., Zost, Seth J., Acreman, Cory M., Gagne, Matthew, Andrew, Shayne F., Carvalho dos Anjos, Deborah Carolina, Foulds, Kathryn E., McLellan, Jason S., Crowe, Jr, James E., Douek, Daniel C., Whelan, Sean P. J., Elbashir, Sayda M., Edwards, Darin K., and Diamond, Michael S.

Published
2024
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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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4. Neutralization, effector function and immune imprinting of Omicron variants

Author

Addetia, Amin, Piccoli, Luca, Case, James Brett, Park, Young-Jun, Beltramello, Martina, Guarino, Barbara, Dang, Ha, de Melo, Guilherme Dias, Pinto, Dora, Sprouse, Kaitlin, Scheaffer, Suzanne M., Bassi, Jessica, Silacci-Fregni, Chiara, Muoio, Francesco, Dini, Marco, Vincenzetti, Lucia, Acosta, Rima, Johnson, Daisy, Subramanian, Sambhavi, Saliba, Christian, Giurdanella, Martina, Lombardo, Gloria, Leoni, Giada, Culap, Katja, McAlister, Carley, Rajesh, Anushka, Dellota, Jr, Exequiel, Zhou, Jiayi, Farhat, Nisar, Bohan, Dana, Noack, Julia, Chen, Alex, Lempp, Florian A., Quispe, Joel, Kergoat, Lauriane, Larrous, Florence, Cameroni, Elisabetta, Whitener, Bradley, Giannini, Olivier, Cippà, Pietro, Ceschi, Alessandro, Ferrari, Paolo, Franzetti-Pellanda, Alessandra, Biggiogero, Maira, Garzoni, Christian, Zappi, Stephanie, Bernasconi, Luca, Kim, Min Jeong, Rosen, Laura E., Schnell, Gretja, Czudnochowski, Nadine, Benigni, Fabio, Franko, Nicholas, Logue, Jennifer K., Yoshiyama, Courtney, Stewart, Cameron, Chu, Helen, Bourhy, Hervé, Schmid, Michael A., Purcell, Lisa A., Snell, Gyorgy, Lanzavecchia, Antonio, Diamond, Michael S., Corti, Davide, and Veesler, David

Published
2023
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6. Thermodynamically coupled biosensors for detecting neutralizing antibodies against SARS-CoV-2 variants

Author

Zhang, Jason Z, Yeh, Hsien-Wei, Walls, Alexandra C, Wicky, Basile IM, Sprouse, Kaitlin R, VanBlargan, Laura A, Treger, Rebecca, Quijano-Rubio, Alfredo, Pham, Minh N, Kraft, John C, Haydon, Ian C, Yang, Wei, DeWitt, Michelle, Bowen, John E, Chow, Cameron M, Carter, Lauren, Ravichandran, Rashmi, Wener, Mark H, Stewart, Lance, Veesler, David, Diamond, Michael S, Greninger, Alexander L, Koelle, David M, and Baker, David

Subjects
Analytical Chemistry, Information and Computing Sciences, Chemical Sciences, Bioengineering, Pneumonia, Lung, Emerging Infectious Diseases, Vaccine Related, Infectious Diseases, Prevention, Pneumonia & Influenza, Biodefense, Biotechnology, Good Health and Well Being, Antibodies, Neutralizing, Antibodies, Viral, Biosensing Techniques, COVID-19, Humans, Neutralization Tests, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Callicarpa nudiflora Hook, luteolin 3 '-O-beta-D-6 ''-acetyl glucopyranoside, pachypodol, hepatocellular carcinoma, cytotoxicity
Abstract

We designed a protein biosensor that uses thermodynamic coupling for sensitive and rapid detection of neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in serum. The biosensor is a switchable, caged luciferase-receptor-binding domain (RBD) construct that detects serum-antibody interference with the binding of virus RBD to angiotensin-converting enzyme 2 (ACE-2) as a proxy for neutralization. Our coupling approach does not require target modification and can better distinguish sample-to-sample differences in analyte binding affinity and abundance than traditional competition-based assays.

Published
2022

7. Phase III Pivotal comparative clinical trial of intranasal (iNCOVACC) and intramuscular COVID 19 vaccine (Covaxin®)

Author

Singh, Chandramani, Verma, Savita, Reddy, Prabhakar, Diamond, Michael S., Curiel, David T., Patel, Chintan, Jain, Manish Kumar, Redkar, Sagar Vivek, Bhate, Amit Suresh, Gundappa, Vivek, Konatham, Rambabu, Toppo, Leelabati, Joshi, Aniket Chandrakant, Kushwaha, Jitendra Singh, Singh, Ajit Pratap, Bawankule, Shilpa, Ella, Raches, Prasad, Sai, Ganneru, Brunda, Chiteti, Siddharth Reddy, Kataram, Sreenivas, and Vadrevu, Krishna Mohan

Published
2023
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13. A pre-vaccination immune metabolic interplay determines the protective antibody response to a dengue virus vaccine

