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1. Endosomal fusion of pH-dependent enveloped viruses requires ion channel TRPM7

Author

Doyle, Catherine A., Busey, Gregory W., Iobst, Wesley H., Kiessling, Volker, Renken, Chloe, Doppalapudi, Hansa, Stremska, Marta E., Manjegowda, Mohan C., Arish, Mohd, Wang, Weiming, Naphade, Shardul, Kennedy, Joel, Bloyet, Louis-Marie, Thompson, Cassandra E., Rothlauf, Paul W., Stipes, Eric J., Whelan, Sean P. J., Tamm, Lukas K., Kreutzberger, Alex J. B., Sun, Jie, and Desai, Bimal N.

Published
2024
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2. 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

3. A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

Author

Mahoney, Matthew, Damalanka, Vishnu C, Tartell, Michael A, Chung, Dong hee, Lourenço, André Luiz, Pwee, Dustin, Bridwell, Anne E Mayer, Hoffmann, Markus, Voss, Jorine, Karmakar, Partha, Azouz, Nurit P, Klingler, Andrea M, Rothlauf, Paul W, Thompson, Cassandra E, Lee, Melody, Klampfer, Lidija, Stallings, Christina L, Rothenberg, Marc E, Pöhlmann, Stefan, Whelan, Sean PJ, O’Donoghue, Anthony J, Craik, Charles S, and Janetka, James W

Subjects
Biological Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Biodefense, Pneumonia, Vaccine Related, Infectious Diseases, Emerging Infectious Diseases, Prevention, Lung, Pneumonia & Influenza, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Benzamidines, Benzothiazoles, COVID-19, Cell Line, Drug Design, Epithelial Cells, Esters, Guanidines, Humans, Mice, Middle East Respiratory Syndrome Coronavirus, Oligopeptides, SARS-CoV-2, Serine Endopeptidases, Small Molecule Libraries, Substrate Specificity, Virus Internalization, COVID-19 Drug Treatment, antiviral, protease inhibitor, structure-based drug discovery, PS-SCL
Abstract

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 (half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.

Published
2021

4. A class II MHC-targeted vaccine elicits immunity against SARS-CoV-2 and its variants

Author

Pishesha, Novalia, Harmand, Thibault J., Rothlauf, Paul W., Praest, Patrique, Alexander, Ryan K., van den Doel, Renate, Liebeskind, Mariel J., Vakaki, Maria A., McCaul, Nicholas, Wijne, Charlotte, Verhaar, Elisha, Pinney, William, Heston, Hailey, Bloyet, Louis-Marie, Pontelli, Marjorie Cornejo, Ilagan, Ma. Xenia G., Lebbink, Robert Jan, Buchser, William J., Wiertz, Emmanuel J. H. J., Whelan, Sean P. J., and Ploegh, Hidde L.

Published
2021

5. Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion

Author

Zang, Ruochen, Case, James Brett, Yutuc, Eylan, Ma, Xiucui, Shen, Sheng, Castro, Maria Florencia Gomez, Liu, Zhuoming, Zeng, Qiru, Zhao, Haiyan, Son, Juhee, Rothlauf, Paul W., Kreutzberger, Alex J. B., Hou, Gaopeng, Zhang, Hu, Bose, Sayantan, Wang, Xin, Vahey, Michael D., Mani, Kartik, Griffiths, William J., Kirchhausen, Tom, Fremont, Daved H., Guo, Haitao, Diwan, Abhinav, Wang, Yuqin, Diamond, Michael S., Whelan, Sean P. J., and Ding, Siyuan

Published
2020

8. Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein

Author

Zost, Seth J., Gilchuk, Pavlo, Chen, Rita E., Case, James Brett, Reidy, Joseph X., Trivette, Andrew, Nargi, Rachel S., Sutton, Rachel E., Suryadevara, Naveenchandra, Chen, Elaine C., Binshtein, Elad, Shrihari, Swathi, Chu, Helen Y., Ostrowski, Mario, Didier, Jonathan E., MacRenaris, Keith W., Jones, Taylor, Day, Samuel, Myers, Luke, Lee, F. Eun-Hyung, Nguyen, Doan C., Sanz, Ignacio, Martinez, David R., Rothlauf, Paul W., Bloyet, Louis-Marie, Whelan, Sean P.J., Baric, Ralph S., Thackray, Larissa B., Diamond, Michael S., Carnahan, Robert H., and Crowe, James E., Jr.

Subjects
Immunological research, Monoclonal antibodies -- Identification and classification, Viral proteins -- Research, Biological sciences, Health
Abstract

Antibodies are a principal determinant of immunity for most RNA viruses and have promise to reduce infection or disease during major epidemics. The novel coronavirus SARS-CoV-2 has caused a global pandemic with millions of infections and hundreds of thousands of deaths to date.sup.1,2. In response, we used a rapid antibody discovery platform to isolate hundreds of human monoclonal antibodies (mAbs) against the SARS-CoV-2 spike (S) protein. We stratify these mAbs into five major classes on the basis of their reactivity to subdomains of S protein as well as their cross-reactivity to SARS-CoV. Many of these mAbs inhibit infection of authentic SARS-CoV-2 virus, with most neutralizing mAbs recognizing the receptor-binding domain (RBD) of S. This work defines sites of vulnerability on SARS-CoV-2 S and demonstrates the speed and robustness of advanced antibody discovery platforms. A platform for rapid antibody discovery enabled the isolation of hundreds of human monoclonal antibodies against SARS-CoV-2 and the prioritization of potent antibody candidates for clinical trials in patients with COVID-19., Author(s): Seth J. Zost [sup.1] , Pavlo Gilchuk [sup.1] , Rita E. Chen [sup.2] [sup.3] , James Brett Case [sup.3] , Joseph X. Reidy [sup.1] , Andrew Trivette [sup.1] , [...]

