31 results on '"Thorne, Lucy G."'
Search Results
2. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19
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Varona, Jose F, Landete, Pedro, Lopez-Martin, Jose A, Estrada, Vicente, Paredes, Roger, Guisado-Vasco, Pablo, de Orueta, Lucia Fernandez, Torralba, Miguel, Fortun, Jesus, Vates, Roberto, Barberan, Jose, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemi, Porras, Lourdes, Gijon, Paloma, Monereo, Alfonso, Abad, Daniel, Zuñiga, Sonia, Sola, Isabel, Rodon, Jordi, Vergara-Alert, Julia, Izquierdo-Useros, Nuria, Fudio, Salvador, Pontes, Maria Jose, de Rivas, Beatriz, de Velasco, Patricia Giron, Nieto, Antonio, Gomez, Javier, Aviles, Pablo, Lubomirov, Rubin, Belgrano, Alvaro, Sopesen, Belen, White, Kris M, Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G, Jolly, Clare, Towers, Greg J, Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, McGovern, Briana L, Rodriguez, M Luis, Enjuanes, Luis, Fernandez-Sousa, Jose M, Krogan, Nevan J, Jimeno, Jose M, and Garcia-Sastre, Adolfo
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Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Research ,Infectious Diseases ,Cancer ,Lung ,Clinical Trials and Supportive Activities ,Patient Safety ,Prevention ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Good Health and Well Being ,Adult ,Aged ,COVID-19 ,Cell Line ,Tumor ,Depsipeptides ,Drug Evaluation ,Preclinical ,Female ,Hospitalization ,Humans ,Kaplan-Meier Estimate ,Length of Stay ,Male ,Middle Aged ,Neutropenia ,Peptides ,Cyclic ,SARS-CoV-2 ,Treatment Outcome ,Viral Load ,COVID-19 Drug Treatment ,Biological sciences ,Biomedical and clinical sciences - Abstract
Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.
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- 2022
3. Evolution of enhanced innate immune evasion by SARS-CoV-2
- Author
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Thorne, Lucy G, Bouhaddou, Mehdi, Reuschl, Ann-Kathrin, Zuliani-Alvarez, Lorena, Polacco, Ben, Pelin, Adrian, Batra, Jyoti, Whelan, Matthew VX, Hosmillo, Myra, Fossati, Andrea, Ragazzini, Roberta, Jungreis, Irwin, Ummadi, Manisha, Rojc, Ajda, Turner, Jane, Bischof, Marie L, Obernier, Kirsten, Braberg, Hannes, Soucheray, Margaret, Richards, Alicia, Chen, Kuei-Ho, Harjai, Bhavya, Memon, Danish, Hiatt, Joseph, Rosales, Romel, McGovern, Briana L, Jahun, Aminu, Fabius, Jacqueline M, White, Kris, Goodfellow, Ian G, Takeuchi, Yasu, Bonfanti, Paola, Shokat, Kevan, Jura, Natalia, Verba, Klim, Noursadeghi, Mahdad, Beltrao, Pedro, Kellis, Manolis, Swaney, Danielle L, García-Sastre, Adolfo, Jolly, Clare, Towers, Greg J, and Krogan, Nevan J
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Immunology ,Medical Microbiology ,Genetics ,Emerging Infectious Diseases ,Infectious Diseases ,Coronaviruses ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,COVID-19 ,Coronavirus Nucleocapsid Proteins ,Evolution ,Molecular ,Humans ,Immune Evasion ,Immunity ,Innate ,Interferons ,Mitochondrial Precursor Protein Import Complex Proteins ,Phosphoproteins ,Phosphorylation ,Proteomics ,RNA ,Viral ,RNA-Seq ,SARS-CoV-2 ,General Science & Technology - Abstract
The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6-all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.