Author

Pelletier, Adam-Nicolas, Sanchez, Gabriela Pacheco, Izmirly, Abdullah, Watson, Mark, Di Pucchio, Tiziana, Carvalho, Karina Inacio, Filali-Mouhim, Abdelali, Paramithiotis, Eustache, Timenetsky, Maria do Carmo S.T., Precioso, Alexander Roberto, Kalil, Jorge, Diamond, Michael S., Haddad, Elias K., Kallas, Esper G., and Sekaly, Rafick Pierre

Published
2024
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14. Genetic loci regulate Sarbecovirus pathogenesis: A comparison across mice and humans

Author

Schäfer, Alexandra, Gralinski, Lisa E., Leist, Sarah R., Hampton, Brea K., Mooney, Michael A., Jensen, Kara L., Graham, Rachel L., Agnihothram, Sudhakar, Jeng, Sophia, Chamberlin, Steven, Bell, Timothy A., Scobey, D. Trevor, Linnertz, Colton L., VanBlargan, Laura A., Thackray, Larissa B., Hock, Pablo, Miller, Darla R., Shaw, Ginger D., Diamond, Michael S., de Villena, Fernando Pardo Manuel, McWeeney, Shannon K., Heise, Mark T., Menachery, Vineet D., Ferris, Martin T., and Baric, Ralph S.

Published
2024
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16. 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

17. Pathophysiology of chikungunya virus infection associated with fatal outcomes

Author

de Souza, William M., Fumagalli, Marcilio J., de Lima, Shirlene T.S., Parise, Pierina L., Carvalho, Deyse C.M., Hernandez, Cristian, de Jesus, Ronaldo, Delafiori, Jeany, Candido, Darlan S., Carregari, Victor C., Muraro, Stefanie P., Souza, Gabriela F., Simões Mello, Leda M., Claro, Ingra M., Díaz, Yamilka, Kato, Rodrigo B., Trentin, Lucas N., Costa, Clauber H.S., Maximo, Ana Carolina B.M., Cavalcante, Karene F., Fiuza, Tayna S., Viana, Vânia A.F., Melo, Maria Elisabeth L., Ferraz, Clarissa P.M., Silva, Débora B., Duarte, Larissa M.F., Barbosa, Priscilla P., Amorim, Mariene R., Judice, Carla C., Toledo-Teixeira, Daniel A., Ramundo, Mariana S., Aguilar, Patricia V., Araújo, Emerson L.L., Costa, Fabio T.M., Cerqueira-Silva, Thiago, Khouri, Ricardo, Boaventura, Viviane S., Figueiredo, Luiz Tadeu M., Fang, Rong, Moreno, Brechla, López-Vergès, Sandra, Mello, Liana Perdigão, Skaf, Munir S., Catharino, Rodrigo R., Granja, Fabiana, Martins-de-Souza, Daniel, Plante, Jessica A., Plante, Kenneth S., Sabino, Ester C., Diamond, Michael S., Eugenin, Eliseo, Proença-Módena, José Luiz, Faria, Nuno R., and Weaver, Scott C.

Published
2024
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21. SARS-CoV-2 Omicron boosting induces de novo B cell response in humans

Author

Alsoussi, Wafaa B., Malladi, Sameer Kumar, Zhou, Julian Q., Liu, Zhuoming, Ying, Baoling, Kim, Wooseob, Schmitz, Aaron J., Lei, Tingting, Horvath, Stephen C., Sturtz, Alexandria J., McIntire, Katherine M., Evavold, Birk, Han, Fangjie, Scheaffer, Suzanne M., Fox, Isabella F., Mirza, Senaa F., Parra-Rodriguez, Luis, Nachbagauer, Raffael, Nestorova, Biliana, Chalkias, Spyros, Farnsworth, Christopher W., Klebert, Michael K., Pusic, Iskra, Strnad, Benjamin S., Middleton, William D., Teefey, Sharlene A., Whelan, Sean P. J., Diamond, Michael S., Paris, Robert, O’Halloran, Jane A., Presti, Rachel M., Turner, Jackson S., and Ellebedy, Ali H.

Published
2023
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23. A potent and broad neutralization of SARS-CoV-2 variants of concern by DARPins

Author

Chonira, Vikas, Kwon, Young D., Gorman, Jason, Case, James Brett, Ku, Zhiqiang, Simeon, Rudo, Casner, Ryan G., Harris, Darcy R., Olia, Adam S., Stephens, Tyler, Shapiro, Lawrence, Bender, Michael F., Boyd, Hannah, Teng, I-Ting, Tsybovsky, Yaroslav, Krammer, Florian, Zhang, Ningyan, Diamond, Michael S., Kwong, Peter D., An, Zhiqiang, and Chen, Zhilei

Published
2023
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26. Global COVID-19 lockdown highlights humans as both threats and custodians of the environment