Published
2020
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9. A small molecule exerts selective antiviral activity by targeting the human cytomegalovirus nuclear egress complex

Author

Chen, Han, primary, Lye, Ming F., additional, Gorgulla, Christoph, additional, Ficarro, Scott B., additional, Cuny, Gregory D., additional, Scott, David A., additional, Wu, Fan, additional, Rothlauf, Paul W., additional, Wang, Xiaoou, additional, Fernandez, Rosio, additional, Pesola, Jean M., additional, Draga, Sorin, additional, Marto, Jarrod A., additional, Hogle, James M., additional, Arthanari, Haribabu, additional, and Coen, Donald M., additional

Published
2023
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10. BSL2-compliant lethal mouse model of SARS-CoV-2 and variants of concern to evaluate therapeutics targeting the Spike protein

Author

Manangeeswaran, Mohanraj, primary, Ireland, Derek D. C., additional, Thacker, Seth G., additional, Lee, Ha-Na, additional, Kelley-Baker, Logan, additional, Lewkowicz, Aaron P., additional, Rothlauf, Paul W., additional, Cornejo Pontelli, Marjorie, additional, Bloyet, Louis-Marie, additional, Eckhaus, Michael A., additional, Mendoza, Mirian I., additional, Whelan, Sean, additional, and Verthelyi, Daniela, additional

Published
2022
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12. 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 C.M., 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 A.M., 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 P.G., 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., Theiler, James, Thomas, Paul G., Trifkovic, Sanja, Türeli, Sina, Turner, Samuel A., Vakaki, Maria A., van Bakel, Harm, VanBlargan, Laura A., Vincent, Leah R., Wallace, Zachary S., Wang, Li, Wang, Maple, Wang, Pengfei, Wang, Wei, Weaver, Scott C., Webby, Richard J., Weiss, Carol D., Wentworth, David E., Weston, Stuart M., Whelan, Sean P.J., Whitener, Bradley M., Wilks, Samuel H., Xie, Xuping, Ying, Baoling, Yoon, Hyejin, Zhou, Bin, Hertz, Tomer, Smith, Derek J., Diamond, Michael S., Post, Diane J., Suthar, Mehul S., 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 C.M., 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 A.M., 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 P.G., 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., Theiler, James, Thomas, Paul G., Trifkovic, Sanja, Türeli, Sina, Turner, Samuel A., Vakaki, Maria A., van Bakel, Harm, VanBlargan, Laura A., Vincent, Leah R., Wallace, Zachary S., Wang, Li, Wang, Maple, Wang, Pengfei, Wang, Wei, Weaver, Scott C., Webby, Richard J., Weiss, Carol D., Wentworth, David E., Weston, Stuart M., Whelan, Sean P.J., Whitener, Bradley M., Wilks, Samuel H., Xie, Xuping, Ying, Baoling, Yoon, Hyejin, Zhou, Bin, Hertz, Tomer, Smith, Derek J., Diamond, Michael S., Post, Diane J., and Suthar, Mehul S.

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

13. JIB-04 Has Broad-Spectrum Antiviral Activity and Inhibits SARS-CoV-2 Replication and Coronavirus Pathogenesis

Author

Son, Juhee, primary, Huang, Shimeng, additional, Zeng, Qiru, additional, Bricker, Traci L., additional, Case, James Brett, additional, Zhou, Jinzhu, additional, Zang, Ruochen, additional, Liu, Zhuoming, additional, Chang, Xinjian, additional, Darling, Tamarand L., additional, Xu, Jian, additional, Harastani, Houda H., additional, Chen, Lu, additional, Gomez Castro, Maria Florencia, additional, Zhao, Yongxiang, additional, Kohio, Hinissan P., additional, Hou, Gaopeng, additional, Fan, Baochao, additional, Niu, Beibei, additional, Guo, Rongli, additional, Rothlauf, Paul W., additional, Bailey, Adam L., additional, Wang, Xin, additional, Shi, Pei-Yong, additional, Martinez, Elisabeth D., additional, Brody, Steven L., additional, Whelan, Sean P. J., additional, Diamond, Michael S., additional, Boon, Adrianus C. M., additional, Li, Bin, additional, and Ding, Siyuan, additional

Published
2022
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14. Longitudinal Study after Sputnik V Vaccination Shows Durable SARS-CoV-2 Neutralizing Antibodies and Reduced Viral Variant Escape to Neutralization over Time

Author

Gonzalez Lopez Ledesma, María M., primary, Sanchez, Lautaro, additional, Ojeda, Diego S., additional, Oviedo Rouco, Santiago, additional, Rossi, Andrés H., additional, Varese, Augusto, additional, Mazzitelli, Ignacio, additional, Pascuale, Carla A., additional, Miglietta, Esteban A., additional, Rodríguez, Pamela E., additional, Pallarés, Horacio M., additional, Costa Navarro, Guadalupe S., additional, Caramelo, Julio J., additional, Rothlauf, Paul W., additional, Liu, Zhuoming, additional, Bloyet, Louis-Marie, additional, Cornejo Pontelli, Marjorie, additional, Rasetto, Natali B., additional, Wenker, Shirley D., additional, Ramis, Lila Y., additional, Bialer, Magalí G., additional, de Leone, María Jose, additional, Hernando, C. Esteban, additional, Bianchimano, Luciana, additional, Ríos, Antonella S., additional, Treffinger Cienfuegos, María Soledad, additional, Rodriguez García, Diana R., additional, Longueira, Yesica, additional, Laufer, Natalia, additional, Alvarez, Diego, additional, Ceballos, Ana, additional, Ochoa, Valeria, additional, Monzani, Cecilia, additional, Turk, Gariela, additional, Salvatori, Melina, additional, Carradori, Jorge, additional, Prost, Katherine, additional, Rima, Alejandra, additional, Varela, Claudia, additional, Ercole, Regina, additional, Toro, Rosana I., additional, Gutierrez, Sebastian, additional, Zubieta, Martín, additional, Acuña, Dolores, additional, Nabaes Jodar, Mercedes S., additional, Torres, Carolina, additional, Mojsiejczuk, Laura, additional, Viegas, Mariana, additional, Velazquez, Pilar, additional, Testa, Clarisa, additional, Kreplak, Nicolas, additional, Yanovsky, Marcelo, additional, Whelan, Sean, additional, Geffner, Jorge, additional, Pifano, Marina, additional, and Gamarnik, Andrea V., additional

Published
2022
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16. Longitudinal Study after Sputnik V Vaccination Shows Durable SARS-CoV-2 Neutralizing Antibodies and Reduced Viral Variant Escape over Time

Author

Gonzalez Lopez Ledesma, María M., primary, Sanchez, Lautaro, additional, Ojeda, Diego S., additional, Rouco, Santiago Oviedo, additional, Rossi, Andres H., additional, Varese, Augusto, additional, Mazzitelli, Ignacio, additional, Pascuale, Carla A., additional, Miglietta, Esteban A., additional, Rodríguez, Pamela E., additional, Pallarés, Horacio M., additional, Costa Navarro, Guadalupe S., additional, Caramelo, Julio J., additional, Rothlauf, Paul W, additional, Liu, Zhuoming, additional, Bloyet, Louis-Marie, additional, Pontelli, Marjorie Cornejo, additional, Rasetto, Natali B., additional, Wenker, Shirley D., additional, Ramis, Lila Y., additional, Bialer, Magalí G., additional, Jose de Leone, María, additional, Hernando, C. Esteban, additional, Bianchimano, Luciana, additional, Rios, Antonella, additional, Treffinger Cienfuegos, María Soledad, additional, Rodriguez García, Diana R., additional, Longueira, Yesica, additional, Laufer, Natalia, additional, Alvarez, Diego, additional, Ceballos, Ana, additional, Ochoa, Valeria, additional, Monzani, Cecilia, additional, Turk, Gariela, additional, Salvatori, Melina, additional, Carradori, Jorge, additional, Prost, Katherine, additional, Rima, Alejandra, additional, Varela, Claudia, additional, Ercole, Regina, additional, Toro, Rosana I., additional, Gutierrez, Sebastian, additional, Zubieta, Martín, additional, Acuña, Dolores, additional, Nabaes Jodar, Mercedes S., additional, Torres, Carolina, additional, Mojsiejczuk, Laura, additional, Viegas, Mariana, additional, Velazquez, Pilar, additional, Testa, Clarisa, additional, Kreplak, Nicolas, additional, Yanovsky, Marcelo, additional, Whelan, Sean, additional, Geffner, Jorge, additional, Pifano, Marina, additional, and Gamarnik, Andrea V., additional