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- 2022
4. SARS-CoV-2 variant biology: immune escape, transmission and fitness
- Author
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Carabelli, Alessandro M., Peacock, Thomas P., Thorne, Lucy G., Harvey, William T., Hughes, Joseph, Peacock, Sharon J., Barclay, Wendy S., de Silva, Thushan I., Towers, Greg J., and Robertson, David L.
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- 2023
- Full Text
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5. SARS-CoV-2 variants evolve convergent strategies to remodel the host response
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Bouhaddou, Mehdi, Reuschl, Ann-Kathrin, Polacco, Benjamin J., Thorne, Lucy G., Ummadi, Manisha R., Ye, Chengjin, Rosales, Romel, Pelin, Adrian, Batra, Jyoti, Jang, Gwendolyn M., Xu, Jiewei, Moen, Jack M., Richards, Alicia L., Zhou, Yuan, Harjai, Bhavya, Stevenson, Erica, Rojc, Ajda, Ragazzini, Roberta, Whelan, Matthew V.X., Furnon, Wilhelm, De Lorenzo, Giuditta, Cowton, Vanessa, Syed, Abdullah M., Ciling, Alison, Deutsch, Noa, Pirak, Daniel, Dowgier, Giulia, Mesner, Dejan, Turner, Jane L., McGovern, Briana L., Rodriguez, M. Luis, Leiva-Rebollo, Rocio, Dunham, Alistair S., Zhong, Xiaofang, Eckhardt, Manon, Fossati, Andrea, Liotta, Nicholas F., Kehrer, Thomas, Cupic, Anastasija, Rutkowska, Magdalena, Mena, Ignacio, Aslam, Sadaf, Hoffert, Alyssa, Foussard, Helene, Olwal, Charles Ochieng’, Huang, Weiqing, Zwaka, Thomas, Pham, John, Lyons, Molly, Donohue, Laura, Griffin, Aliesha, Nugent, Rebecca, Holden, Kevin, Deans, Robert, Aviles, Pablo, Lopez-Martin, Jose A., Jimeno, Jose M., Obernier, Kirsten, Fabius, Jacqueline M., Soucheray, Margaret, Hüttenhain, Ruth, Jungreis, Irwin, Kellis, Manolis, Echeverria, Ignacia, Verba, Kliment, Bonfanti, Paola, Beltrao, Pedro, Sharan, Roded, Doudna, Jennifer A., Martinez-Sobrido, Luis, Patel, Arvind H., Palmarini, Massimo, Miorin, Lisa, White, Kris, Swaney, Danielle L., Garcia-Sastre, Adolfo, Jolly, Clare, Zuliani-Alvarez, Lorena, Towers, Greg J., and Krogan, Nevan J.
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- 2023
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6. Publisher Correction: Evolution of enhanced innate immune evasion by SARS-CoV-2
- Author
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Thorne, Lucy G., Bouhaddou, Mehdi, Reuschl, Ann-Kathrin, Zuliani-Alvarez, Lorena, Polacco, Ben, Pelin, Adrian, Batra, Jyoti, Whelan, Matthew V. X., Hosmillo, Myra, Fossati, Andrea, Ragazzini, Roberta, Jungreis, Irwin, Ummadi, Manisha, Rojc, Ajda, Turner, Jane, Bischof, Marie L., Obernier, Kirsten, Braberg, Hannes, Soucheray, Margaret, Richards, Alicia, Chen, Kuei-Ho, Harjai, Bhavya, Memon, Danish, Hiatt, Joseph, Rosales, Romel, McGovern, Briana L., Jahun, Aminu, Fabius, Jacqueline M., White, Kris, Goodfellow, Ian G., Takeuchi, Yasu, Bonfanti, Paola, Shokat, Kevan, Jura, Natalia, Verba, Klim, Noursadeghi, Mahdad, Beltrao, Pedro, Kellis, Manolis, Swaney, Danielle L., García-Sastre, Adolfo, Jolly, Clare, Towers, Greg J., and Krogan, Nevan J.