Author

Bates, Amanda E, Primack, Richard B, Biggar, Brandy S, Bird, Tomas J, Clinton, Mary E, Command, Rylan J, Richards, Cerren, Shellard, Marc, Geraldi, Nathan R, Vergara, Valeria, Acevedo-Charry, Orlando, Colón-Piñeiro, Zuania, Ocampo, David, Ocampo-Peñuela, Natalia, Sánchez-Clavijo, Lina M, Adamescu, Cristian M, Cheval, Sorin, Racoviceanu, Tudor, Adams, Matthew D, Kalisa, Egide, Kuuire, Vincent Z, Aditya, Vikram, Anderwald, Pia, Wiesmann, Samuel, Wipf, Sonja, Badihi, Gal, Henderson, Matthew G, Loetscher, Hanspeter, Baerenfaller, Katja, Benedetti-Cecchi, Lisandro, Bulleri, Fabio, Bertocci, Iacopo, Maggi, Elena, Rindi, Luca, Ravaglioli, Chiara, Boerder, Kristina, Bonnel, Julien, Mathias, Delphine, Archambault, Philippe, Chauvaud, Laurent, Braun, Camrin D, Thorrold, Simon R, Brownscombe, Jacob W, Midwood, Jonathan D, Boston, Christine M, Brooks, Jill L, Cooke, Steven J, China, Victor, Roll, Uri, Belmaker, Jonathan, Zvuloni, Assaf, Coll, Marta, Ortega, Miquel, Connors, Brendan, Lacko, Lisa, Jayathilake, Dinusha RM, Costello, Mark J, Crimmins, Theresa M, Barnett, LoriAnne, Denny, Ellen G, Gerst, Katharine L, Marsh, RL, Posthumus, Erin E, Rodriguez, Reilly, Rosemartin, Alyssa, Schaffer, Sara N, Switzer, Jeff R, Wong, Kevin, Cunningham, Susan J, Sumasgutner, Petra, Amar, Arjun, Thomson, Robert L, Stofberg, Miqkayla, Hofmeyr, Sally, Suri, Jessleena, Stuart-Smith, Rick D, Day, Paul B, Edgar, Graham J, Cooper, Antonia T, De Leo, Fabio Cabrera, Garner, Grant, Brisay, Paulson G Des, Schrimpf, Michael B, Koper, Nicola, Diamond, Michael S, Dwyer, Ross G, Baker, Cameron J, Franklin, Craig E, Efrat, Ron, Berger-Tal, Oded, Hatzofe, Ohad, Eguíluz, Víctor M, Rodríguez, Jorge P, Fernández-Gracia, Juan, Elustondo, David, Calatayud, Vicent, English, Philina A, Archer, Stephanie K, Dudas, Sarah E, and Haggarty, Dana R

Subjects
Life on Land, Pandemic, Biodiversity, Restoration, Global monitoring, Environmental Sciences, Biological Sciences, Agricultural and Veterinary Sciences, Ecology
Abstract

The global lockdown to mitigate COVID-19 pandemic health risks has altered human interactions with nature. Here, we report immediate impacts of changes in human activities on wildlife and environmental threats during the early lockdown months of 2020, based on 877 qualitative reports and 332 quantitative assessments from 89 different studies. Hundreds of reports of unusual species observations from around the world suggest that animals quickly responded to the reductions in human presence. However, negative effects of lockdown on conservation also emerged, as confinement resulted in some park officials being unable to perform conservation, restoration and enforcement tasks, resulting in local increases in illegal activities such as hunting. Overall, there is a complex mixture of positive and negative effects of the pandemic lockdown on nature, all of which have the potential to lead to cascading responses which in turn impact wildlife and nature conservation. While the net effect of the lockdown will need to be assessed over years as data becomes available and persistent effects emerge, immediate responses were detected across the world. Thus, initial qualitative and quantitative data arising from this serendipitous global quasi-experimental perturbation highlights the dual role that humans play in threatening and protecting species and ecosystems. Pathways to favorably tilt this delicate balance include reducing impacts and increasing conservation effectiveness.

Published
2021

28. Hypergraph Models of Biological Networks to Identify Genes Critical to Pathogenic Viral Response

Author

Feng, Song, Heath, Emily, Jefferson, Brett, Joslyn, Cliff, Kvinge, Henry, Mitchell, Hugh D., Praggastis, Brenda, Eisfeld, Amie J., Sims, Amy C., Thackray, Larissa B., Fan, Shufang, Walters, Kevin B., Halfmann, Peter J., Westhoff-Smith, Danielle, Tan, Qing, Menachery, Vineet D., Sheahan, Timothy P., Cockrell, Adam S., Kocher, Jacob F., Stratton, Kelly G., Heller, Natalie C., Bramer, Lisa M., Diamond, Michael S., Baric, Ralph S., Waters, Katrina M., Kawaoka, Yoshihiro, McDermott, Jason E., and Purvine, Emilie

Subjects
Quantitative Biology - Quantitative Methods, Mathematics - Combinatorics, 92C42, 92-08, 05C65
Abstract

Background: Representing biological networks as graphs is a powerful approach to reveal underlying patterns, signatures, and critical components from high-throughput biomolecular data. However, graphs do not natively capture the multi-way relationships present among genes and proteins in biological systems. Hypergraphs are generalizations of graphs that naturally model multi-way relationships and have shown promise in modeling systems such as protein complexes and metabolic reactions. In this paper we seek to understand how hypergraphs can more faithfully identify, and potentially predict, important genes based on complex relationships inferred from genomic expression data sets. Results: We compiled a novel data set of transcriptional host response to pathogenic viral infections and formulated relationships between genes as a hypergraph where hyperedges represent significantly perturbed genes, and vertices represent individual biological samples with specific experimental conditions. We find that hypergraph betweenness centrality is a superior method for identification of genes important to viral response when compared with graph centrality. Conclusions: Our results demonstrate the utility of using hypergraphs to represent complex biological systems and highlight central important responses in common to a variety of highly pathogenic viruses.