Published
2021
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17. Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

Author

Puray-Chavez, Maritza, primary, LaPak, Kyle M., additional, Schrank, Travis P., additional, Elliott, Jennifer L., additional, Bhatt, Dhaval P., additional, Agajanian, Megan J., additional, Jasuja, Ria, additional, Lawson, Dana Q., additional, Davis, Keanu, additional, Rothlauf, Paul W., additional, Liu, Zhuoming, additional, Jo, Heejoon, additional, Lee, Nakyung, additional, Tenneti, Kasyap, additional, Eschbach, Jenna E., additional, Shema Mugisha, Christian, additional, Cousins, Emily M., additional, Cloer, Erica W., additional, Vuong, Hung R., additional, VanBlargan, Laura A., additional, Bailey, Adam L., additional, Gilchuk, Pavlo, additional, Crowe, James E., additional, Diamond, Michael S., additional, Hayes, D. Neil, additional, Whelan, Sean P.J., additional, Horani, Amjad, additional, Brody, Steven L., additional, Goldfarb, Dennis, additional, Major, M. Ben, additional, and Kutluay, Sebla B., additional

Published
2021
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18. A class II MHC-targeted vaccine elicits immunity against SARS-CoV-2 and its variants

Author

MMB Research line 3a, Infection & Immunity, Pishesha, Novalia, Harmand, Thibault J, Rothlauf, Paul W, Praest, Patrique, Alexander, Ryan K, van den Doel, Renate, Liebeskind, Mariel J, Vakaki, Maria A, McCaul, Nicholas, Wijne, Charlotte, Verhaar, Elisha, Pinney, William, Heston, Hailey, Bloyet, Louis-Marie, Pontelli, Marjorie Cornejo, Ilagan, Ma Xenia G, Jan Lebbink, Robert, Buchser, William J, Wiertz, Emmanuel J H J, Whelan, Sean P J, Ploegh, Hidde L, MMB Research line 3a, Infection & Immunity, Pishesha, Novalia, Harmand, Thibault J, Rothlauf, Paul W, Praest, Patrique, Alexander, Ryan K, van den Doel, Renate, Liebeskind, Mariel J, Vakaki, Maria A, McCaul, Nicholas, Wijne, Charlotte, Verhaar, Elisha, Pinney, William, Heston, Hailey, Bloyet, Louis-Marie, Pontelli, Marjorie Cornejo, Ilagan, Ma Xenia G, Jan Lebbink, Robert, Buchser, William J, Wiertz, Emmanuel J H J, Whelan, Sean P J, and Ploegh, Hidde L

Published
2021

19. A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

Author

Mahoney, Matthew, primary, Damalanka, Vishnu C., additional, Tartell, Michael A., additional, Chung, Dong Hee, additional, Lourenco, André Luiz, additional, Pwee, Dustin, additional, Mayer Bridwell, Anne E., additional, Hoffmann, Markus, additional, Voss, Jorine, additional, Karmakar, Partha, additional, Azouz, Nurit, additional, Klingler, Andrea M., additional, Rothlauf, Paul W., additional, Thompson, Cassandra E., additional, Lee, Melody, additional, Klampfer, Lidija, additional, Stallings, Christina, additional, Rothenberg, Marc E., additional, Pöhlmann, Stefan, additional, Whelan, Sean P., additional, O’Donoghue, Anthony J., additional, Craik, Charles S., additional, and Janetka, James W., additional

Published
2021
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20. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Author

McCallum, Matthew, primary, De Marco, Anna, additional, Lempp, Florian A., additional, Tortorici, M. Alejandra, additional, Pinto, Dora, additional, Walls, Alexandra C., additional, Beltramello, Martina, additional, Chen, Alex, additional, Liu, Zhuoming, additional, Zatta, Fabrizia, additional, Zepeda, Samantha, additional, di Iulio, Julia, additional, Bowen, John E., additional, Montiel-Ruiz, Martin, additional, Zhou, Jiayi, additional, Rosen, Laura E., additional, Bianchi, Siro, additional, Guarino, Barbara, additional, Fregni, Chiara Silacci, additional, Abdelnabi, Rana, additional, Foo, Shi-Yan Caroline, additional, Rothlauf, Paul W., additional, Bloyet, Louis-Marie, additional, Benigni, Fabio, additional, Cameroni, Elisabetta, additional, Neyts, Johan, additional, Riva, Agostino, additional, Snell, Gyorgy, additional, Telenti, Amalio, additional, Whelan, Sean P.J., additional, Virgin, Herbert W., additional, Corti, Davide, additional, Pizzuto, Matteo Samuele, additional, and Veesler, David, additional

Published
2021
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21. Nitazoxanide and JIB-04 have broad-spectrum antiviral activity and inhibit SARS-CoV-2 replication in cell culture and coronavirus pathogenesis in a pig model

Author

Son, Juhee, Huang, Shimeng, Zeng, Qiru, Bricker, Traci L., Case, James Brett, Zhou, Jinzhu, Zang, Ruochen, Liu, Zhuoming, Chang, Xinjian, Harastani, Houda H., Chen, Lu, Castro, Maria Florencia Gomez, Zhao, Yongxiang, Kohio, Hinissan P., Hou, Gaopeng, Fan, Baochao, Niu, Beibei, Guo, Rongli, Rothlauf, Paul W., Bailey, Adam L., Wang, Xin, Shi, Pei-Yong, Whelan, Sean P.J., Diamond, Michael S., Boon, Adrianus C.M., Li, Bin, and Ding, Siyuan

Subjects
viruses, Article
Abstract

Pathogenic coronaviruses represent a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified several small-molecule inhibitors that potently block the replication of the newly emerged severe acute respiratory syndrome virus 2 (SARS-CoV-2). Two compounds, nitazoxanide and JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with an EC (50) of 4.90 μM and 0.69 μM, respectively, with specificity indices of greater than 150. Both inhibitors had in vitro antiviral activity in multiple cell types against some DNA and RNA viruses, including porcine transmissible gastroenteritis virus. In an in vivo porcine model of coronavirus infection, administration of JIB-04 reduced virus infection and associated tissue pathology, which resulted in improved body weight gain and survival. These results highlight the potential utility of nitazoxanide and JIB-04 as antiviral agents against SARS-CoV-2 and other viral pathogens.