Published
2020

29. In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains

Author

Chen, Rita E, Winkler, Emma S, Case, James Brett, Aziati, Ishmael D, Bricker, Traci L, Joshi, Astha, Darling, Tamarand L, Ying, Baoling, Errico, John M, Shrihari, Swathi, VanBlargan, Laura A, Xie, Xuping, Gilchuk, Pavlo, Zost, Seth J, Droit, Lindsay, Liu, Zhuoming, Stumpf, Spencer, Wang, David, Handley, Scott A, Stine, W Blaine, Shi, Pei-Yong, Davis-Gardner, Meredith E, Suthar, Mehul S, Knight, Miguel Garcia, Andino, Raul, Chiu, Charles Y, Ellebedy, Ali H, Fremont, Daved H, Whelan, Sean PJ, Crowe, James E, Purcell, Lisa, Corti, Davide, Boon, Adrianus CM, and Diamond, Michael S

Subjects
Infectious Diseases, Pneumonia & Influenza, Immunization, Biodefense, Biotechnology, Lung, Vaccine Related, Pneumonia, Prevention, Emerging Infectious Diseases, Infection, Angiotensin-Converting Enzyme 2, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, COVID-19, Chlorocebus aethiops, Female, Humans, Male, Mesocricetus, Mice, Mice, Transgenic, Neutralization Tests, Post-Exposure Prophylaxis, Pre-Exposure Prophylaxis, SARS-CoV-2, Serine Endopeptidases, Spike Glycoprotein, Coronavirus, Vero Cells, General Science & Technology
Abstract

Rapidly emerging SARS-CoV-2 variants jeopardize antibody-based countermeasures. Although cell culture experiments have demonstrated a loss of potency of several anti-spike neutralizing antibodies against variant strains of SARS-CoV-21-3, the in vivo importance of these results remains uncertain. Here we report the in vitro and in vivo activity of a panel of monoclonal antibodies (mAbs), which correspond to many in advanced clinical development by Vir Biotechnology, AbbVie, AstraZeneca, Regeneron and Lilly, against SARS-CoV-2 variant viruses. Although some individual mAbs showed reduced or abrogated neutralizing activity in cell culture against B.1.351, B.1.1.28, B.1.617.1 and B.1.526 viruses with mutations at residue E484 of the spike protein, low prophylactic doses of mAb combinations protected against infection by many variants in K18-hACE2 transgenic mice, 129S2 immunocompetent mice and hamsters, without the emergence of resistance. Exceptions were LY-CoV555 monotherapy and LY-CoV555 and LY-CoV016 combination therapy, both of which lost all protective activity, and the combination of AbbVie 2B04 and 47D11, which showed a partial loss of activity. When administered after infection, higher doses of several mAb cocktails protected in vivo against viruses with a B.1.351 spike gene. Therefore, many-but not all-of the antibody products with Emergency Use Authorization should retain substantial efficacy against the prevailing variant strains of SARS-CoV-2.

Published
2021

30. Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice

Author

Scheaffer, Suzanne M., Lee, Diana, Whitener, Bradley, Ying, Baoling, Wu, Kai, Liang, Chieh-Yu, Jani, Hardik, Martin, Philippa, Amato, Nicholas J., Avena, Laura E., Berrueta, Daniela Montes, Schmidt, Stephen D., O’Dell, Sijy, Nasir, Arshan, Chuang, Gwo-Yu, Stewart-Jones, Guillaume, Koup, Richard A., Doria-Rose, Nicole A., Carfi, Andrea, Elbashir, Sayda M., Thackray, Larissa B., Edwards, Darin K., and Diamond, Michael S.

Published
2023
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32. A compendium of multi-omics data illuminating host responses to lethal human virus infections

Author

Eisfeld, Amie J., Anderson, Lindsey N., Fan, Shufang, Walters, Kevin B., Halfmann, Peter J., Westhoff Smith, Danielle, Thackray, Larissa B., Tan, Qing, Sims, Amy C., Menachery, Vineet D., Schäfer, Alexandra, Sheahan, Timothy P., Cockrell, Adam S., Stratton, Kelly G., Webb-Robertson, Bobbie-Jo M., Kyle, Jennifer E., Burnum-Johnson, Kristin E., Kim, Young-Mo, Nicora, Carrie D., Peralta, Zuleyma, N’jai, Alhaji U., Sahr, Foday, van Bakel, Harm, Diamond, Michael S., Baric, Ralph S., Metz, Thomas O., Smith, Richard D., Kawaoka, Yoshihiro, and Waters, Katrina M.

Published
2024
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35. Zika virus oncolytic activity requires CD8+ T cells and is boosted by immune checkpoint blockade

Author

Nair, Sharmila, Mazzoccoli, Luciano, Jash, Arijita, Govero, Jennifer, Bais, Sachendra S, Hu, Tong, Fontes-Garfias, Camila R, Shan, Chao, Okada, Hideho, Shresta, Sujan, Rich, Jeremy N, Shi, Pei-Yong, Diamond, Michael S, and Chheda, Milan G

Subjects
Cancer, Immunization, Brain Cancer, Rare Diseases, Vaccine Related, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Brain Disorders, Neurosciences, Orphan Drug, Stem Cell Research - Nonembryonic - Human, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Good Health and Well Being, Animals, Brain Neoplasms, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Combined Modality Therapy, Female, Glioblastoma, Humans, Immune Checkpoint Inhibitors, Mice, Mice, Inbred C57BL, Neoplasms, Experimental, Oncolytic Virotherapy, Oncolytic Viruses, Tumor Microenvironment, Zika Virus, Brain cancer, Cancer immunotherapy, Immunology, Oncology
Abstract

Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increased recruitment of CD8+ T and myeloid cells to the tumor microenvironment. CD8+ T cells were required for ZIKV-dependent tumor clearance because survival benefits were lost with CD8+ T cell depletion. Moreover, while anti-PD-1 antibody monotherapy moderately improved tumor survival, when coadministered with ZIKV, survival increased. ZIKV-mediated tumor clearance also resulted in durable protection against syngeneic tumor rechallenge, which also depended on CD8+ T cells. To address safety concerns, we generated an immune-sensitized ZIKV strain, which was effective alone or in combination with immunotherapy. Thus, oncolytic ZIKV treatment can be leveraged by immunotherapies, which may prompt combination treatment paradigms for adult patients with GBM.

Published
2021

36. The Relationship Between Intelligence Mindset and Test Anxiety as Mediated by Effort Regulation

Author

Pelakh, Avital, Good, Melanie L, Kuo, Eric, Nokes-Malach, Timothy, Tumminia, Michael J, Jamal-Orozco, Nabila, Diamond, Michael S., Adelman, Amy, and Galla, Brian

Subjects
cognitive science
Abstract

Test anxiety affects a sizable proportion of college students, especially in competitive STEM fields. Prior research has proposed interventions aimed at changing students’ implicit beliefs about intelligence (intelligence mindset) to help reduce students’ test anxiety, but results have been mixed and the mechanisms underlying this relationship are unclear. We propose that students’ beliefs about effort regulation may partially mediate the relationship between intelligence mindsets and test anxiety. We tested our model as an exploratory post-hoc analysis in a small sample of introductory physics students reporting psychological threat in a laboratory study. Effort regulation was measured as self-reported judgements of persistence in the face of difficulty and test anxiety was measured on a problem by problem basis during a laboratory physics assessment. Students’ intelligence mindset at pretest was a significant predictor of test anxiety at posttest, and this relationship was mediated by self-reported effort regulation. We discuss potential implications of these findings for mindset-based interventions aimed at reducing test anxiety.

Published
2021

37. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells

Author

Lee, Jaewoong, Robinson, Mark E, Ma, Ning, Artadji, Dewan, Ahmed, Mohamed A, Xiao, Gang, Sadras, Teresa, Deb, Gauri, Winchester, Janet, Cosgun, Kadriye Nehir, Geng, Huimin, Chan, Lai N, Kume, Kohei, Miettinen, Teemu P, Zhang, Ye, Nix, Matthew A, Klemm, Lars, Chen, Chun Wei, Chen, Jianjun, Khairnar, Vishal, Wiita, Arun P, Thomas-Tikhonenko, Andrei, Farzan, Michael, Jung, Jae U, Weinstock, David M, Manalis, Scott R, Diamond, Michael S, Vaidehi, Nagarajan, and Müschen, Markus

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Hematology, Cancer, Lymphoma, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Animals, Antigens, CD19, B-Lymphocytes, Cell Transformation, Neoplastic, Female, Germinal Center, Humans, Integrins, Membrane Microdomains, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Models, Molecular, Phosphatidylinositol 3-Kinases, Phosphatidylinositol Phosphates, Phosphorylation, RNA-Binding Proteins, Receptors, Antigen, B-Cell, Signal Transduction, General Science & Technology
Abstract

Interferon-induced transmembrane protein 3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection1-3. Here we studied clinical cohorts of patients with B cell leukaemia and lymphoma, and identified IFITM3 as a strong predictor of poor outcome. In normal resting B cells, IFITM3 was minimally expressed and mainly localized in endosomes. However, engagement of the B cell receptor (BCR) induced both expression of IFITM3 and phosphorylation of this protein at Tyr20, which resulted in the accumulation of IFITM3 at the cell surface. In B cell leukaemia, oncogenic kinases phosphorylate IFITM3 at Tyr20, which causes constitutive localization of this protein at the plasma membrane. In a mouse model, Ifitm3-/- naive B cells developed in normal numbers; however, the formation of germinal centres and the production of antigen-specific antibodies were compromised. Oncogenes that induce the development of leukaemia and lymphoma did not transform Ifitm3-/- B cells. Conversely, the phosphomimetic IFITM3(Y20E) mutant induced oncogenic PI3K signalling and initiated the transformation of premalignant B cells. Mechanistic experiments revealed that IFITM3 functions as a PIP3 scaffold and central amplifier of PI3K signalling. The amplification of PI3K signals depends on IFITM3 using two lysine residues (Lys83 and Lys104) in its conserved intracellular loop as a scaffold for the accumulation of PIP3. In Ifitm3-/- B cells, lipid rafts were depleted of PIP3, which resulted in the defective expression of over 60 lipid-raft-associated surface receptors, and impaired BCR signalling and cellular adhesion. We conclude that the phosphorylation of IFITM3 that occurs after B cells encounter antigen induces a dynamic switch from antiviral effector functions in endosomes to a PI3K amplification loop at the cell surface. IFITM3-dependent amplification of PI3K signalling, which in part acts downstream of the BCR, is critical for the rapid expansion of B cells with high affinity to antigen. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signalling complexes and amplify PI3K signalling for malignant transformation.