Published
2020

22. Inhibition of PIKfyve kinase prevents infection by EBOV and SARS-CoV-2

Author

Kang, Yuan-Lin, Chou, Yi-Ying, Rothlauf, Paul W., Liu, Zhuoming, Soh, Timothy K., Cureton, David, Case, James Brett, Chen, Rita E., Diamond, Michael S., Whelan, Sean P. J., and Kirchhausen, Tom

Subjects
viruses
Abstract

Virus entry is a multistep process. It initiates when the virus attaches to the host cell and ends when the viral contents reach the cytosol. Genetically unrelated viruses can subvert analogous subcellular mechanisms and use similar trafficking pathways for successful entry. Antiviral strategies targeting early steps of infection are therefore appealing, particularly when the probability for successful interference through a common step is highest. We describe here potent inhibitory effects on content release and infection by chimeric VSV containing the envelope proteins of EBOV (VSV-EBOV) or SARS-CoV-2 (VSV-SARS-CoV-2) elicited by Apilimod and Vacuolin-1, small molecule inhibitors of the main endosomal Phosphatidylinositol-3-Phosphate/Phosphatidylinositol 5-Kinase, PIKfyve. We also describe potent inhibition of SARS-CoV-2 strain 2019-nCoV/USA-WA1/2020 by Apilimod. These results define new tools for studying the intracellular trafficking of pathogens elicited by inhibition of PIKfyve kinase and suggest the potential for targeting this kinase in developing a small-molecule antiviral against SARS-CoV-2.

Published
2020
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23. Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition

Author

Greaney, Allison J., primary, Starr, Tyler N., additional, Gilchuk, Pavlo, additional, Zost, Seth J., additional, Binshtein, Elad, additional, Loes, Andrea N., additional, Hilton, Sarah K., additional, Huddleston, John, additional, Eguia, Rachel, additional, Crawford, Katharine H.D., additional, Dingens, Adam S., additional, Nargi, Rachel S., additional, Sutton, Rachel E., additional, Suryadevara, Naveenchandra, additional, Rothlauf, Paul W., additional, Liu, Zhuoming, additional, Whelan, Sean P.J., additional, Carnahan, Robert H., additional, Crowe, James E., additional, and Bloom, Jesse D., additional

Published
2021
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24. Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization

Author

Liu, Zhuoming, primary, VanBlargan, Laura A., additional, Bloyet, Louis-Marie, additional, Rothlauf, Paul W., additional, Chen, Rita E., additional, Stumpf, Spencer, additional, Zhao, Haiyan, additional, Errico, John M., additional, Theel, Elitza S., additional, Liebeskind, Mariel J., additional, Alford, Brynn, additional, Buchser, William J., additional, Ellebedy, Ali H., additional, Fremont, Daved H., additional, Diamond, Michael S., additional, and Whelan, Sean P. J., additional

Published
2020
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25. JIB-04 has broad-spectrum antiviral activity and inhibits SARS-CoV-2 replication and coronavirus pathogenesis

Author

Son, Juhee, primary, Huang, Shimeng, additional, Zeng, Qiru, additional, Bricker, Traci L., additional, Case, James Brett, additional, Zhou, Jinzhu, additional, Zang, Ruochen, additional, Liu, Zhuoming, additional, Chang, Xinjian, additional, Harastani, Houda H., additional, Chen, Lu, additional, Gomez Castro, Maria Florencia, additional, Zhao, Yongxiang, additional, Kohio, Hinissan P., additional, Hou, Gaopeng, additional, Fan, Baochao, additional, Niu, Beibei, additional, Guo, Rongli, additional, Rothlauf, Paul W., additional, Bailey, Adam L., additional, Wang, Xin, additional, Shi, Pei-Yong, additional, Martinez, Elisabeth D., additional, Whelan, Sean P.J., additional, Diamond, Michael S., additional, Boon, Adrianus C.M., additional, Li, Bin, additional, and Ding, Siyuan, additional

Published
2020
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26. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition

Author

Greaney, Allison J., primary, Starr, Tyler N., additional, Gilchuk, Pavlo, additional, Zost, Seth J., additional, Binshtein, Elad, additional, Loes, Andrea N., additional, Hilton, Sarah K., additional, Huddleston, John, additional, Eguia, Rachel, additional, Crawford, Katharine H.D., additional, Dingens, Adam S., additional, Nargi, Rachel S., additional, Sutton, Rachel E., additional, Suryadevara, Naveenchandra, additional, Rothlauf, Paul W., additional, Liu, Zhuoming, additional, Whelan, Sean P.J., additional, Carnahan, Robert H., additional, Crowe, James E., additional, and Bloom, Jesse D., additional

Published
2020
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27. Replication-Competent Vesicular Stomatitis Virus Vaccine Vector Protects against SARS-CoV-2-Mediated Pathogenesis in Mice

Author

Case, James Brett, primary, Rothlauf, Paul W., additional, Chen, Rita E., additional, Kafai, Natasha M., additional, Fox, Julie M., additional, Smith, Brittany K., additional, Shrihari, Swathi, additional, McCune, Broc T., additional, Harvey, Ian B., additional, Keeler, Shamus P., additional, Bloyet, Louis-Marie, additional, Zhao, Haiyan, additional, Ma, Meisheng, additional, Adams, Lucas J., additional, Winkler, Emma S., additional, Holtzman, Michael J., additional, Fremont, Daved H., additional, Whelan, Sean P.J., additional, and Diamond, Michael S., additional

Published
2020
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28. Neutralizing Antibody and Soluble ACE2 Inhibition of a Replication-Competent VSV-SARS-CoV-2 and a Clinical Isolate of SARS-CoV-2

Author

Case, James Brett, primary, Rothlauf, Paul W., additional, Chen, Rita E., additional, Liu, Zhuoming, additional, Zhao, Haiyan, additional, Kim, Arthur S., additional, Bloyet, Louis-Marie, additional, Zeng, Qiru, additional, Tahan, Stephen, additional, Droit, Lindsay, additional, Ilagan, Ma. Xenia G., additional, Tartell, Michael A., additional, Amarasinghe, Gaya, additional, Henderson, Jeffrey P., additional, Miersch, Shane, additional, Ustav, Mart, additional, Sidhu, Sachdev, additional, Virgin, Herbert W., additional, Wang, David, additional, Ding, Siyuan, additional, Corti, Davide, additional, Theel, Elitza S., additional, Fremont, Daved H., additional, Diamond, Michael S., additional, and Whelan, Sean P.J., additional