Published
2020

38. Influenza virus repurposes the antiviral protein IFIT2 to promote translation of viral mRNAs

Author

Tran, Vy, Ledwith, Mitchell P, Thamamongood, Thiprampai, Higgins, Christina A, Tripathi, Shashank, Chang, Max W, Benner, Christopher, García-Sastre, Adolfo, Schwemmle, Martin, Boon, Adrianus CM, Diamond, Michael S, and Mehle, Andrew

Subjects
Influenza, Infectious Diseases, Pneumonia & Influenza, Biodefense, Vaccine Related, Prevention, Emerging Infectious Diseases, Genetics, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Aetiology, Underpinning research, Infection, Animals, Apoptosis Regulatory Proteins, Cell Line, Host-Pathogen Interactions, Humans, Influenza A virus, Influenza, Human, Mice, Mice, Knockout, Protein Biosynthesis, RNA, Messenger, RNA, Viral, RNA-Binding Proteins, Virus Replication, Microbiology, Medical Microbiology
Abstract

Cells infected by influenza virus mount a large-scale antiviral response and most cells ultimately initiate cell-death pathways in an attempt to suppress viral replication. We performed a CRISPR-Cas9-knockout selection designed to identify host factors required for replication after viral entry. We identified a large class of presumptive antiviral factors that unexpectedly act as important proviral enhancers during influenza virus infection. One of these, IFIT2, is an interferon-stimulated gene with well-established antiviral activity but limited mechanistic understanding. As opposed to suppressing infection, we show in the present study that IFIT2 is instead repurposed by influenza virus to promote viral gene expression. CLIP-seq demonstrated that IFIT2 binds directly to viral and cellular messenger RNAs in AU-rich regions, with bound cellular transcripts enriched in interferon-stimulated mRNAs. Polysome and ribosome profiling revealed that IFIT2 prevents ribosome pausing on bound mRNAs. Together, the data link IFIT2 binding to enhanced translational efficiency for viral and cellular mRNAs and ultimately viral replication. Our findings establish a model for the normal function of IFIT2 as a protein that increases translation of cellular mRNAs to support antiviral responses and explain how influenza virus uses this same activity to redirect a classically antiviral protein into a proviral effector.

Published
2020

40. Identification of Dengue Virus Serotype 3 Specific Antigenic Sites Targeted by Neutralizing Human Antibodies

Author

Young, Ellen, Carnahan, Robert H, Andrade, Daniela V, Kose, Nurgun, Nargi, Rachel S, Fritch, Ethan J, Munt, Jennifer E, Doyle, Michael P, White, Laura, Baric, Thomas J, Stoops, Mark, DeSilva, Aravinda, Tse, Longping V, Martinez, David R, Zhu, Deanna, Metz, Stefan, Wong, Marcus P, Espinosa, Diego A, Montoya, Magelda, Biering, Scott B, Sukulpolvi-Petty, Soila, Kuan, Guillermina, Balmaseda, Angel, Diamond, Michael S, Harris, Eva, Crowe, James E, and Baric, Ralph S

Subjects
Clinical Research, Immunization, Biotechnology, Biodefense, Infectious Diseases, Emerging Infectious Diseases, Prevention, Rare Diseases, Vector-Borne Diseases, Vaccine Related, Infection, Good Health and Well Being, Adolescent, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, B-Lymphocytes, Child, Child, Preschool, Chlorocebus aethiops, Dengue, Dengue Vaccines, Dengue Virus, Epitope Mapping, Epitopes, Humans, Mice, Models, Molecular, Nicaragua, Sequence Alignment, Serogroup, Vero Cells, Viral Envelope Proteins, Virion, DENV3, antigenic site, chimeric virus, dengue virus serotype 3, envelope protein, flavivirus, functional epitopes, in vivo protection, neutralizing monoclonal antibodies, Microbiology, Medical Microbiology, Immunology
Abstract

The rational design of dengue virus (DENV) vaccines requires a detailed understanding of the molecular basis for antibody-mediated immunity. The durably protective antibody response to DENV after primary infection is serotype specific. However, there is an incomplete understanding of the antigenic determinants for DENV type-specific (TS) antibodies, especially for DENV serotype 3, which has only one well-studied, strongly neutralizing human monoclonal antibody (mAb). Here, we investigated the human B cell response in children after natural DENV infection in the endemic area of Nicaragua and isolated 15 DENV3 TS mAbs recognizing the envelope (E) glycoprotein. Functional epitope mapping of these mAbs and small animal prophylaxis studies revealed a complex landscape with protective epitopes clustering in at least 6-7 antigenic sites. Potently neutralizing TS mAbs recognized sites principally in E glycoprotein domains I and II, and patterns suggest frequent recognition of quaternary structures on the surface of viral particles.

Published
2020

41. An Evolutionary Insertion in the Mxra8 Receptor-Binding Site Confers Resistance to Alphavirus Infection and Pathogenesis

Author

Kim, Arthur S, Zimmerman, Ofer, Fox, Julie M, Nelson, Christopher A, Basore, Katherine, Zhang, Rong, Durnell, Lorellin, Desai, Chandni, Bullock, Christopher, Deem, Sharon L, Oppenheimer, Jonas, Shapiro, Beth, Wang, Ting, Cherry, Sara, Coyne, Carolyn B, Handley, Scott A, Landis, Michael J, Fremont, Daved H, and Diamond, Michael S

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Emerging Infectious Diseases, Vector-Borne Diseases, Prevention, Biodefense, Vaccine Related, Infectious Diseases, Infection, Good Health and Well Being, Amino Acid Sequence, Animals, Binding Sites, Cattle, Chikungunya Fever, Chikungunya virus, Chlorocebus aethiops, Disease Resistance, Evolution, Molecular, Female, Gene Knock-In Techniques, HEK293 Cells, Humans, Immunoglobulins, Membrane Proteins, Mice, Mice, Inbred C57BL, Molecular Docking Simulation, NIH 3T3 Cells, Protein Domains, Receptors, Virus, Vero Cells, Bovinae, X-ray crystallography, alphavirus, evolution, infection, pathogenesis, receptor, Microbiology, Immunology, Biochemistry and cell biology, Medical microbiology
Abstract

Alphaviruses are emerging, mosquito-transmitted RNA viruses with poorly understood cellular tropism and species selectivity. Mxra8 is a receptor for multiple alphaviruses including chikungunya virus (CHIKV). We discovered that while expression of mouse, rat, chimpanzee, dog, horse, goat, sheep, and human Mxra8 enables alphavirus infection in cell culture, cattle Mxra8 does not. Cattle Mxra8 encodes a 15-amino acid insertion in its ectodomain that prevents Mxra8 binding to CHIKV. Identical insertions are present in zebu, yak, and the extinct auroch. As other Bovinae lineages contain related Mxra8 sequences, this insertion likely occurred at least 5 million years ago. Removing the Mxra8 insertion in Bovinae enhances alphavirus binding and infection, while introducing the insertion into mouse Mxra8 blocks CHIKV binding, prevents infection by multiple alphaviruses in cells, and mitigates CHIKV-induced pathogenesis in mice. Our studies on how this insertion provides resistance to CHIKV infection could facilitate countermeasures that disrupt Mxra8 interactions with alphaviruses.

Published
2020

42. Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis

Author

Zhu, Zhe, Mesci, Pinar, Bernatchez, Jean A, Gimple, Ryan C, Wang, Xiuxing, Schafer, Simon T, Wettersten, Hiromi I, Beck, Sungjun, Clark, Alex E, Wu, Qiulian, Prager, Briana C, Kim, Leo JY, Dhanwani, Rekha, Sharma, Sonia, Garancher, Alexandra, Weis, Sara M, Mack, Stephen C, Negraes, Priscilla D, Trujillo, Cleber A, Penalva, Luiz O, Feng, Jing, Lan, Zhou, Zhang, Rong, Wessel, Alex W, Dhawan, Sanjay, Diamond, Michael S, Chen, Clark C, Wechsler-Reya, Robert J, Gage, Fred H, Hu, Hongzhen, Siqueira-Neto, Jair L, Muotri, Alysson R, Cheresh, David A, and Rich, Jeremy N

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Immunology, Stem Cell Research - Nonembryonic - Non-Human, Cancer, Stem Cell Research, Brain Cancer, Clinical Research, Neurosciences, Stem Cell Research - Nonembryonic - Human, Rare Diseases, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Glioblastoma, Humans, Neural Stem Cells, Receptors, Vitronectin, SOXB1 Transcription Factors, Zika Virus, Zika Virus Infection, Integrin αvβ5, Sox2, Zika, cancer stem cell, glioblastoma, glioblastoma stem cell, glioma, interferon, oncolytic virus, organoid, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvβ5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvβ5 inhibition. Collectively, our studies identify integrin αvβ5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.