Published
2020
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29. Replication-competent vesicular stomatitis virus vaccine vector protects against SARS-CoV-2-mediated pathogenesis

Author

Case, James Brett, primary, Rothlauf, Paul W., additional, Chen, Rita E., additional, Kafai, Natasha M., additional, Fox, Julie M., additional, Shrihari, Swathi, additional, McCune, Broc T., additional, Harvey, Ian B., additional, Smith, Brittany, additional, Keeler, Shamus P., additional, Bloyet, Louis-Marie, additional, Winkler, Emma S., additional, Holtzman, Michael J., additional, Fremont, Daved H., additional, Whelan, Sean P.J., additional, and Diamond, Michael S., additional

Published
2020
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30. Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion

Author

Zang, Ruochen, primary, Case, James Brett, additional, Gomez Castro, Maria Florencia, additional, Liu, Zhuoming, additional, Zeng, Qiru, additional, Zhao, Haiyan, additional, Son, Juhee, additional, Rothlauf, Paul W., additional, Hou, Gaopeng, additional, Bose, Sayantan, additional, Wang, Xin, additional, Vahey, Michael D., additional, Kirchhausen, Tomas, additional, Fremont, Daved H., additional, Diamond, Michael S., additional, Whelan, Sean P.J., additional, and Ding, Siyuan, additional

Published
2020
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31. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes

Author

Zang, Ruochen, primary, Castro, Maria Florencia Gomez, additional, McCune, Broc T., additional, Zeng, Qiru, additional, Rothlauf, Paul W., additional, Sonnek, Naomi M., additional, Liu, Zhuoming, additional, Brulois, Kevin F., additional, Wang, Xin, additional, Greenberg, Harry B., additional, Diamond, Michael S., additional, Ciorba, Matthew A., additional, Whelan, Sean P. J., additional, and Ding, Siyuan, additional

Published
2020
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32. TMPRSS2 and TMPRSS4 mediate SARS-CoV-2 infection of human small intestinal enterocytes

Author

Zang, Ruochen, primary, Castro, Maria F.G., additional, McCune, Broc T., additional, Zeng, Qiru, additional, Rothlauf, Paul W., additional, Sonnek, Naomi M., additional, Liu, Zhuoming, additional, Brulois, Kevin F., additional, Wang, Xin, additional, Greenberg, Harry B., additional, Diamond, Michael S., additional, Ciorba, Matthew A., additional, Whelan, Sean P.J., additional, and Ding, Siyuan, additional

Published
2020
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35. Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion.

Author

Ruochen Zang, Case, James Brett, Yutuc, Eylan, Xiucui Ma, Sheng Shen, Gomez Castro, Maria Florencia, Zhuoming Liu, Qiru Zeng, Haiyan Zhao, Juhee Son, Rothlauf, Paul W., Kreutzberger, Alex J. B., Gaopeng Hou, Hu Zhang, Bose, Sayantan, Xin Wang, Vahey, Michael D., Mani, Kartik, Griffiths, William J., and Kirchhausen, Tom

Subjects
MEMBRANE fusion, SARS-CoV-2, VESICULAR stomatitis, CHOLESTEROL, MEMBRANE proteins
Abstract

Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development. [ABSTRACT FROM AUTHOR]

Published
2020
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36. Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2.

Author

Yuan-Lin Kang, Yi-ying Chou, Rothlauf, Paul W., Zhuoming Liu, Soh, Timothy K., Cureton, David, Case, James Brett, Chen, Rita E., Diamon, Michael S., Whelan, Sean P. J., and Kirchhausen, Tom

Subjects
EBOLA virus, SARS-CoV-2, VESICULAR stomatitis, INFECTION
Abstract

Virus entry is a multistep process. It initiates when the virus attaches to the host cell and ends when the viral contents reach the cytosol. Genetically unrelated viruses can subvert analogous subcellular mechanisms and use similar trafficking pathways for successful entry. Antiviral strategies targeting early steps of infection are therefore appealing, particularly when the probability for successful interference through a common step is highest. We describe here potent inhibitory effects on content release and infection by chimeric vesicular stomatitis virus (VSV) containing the envelope proteins of Zaire ebolavirus (VSV-ZEBOV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (VSV-SARS-CoV-2) elicited by Apilimod and Vacuolin-1, small-molecule inhibitors of the main endosomal phosphatidylinositol-3-phosphate/phosphatidylinositol 5-kinase, PIKfyve. We also describe potent inhibition of SARS-CoV-2 strain 2019-nCoV/USA-WA1/2020 by Apilimod. These results define tools for studying the intracellular trafficking of pathogens elicited by inhibition of PIKfyve kinase and suggest the potential for targeting this kinase in developing small-molecule antivirals against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Published
2020
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38. Defining the risk of SARS-CoV-2 variants on immune protection

Author

Marciela M. DeGrace, Elodie Ghedin, Matthew B. Frieman, Florian Krammer, Alba Grifoni, Arghavan Alisoltani, Galit Alter, Rama R. Amara, Ralph S. Baric, Dan H. Barouch, Jesse D. Bloom, Louis-Marie Bloyet, Gaston Bonenfant, Adrianus C. M. Boon, Eli A. Boritz, Debbie L. Bratt, Traci L. Bricker, Liliana Brown, William J. Buchser, Juan Manuel Carreño, Liel Cohen-Lavi, Tamarand L. Darling, Meredith E. Davis-Gardner, Bethany L. Dearlove, Han Di, Meike Dittmann, Nicole A. Doria-Rose, Daniel C. Douek, Christian Drosten, Venkata-Viswanadh Edara, Ali Ellebedy, Thomas P. Fabrizio, Guido Ferrari, Will M. Fischer, William C. Florence, Ron A. M. Fouchier, John Franks, Adolfo García-Sastre, Adam Godzik, Ana Silvia Gonzalez-Reiche, Aubree Gordon, Bart L. Haagmans, Peter J. Halfmann, David D. Ho, Michael R. Holbrook, Yaoxing Huang, Sarah L. James, Lukasz Jaroszewski, Trushar Jeevan, Robert M. Johnson, Terry C. Jones, Astha Joshi, Yoshihiro Kawaoka, Lisa Kercher, Marion P. G. Koopmans, Bette Korber, Eilay Koren, Richard A. Koup, Eric B. LeGresley, Jacob E. Lemieux, Mariel J. Liebeskind, Zhuoming Liu, Brandi Livingston, James P. Logue, Yang Luo, Adrian B. McDermott, Margaret J. McElrath, Victoria A. Meliopoulos, Vineet D. Menachery, David C. Montefiori, Barbara Mühlemann, Vincent J. Munster, Jenny E. Munt, Manoj S. Nair, Antonia Netzl, Anna M. Niewiadomska, Sijy O’Dell, Andrew Pekosz, Stanley Perlman, Marjorie C. Pontelli, Barry Rockx, Morgane Rolland, Paul W. Rothlauf, Sinai Sacharen, Richard H. Scheuermann, Stephen D. Schmidt, Michael Schotsaert, Stacey Schultz-Cherry, Robert A. Seder, Mayya Sedova, Alessandro Sette, Reed S. Shabman, Xiaoying Shen, Pei-Yong Shi, Maulik Shukla, Viviana Simon, Spencer Stumpf, Nancy J. Sullivan, Larissa B. Thackray, James Theiler, Paul G. Thomas, Sanja Trifkovic, Sina Türeli, Samuel A. Turner, Maria A. Vakaki, Harm van Bakel, Laura A. VanBlargan, Leah R. Vincent, Zachary S. Wallace, Li Wang, Maple Wang, Pengfei Wang, Wei Wang, Scott C. Weaver, Richard J. Webby, Carol D. Weiss, David E. Wentworth, Stuart M. Weston, Sean P. J. Whelan, Bradley M. Whitener, Samuel H. Wilks, Xuping Xie, Baoling Ying, Hyejin Yoon, Bin Zhou, Tomer Hertz, Derek J. Smith, Michael S. Diamond, Diane J. Post, Mehul S. Suthar, Ghedin, Elodie [0000-0002-1515-725X], Frieman, Matthew B [0000-0003-0107-0775], Krammer, Florian [0000-0003-4121-776X], Grifoni, Alba [0000-0002-2209-5966], Alter, Galit [0000-0002-7680-9215], Amara, Rama R [0000-0002-6309-6797], Baric, Ralph S [0000-0001-6827-8701], Barouch, Dan H [0000-0001-5127-4659], Bloom, Jesse D [0000-0003-1267-3408], Bloyet, Louis-Marie [0000-0002-5648-3190], Boon, Adrianus CM [0000-0002-4700-8224], Bratt, Debbie L [0000-0002-5822-5558], Buchser, William J [0000-0002-6675-6359], Cohen-Lavi, Liel [0000-0001-6909-4779], Dearlove, Bethany L [0000-0003-3653-4592], Drosten, Christian [0000-0001-7923-0519], Edara, Venkata-Viswanadh [0000-0001-9321-7839], Ellebedy, Ali [0000-0002-6129-2532], Fabrizio, Thomas P [0000-0002-8960-0728], Fouchier, Ron AM [0000-0001-8095-2869], García-Sastre, Adolfo [0000-0002-6551-1827], Godzik, Adam [0000-0002-2425-852X], Gonzalez-Reiche, Ana Silvia [0000-0003-3583-4497], Gordon, Aubree [0000-0002-9352-7877], Haagmans, Bart L [0000-0001-6221-2015], Ho, David D [0000-0003-1627-149X], Holbrook, Michael R [0000-0002-0824-2667], Huang, Yaoxing [0000-0001-6270-1644], James, Sarah L [0000-0002-6969-1167], Johnson, Robert M [0000-0002-1976-7688], Jones, Terry C [0000-0003-1120-9531], Joshi, Astha [0000-0003-4914-8228], Kawaoka, Yoshihiro [0000-0001-5061-8296], Kercher, Lisa [0000-0001-6300-0452], Koopmans, Marion PG [0000-0002-5204-2312], Korber, Bette [0000-0002-2026-5757], LeGresley, Eric B [0000-0002-5286-5693], Liebeskind, Mariel J [0000-0003-4595-0651], Liu, Zhuoming [0000-0001-8198-0976], Logue, James P [0000-0002-7410-9741], Luo, Yang [0000-0003-3277-8792], McDermott, Adrian B [0000-0003-0616-9117], Meliopoulos, Victoria A [0000-0003-1442-9177], Menachery, Vineet D [0000-0001-8803-7606], Munster, Vincent J [0000-0002-2288-3196], Nair, Manoj S [0000-0002-5994-3957], Netzl, Antonia [0000-0001-8034-2382], Pekosz, Andrew [0000-0003-3248-1761], Perlman, Stanley [0000-0003-4213-2354], Rockx, Barry [0000-0003-2463-027X], Rolland, Morgane [0000-0003-3650-8490], Rothlauf, Paul W [0000-0002-0941-4467], Scheuermann, Richard H [0000-0003-1355-892X], Schotsaert, Michael [0000-0003-3156-3132], Schultz-Cherry, Stacey [0000-0002-2021-727X], Seder, Robert A [0000-0003-3133-0849], Shabman, Reed S [0000-0003-3272-3484], Shi, Pei-Yong [0000-0001-5553-1616], Simon, Viviana [0000-0002-6416-5096], Thackray, Larissa B [0000-0002-9380-6569], Thomas, Paul G [0000-0001-7955-0256], Trifkovic, Sanja [0000-0002-0710-9514], Türeli, Sina [0000-0001-7342-9295], van Bakel, Harm [0000-0002-1376-6916], VanBlargan, Laura A [0000-0002-8922-8946], Vincent, Leah R [0000-0001-9262-1813], Wallace, Zachary S [0000-0003-0237-501X], Wang, Pengfei [0000-0003-2454-7652], Weaver, Scott C [0000-0001-8016-8556], Webby, Richard J [0000-0002-4397-7132], Weiss, Carol D [0000-0002-9965-1289], Wentworth, David E [0000-0002-5190-980X], Weston, Stuart M [0000-0001-9840-2953], Whelan, Sean PJ [0000-0003-1564-8590], Whitener, Bradley M [0000-0001-6652-0701], Xie, Xuping [0000-0003-0918-016X], Yoon, Hyejin [0000-0002-3344-9096], Hertz, Tomer [0000-0002-0561-1578], Smith, Derek J [0000-0002-2393-1890], Diamond, Michael S [0000-0002-8791-3165], Post, Diane J [0000-0003-3890-9116], Suthar, Mehul S [0000-0002-2686-8380], and Apollo - University of Cambridge Repository

Subjects
Multidisciplinary, COVID-19 Vaccines, Pharmacogenomic Variants, Virulence, SARS-CoV-2, COVID-19, Biological Evolution, Article, United States, SDG 3 - Good Health and Well-being, National Institute of Allergy and Infectious Diseases (U.S.), Animals, Humans, Pandemics
Abstract

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced following 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 (NIAID) within the National Institutes of Health (NIH) established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants potentially impacting transmission, virulence, and resistance to convalescent and vaccine-induced immunity. The SAVE program serves as a critical data-generating component of the United States 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 pivotal findings facilitated by this collaborative approach and identify future challenges. This program serves as a template for the response against rapidly evolving pandemic pathogens by monitoring viral evolution in the human population to identify variants that could erode the effectiveness of countermeasures.