Published
2020

43. Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques

Author

King, Hannah A. D., Joyce, M. Gordon, Lakhal-Naouar, Ines, Ahmed, Aslaa, Cincotta, Camila Macedo, Subra, Caroline, Peachman, Kristina K., Hack, Holly R., Chen, Rita E., Thomas, Paul V., Chen, Wei-Hung, Sankhala, Rajeshwer S., Hajduczki, Agnes, Martinez, Elizabeth J., Peterson, Caroline E., Chang, William C., Choe, Misook, Smith, Clayton, Headley, Jarrett A., Elyard, Hanne A., Cook, Anthony, Anderson, Alexander, Wuertz, Kathryn McGuckin, Dong, Ming, Swafford, Isabella, Case, James B., Currier, Jeffrey R., Lal, Kerri G., Amare, Mihret F., Dussupt, Vincent, Molnar, Sebastian, Daye, Sharon P., Zeng, Xiankun, Barkei, Erica K., Alfson, Kendra, Staples, Hilary M., Carrion, Ricardo, Krebs, Shelly J., Paquin-Proulx, Dominic, Karasavvas, Nicos, Polonis, Victoria R., Jagodzinski, Linda L., Vasan, Sandhya, Scott, Paul T., Huang, Yaoxing, Nair, Manoj S., Ho, David D., de Val, Natalia, Diamond, Michael S., Lewisi, Mark G., Rao, Mangala, Matyas, Gary R., Gromowski, Gregory D., Peel, Sheila A., Michael, Nelson L., Modjarrad, Kayvon, and Bolton, Diane L.

Published
2021

46. Vertebrate-class-specific binding modes of the alphavirus receptor MXRA8

Author

Zimmerman, Ofer, Zimmerman, Maxwell I., Raju, Saravanan, Nelson, Christopher A., Errico, John M., Madden, Emily A., Holmes, Autumn C., Hassan, Ahmed O., VanBlargan, Laura A., Kim, Arthur S., Adams, Lucas J., Basore, Katherine, Whitener, Bradley M., Palakurty, Sathvik, Davis-Adams, Hannah G., Sun, Chengqun, Gilliland, Theron, Jr., Earnest, James T., Ma, Hongming, Ebel, Gregory D., Zmasek, Christian, Scheuermann, Richard H., Klimstra, William B., Fremont, Daved H., and Diamond, Michael S.

Published
2023
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49. Characterization and antiviral susceptibility of SARS-CoV-2 Omicron BA.2

Author

Uraki, Ryuta, Kiso, Maki, Iida, Shun, Imai, Masaki, Takashita, Emi, Kuroda, Makoto, Halfmann, Peter J., Loeber, Samantha, Maemura, Tadashi, Yamayoshi, Seiya, Fujisaki, Seiichiro, Wang, Zhongde, Ito, Mutsumi, Ujie, Michiko, Iwatsuki-Horimoto, Kiyoko, Furusawa, Yuri, Wright, Ryan, Chong, Zhenlu, Ozono, Seiya, Yasuhara, Atsuhiro, Ueki, Hiroshi, Sakai-Tagawa, Yuko, Li, Rong, Liu, Yanan, Larson, Deanna, Koga, Michiko, Tsutsumi, Takeya, Adachi, Eisuke, Saito, Makoto, Yamamoto, Shinya, Hagihara, Masao, Mitamura, Keiko, Sato, Tetsuro, Hojo, Masayuki, Hattori, Shin-ichiro, Maeda, Kenji, Valdez, Riccardo, Okuda, Moe, Murakami, Jurika, Duong, Calvin, Godbole, Sucheta, Douek, Daniel C., Maeda, Ken, Watanabe, Shinji, Gordon, Aubree, Ohmagari, Norio, Yotsuyanagi, Hiroshi, Diamond, Michael S., Hasegawa, Hideki, Mitsuya, Hiroaki, Suzuki, Tadaki, and Kawaoka, Yoshihiro

Published
2022
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50. Comparative analysis of SARS-CoV-2 neutralization titers reveals consistency between human and animal model serum and across assays

Author

Mühlemann, Barbara, primary, Wilks, Samuel H., additional, Baracco, Lauren, additional, Bekliz, Meriem, additional, Carreño, Juan Manuel, additional, Corman, Victor M., additional, Davis-Gardner, Meredith E., additional, Dejnirattisai, Wanwisa, additional, Diamond, Michael S., additional, Douek, Daniel C., additional, Drosten, Christian, additional, Eckerle, Isabella, additional, Edara, Venkata-Viswanadh, additional, Ellis, Madison, additional, Fouchier, Ron A. M., additional, Frieman, Matthew, additional, Godbole, Sucheta, additional, Haagmans, Bart, additional, Halfmann, Peter J., additional, Henry, Amy R., additional, Jones, Terry C., additional, Katzelnick, Leah C., additional, Kawaoka, Yoshihiro, additional, Kimpel, Janine, additional, Krammer, Florian, additional, Lai, Lilin, additional, Liu, Chang, additional, Lusvarghi, Sabrina, additional, Meyer, Benjamin, additional, Mongkolsapaya, Juthathip, additional, Montefiori, David C., additional, Mykytyn, Anna, additional, Netzl, Antonia, additional, Pollett, Simon, additional, Rössler, Annika, additional, Screaton, Gavin R., additional, Shen, Xiaoying, additional, Sigal, Alex, additional, Simon, Viviana, additional, Subramanian, Rahul, additional, Supasa, Piyada, additional, Suthar, Mehul S., additional, Türeli, Sina, additional, Wang, Wei, additional, Weiss, Carol D., additional, and Smith, Derek J., additional

Published
2024
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