Published
2022

39. Noninvasive Immuno-PET Imaging of CD8 + T Cell Behavior in Influenza A Virus-Infected Mice.

Author

Rothlauf PW, Li Z, Pishesha N, Xie YJ, Woodham AW, Bousbaine D, Kolifrath SC, Verschoor VL, and Ploegh HL

Subjects
Amino Acid Sequence, Animals, Biomarkers, CD8-Positive T-Lymphocytes metabolism, Cell Tracking, Disease Models, Animal, Immunophenotyping, Mice, Models, Molecular, Molecular Probes chemistry, Orthomyxoviridae Infections metabolism, Orthomyxoviridae Infections virology, Peptides chemistry, CD8-Positive T-Lymphocytes immunology, Influenza A virus immunology, Molecular Imaging methods, Orthomyxoviridae Infections diagnosis, Orthomyxoviridae Infections immunology, Positron-Emission Tomography methods
Abstract

Immuno-positron emission tomography (immuno-PET) is a noninvasive imaging method that enables tracking of immune cells in living animals. We used a nanobody that recognizes mouse CD8α and labeled it with 89 Zr to image mouse CD8 + T cells in the course of an infection with influenza A virus (IAV). The CD8 + signal showed a strong increase in the mediastinal lymph node (MLN) and thymus as early as 4 days post-infection (dpi), and as early as 6 dpi in the lungs. Over the course of the infection, CD8 + T cells were at first distributed diffusely throughout the lungs and then accumulated more selectively in specific regions of the lungs. These distributions correlated with morbidity as mice reached the peak of weight loss over this interval. CD8 + T cells obtained from control or IAV-infected mice showed a difference in their distribution and migration when comparing their fate upon labeling ex vivo with 89 Zr-labeled anti-CD8α nanobody and transfer into infected versus control animals. CD8 + T cells from infected mice, upon transfer, appear to be trained to persist in the lungs, even of uninfected mice. Immuno-PET imaging thus allows noninvasive, dynamic monitoring of the immune response to infectious agents in living animals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rothlauf, Li, Pishesha, Xie, Woodham, Bousbaine, Kolifrath, Verschoor and Ploegh.)

Published
2021
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40. JIB-04 has broad-spectrum antiviral activity and inhibits SARS-CoV-2 replication and coronavirus pathogenesis.

Author

Son J, Huang S, Zeng Q, Bricker TL, Case JB, Zhou J, Zang R, Liu Z, Chang X, Harastani HH, Chen L, Castro MFG, Zhao Y, Kohio HP, Hou G, Fan B, Niu B, Guo R, Rothlauf PW, Bailey AL, Wang X, Shi PY, Martinez ED, Whelan SPJ, Diamond MS, Boon ACM, Li B, and Ding S

Abstract

Pathogenic coronaviruses represent a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified several small-molecule inhibitors that potently block the replication of the newly emerged severe acute respiratory syndrome virus 2 (SARS-CoV-2). Among them, JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with an EC 50 of 695 nM, with a specificity index of greater than 1,000. JIB-04 showed in vitro antiviral activity in multiple cell types against several DNA and RNA viruses, including porcine coronavirus transmissible gastroenteritis virus. In an in vivo porcine model of coronavirus infection, administration of JIB-04 reduced virus infection and associated tissue pathology, which resulted in improved weight gain and survival. These results highlight the potential utility of JIB-04 as an antiviral agent against SARS-CoV-2 and other viral pathogens., Competing Interests: Competing interests The Boon laboratory has scientific research agreements with AI therapeutics, Greenlight Biosciences and Nano Targeting & Therapy Biopharma Inc. M.S.D. is a consultant for Inbios, Eli Lilly, Vir Biotechnology, NGM Biopharmaceuticals, and Emergent BioSolutions and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory at Washington University School of Medicine has received unrelated sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions.

Published
2021
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41. A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells.

Author

Mahoney M, Damalanka VC, Tartell MA, Chung DH, Lourenco AL, Pwee D, Mayer Bridwell AE, Hoffmann M, Voss J, Karmakar P, Azouz N, Klingler AM, Rothlauf PW, Thompson CE, Lee M, Klampfer L, Stallings C, Rothenberg ME, Pöhlmann S, Whelan SP, O'Donoghue AJ, Craik CS, and Janetka JW

Abstract

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered a novel class of small molecule ketobenzothiazole TMPRSS2 inhibitors with significantly improved activity over existing irreversible inhibitors Camostat and Nafamostat. Lead compound MM3122 ( 4 ) has an IC 50 of 340 pM against recombinant full-length TMPRSS2 protein, an EC 50 of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV SARS-CoV-2 chimeric virus, and an EC 50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East Respiratory Syndrome Coronavirus (MERS-CoV) cell entry with an EC 50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice with a half-life of 8.6 hours in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.

Published
2021
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42. Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell.

Author

Puray-Chavez M, LaPak KM, Schrank TP, Elliott JL, Bhatt DP, Agajanian MJ, Jasuja R, Lawson DQ, Davis K, Rothlauf PW, Jo H, Lee N, Tenneti K, Eschbach JE, Mugisha CS, Vuong HR, Bailey AL, Hayes DN, Whelan SPJ, Horani A, Brody SL, Goldfarb D, Major MB, and Kutluay SB

Abstract

Established in vitro models for SARS-CoV-2 infection are limited and include cell lines of non-human origin and those engineered to overexpress ACE2, the cognate host cell receptor. We identified human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of ACE2. Infection of H522 cells required the SARS-CoV-2 spike protein, though in contrast to ACE2-dependent models, spike alone was not sufficient for H522 infection. Temporally resolved transcriptomic and proteomic profiling revealed alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type-I interferon signaling. Focused chemical screens point to important roles for clathrin-mediated endocytosis and endosomal cathepsins in SARS-CoV-2 infection of H522 cells. These findings imply the utilization of an alternative SARS-CoV-2 host cell receptor which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.

Published
2021
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43. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2.

Author

McCallum M, Marco A, Lempp F, Tortorici MA, Pinto D, Walls AC, Beltramello M, Chen A, Liu Z, Zatta F, Zepeda S, di Iulio J, Bowen JE, Montiel-Ruiz M, Zhou J, Rosen LE, Bianchi S, Guarino B, Fregni CS, Abdelnabi R, Caroline Foo SY, Rothlauf PW, Bloyet LM, Benigni F, Cameroni E, Neyts J, Riva A, Snell G, Telenti A, Whelan SPJ, Virgin HW, Corti D, Pizzuto MS, and Veesler D

Abstract

SARS-CoV-2 entry into host cells is orchestrated by the spike (S) glycoprotein that contains an immunodominant receptor-binding domain (RBD) targeted by the largest fraction of neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge. SARS-CoV-2 variants, including the 501Y.V2 and B.1.1.7 lineages, harbor frequent mutations localized in the NTD supersite suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs to protective immunity.

Published
2021
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44. Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization.

Author

Liu Z, VanBlargan LA, Bloyet LM, Rothlauf PW, Chen RE, Stumpf S, Zhao H, Errico JM, Theel ES, Liebeskind MJ, Alford B, Buchser WJ, Ellebedy AH, Fremont DH, Diamond MS, and Whelan SPJ

Abstract

Although neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics, viral escape mutants could compromise their efficacy. To define the immune-selected mutational landscape in S protein, we used a VSV-eGFP-SARS-CoV-2-S chimeric virus and 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) to generate 50 different escape mutants. The variants were mapped onto the RBD structure and evaluated for cross-resistance to mAbs and convalescent human sera. Each mAb had a unique resistance profile, although many shared residues within an epitope. Some variants ( e.g ., S477N) were resistant to neutralization by multiple mAbs, whereas others ( e.g ., E484K) escaped neutralization by convalescent sera, suggesting some humans induce a narrow repertoire of neutralizing antibodies. Comparing the antibody-mediated mutational landscape in S with sequence variation in circulating SARS-CoV-2, we define substitutions that may attenuate neutralizing immune responses in some humans.

Published
2021
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45. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition.

Author

Greaney AJ, Starr TN, Gilchuk P, Zost SJ, Binshtein E, Loes AN, Hilton SK, Huddleston J, Eguia R, Crawford KHD, Dingens AS, Nargi RS, Sutton RE, Suryadevara N, Rothlauf PW, Liu Z, Whelan SPJ, Carnahan RH, Crowe JE Jr, and Bloom JD

Abstract

Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and make a major contribution to the neutralizing antibody response elicited by infection. Here, we describe a deep mutational scanning method to map how all amino-acid mutations in the RBD affect antibody binding, and apply this method to 10 human monoclonal antibodies. The escape mutations cluster on several surfaces of the RBD that broadly correspond to structurally defined antibody epitopes. However, even antibodies targeting the same RBD surface often have distinct escape mutations. The complete escape maps predict which mutations are selected during viral growth in the presence of single antibodies, and enable us to design escape-resistant antibody cocktails-including cocktails of antibodies that compete for binding to the same surface of the RBD but have different escape mutations. Therefore, complete escape-mutation maps enable rational design of antibody therapeutics and assessment of the antigenic consequences of viral evolution., Competing Interests: Declarations of Interests J.E.C. has served as a consultant for Sanofi; is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines; is a recipient of previous unrelated research grants from Moderna and Sanofi; and is a founder of IDBiologics. Vanderbilt University has applied for patents concerning SARS-CoV-2 antibodies analyzed in this work. S.P.J.W. and P.W.R. have filed a disclosure with Washington University for the recombinant VSV. The other authors declare no competing interests.

Published
2020
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46. Replication-competent vesicular stomatitis virus vaccine vector protects against SARS-CoV-2-mediated pathogenesis.

Author

Case JB, Rothlauf PW, Chen RE, Kafai NM, Fox JM, Shrihari S, McCune BT, Harvey IB, Smith B, Keeler SP, Bloyet LM, Winkler ES, Holtzman MJ, Fremont DH, Whelan SPJ, and Diamond MS

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of human infections and hundreds of thousands of deaths. Accordingly, an effective vaccine is of critical importance in mitigating coronavirus induced disease 2019 (COVID-19) and curtailing the pandemic. We developed a replication-competent vesicular stomatitis virus (VSV)-based vaccine by introducing a modified form of the SARS-CoV-2 spike gene in place of the native glycoprotein gene (VSV-eGFP-SARS-CoV-2). Immunization of mice with VSV-eGFP-SARS-CoV-2 elicits high titers of antibodies that neutralize SARS-CoV-2 infection and target the receptor binding domain that engages human angiotensin converting enzyme-2 (ACE2). Upon challenge with a human isolate of SARS-CoV-2, mice expressing human ACE2 and immunized with VSV-eGFP-SARS-CoV-2 show profoundly reduced viral infection and inflammation in the lung indicating protection against pneumonia. Finally, passive transfer of sera from VSV-eGFP-SARS-CoV-2-immunized animals protects naïve mice from SARS-CoV-2 challenge. These data support development of VSV-eGFP-SARS-CoV-2 as an attenuated, replication-competent vaccine against SARS-CoV-2.

Published
2020
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47. Neutralizing antibody and soluble ACE2 inhibition of a replication-competent VSV-SARS-CoV-2 and a clinical isolate of SARS-CoV-2.

Author

Case JB, Rothlauf PW, Chen RE, Liu Z, Zhao H, Kim AS, Bloyet LM, Zeng Q, Tahan S, Droit L, Ilagan MXG, Tartell MA, Amarasinghe G, Henderson JP, Miersch S, Ustav M, Sidhu S, Virgin HW, Wang D, Ding S, Corti D, Theel ES, Fremont DH, Diamond MS, and Whelan SPJ

Abstract

Antibody-based interventions against SARS-CoV-2 could limit morbidity, mortality, and possibly disrupt epidemic transmission. An anticipated correlate of such countermeasures is the level of neutralizing antibodies against the SARS-CoV-2 spike protein, yet there is no consensus as to which assay should be used for such measurements. Using an infectious molecular clone of vesicular stomatitis virus (VSV) that expresses eGFP as a marker of infection, we replaced the glycoprotein gene (G) with the spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and developed a high-throughput imaging-based neutralization assay at biosafety level 2. We also developed a focus reduction neutralization test with a clinical isolate of SARS-CoV-2 at biosafety level 3. We compared the neutralizing activities of monoclonal and polyclonal antibody preparations, as well as ACE2-Fc soluble decoy protein in both assays and find an exceptionally high degree of concordance. The two assays will help define correlates of protection for antibody-based countermeasures including therapeutic antibodies, immune γ-globulin or plasma preparations, and vaccines against SARS-CoV-2. Replication-competent VSV-eGFP-SARSCoV-2 provides a rapid assay for testing inhibitors of SARS-CoV-2 mediated entry that can be performed in 7.5 hours under reduced biosafety containment., Competing Interests: COMPETING FINANCIAL INTERESTS M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and on the Scientific Advisory Board of Moderna. D.C. and H.W.V. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. S.P.J.W. and P.W.R. have filed a disclosure with Washington University for the recombinant VSV.

Published
2020
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