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- 2022
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7. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19
- Author
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Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), National Institute of Allergy and Infectious Diseases (US), Swiss National Science Foundation, Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Vergara-Alert, Júlia, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, Belgrano, Álvaro, Sopesén, Belén, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin; Thorne, Lucy G.; Jolly, Claire; Towers, Greg J.; Zuliani-Alvarez, Lorena; Bouhaddou, Mehdi; Obernier, Kirsten; Enjuanes Sánchez, Luis CSIC ORCID ; Fernández-Sousa, José M.; Plitidepsin – COVID - 19 Study Group; Krogan, Nevan J.; Jimeno, José M.; García-Sastre, Adolfo, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, McGovern, Briana L., Rodríguez, M. Luis, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Krogan, Nevan J., Jimeno, José M., García-Sastre, Adolfo, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), National Institute of Allergy and Infectious Diseases (US), Swiss National Science Foundation, Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Vergara-Alert, Júlia, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, Belgrano, Álvaro, Sopesén, Belén, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin; Thorne, Lucy G.; Jolly, Claire; Towers, Greg J.; Zuliani-Alvarez, Lorena; Bouhaddou, Mehdi; Obernier, Kirsten; Enjuanes Sánchez, Luis CSIC ORCID ; Fernández-Sousa, José M.; Plitidepsin – COVID - 19 Study Group; Krogan, Nevan J.; Jimeno, José M.; García-Sastre, Adolfo, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, McGovern, Briana L., Rodríguez, M. Luis, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Krogan, Nevan J., Jimeno, José M., and García-Sastre, Adolfo
- Abstract
Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.
- Published
- 2022
8. SARS-CoV-2 variant biology: immune escape, transmission and fitness
- Author
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Carabelli, Alessandro M, Peacock, Thomas P, Thorne, Lucy G, Harvey, William T, Hughes, Joseph, COVID-19 Genomics UK Consortium, Peacock, Sharon J, Barclay, Wendy S, De Silva, Thushan I, Towers, Greg J, Robertson, David L, Carabelli, Alessandro M [0000-0003-3625-4021], Harvey, William T [0000-0001-9529-1127], Hughes, Joseph [0000-0003-2556-2563], Peacock, Sharon J [0000-0002-1718-2782], Robertson, David L [0000-0001-6338-0221], and Apollo - University of Cambridge Repository
- Subjects
SARS-CoV-2 ,Humans ,COVID-19 ,Biology ,Immunity, Innate - Abstract
In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. These highly mutated forms of SARS-CoV-2 had enhanced rates of transmission relative to previous variants and were termed 'variants of concern' (VOCs). Designated Alpha, Beta, Gamma, Delta and Omicron, the VOCs emerged independently from one another, and in turn each rapidly became dominant, regionally or globally, outcompeting previous variants. The success of each VOC relative to the previously dominant variant was enabled by altered intrinsic functional properties of the virus and, to various degrees, changes to virus antigenicity conferring the ability to evade a primed immune response. The increased virus fitness associated with VOCs is the result of a complex interplay of virus biology in the context of changing human immunity due to both vaccination and prior infection. In this Review, we summarize the literature on the relative transmissibility and antigenicity of SARS-CoV-2 variants, the role of mutations at the furin spike cleavage site and of non-spike proteins, the potential importance of recombination to virus success, and SARS-CoV-2 evolution in the context of T cells, innate immunity and population immunity. SARS-CoV-2 shows a complicated relationship among virus antigenicity, transmission and virulence, which has unpredictable implications for the future trajectory and disease burden of COVID-19.
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- 2023
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9. SARS-CoV-2 evolution influences GBP and IFITM sensitivity
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Mesner, Dejan, primary, Reuschl, Ann-Kathrin, additional, Whelan, Matthew V. X., additional, Bronzovich, Taylor, additional, Haider, Tafhima, additional, Thorne, Lucy G., additional, Ragazzini, Roberta, additional, Bonfanti, Paola, additional, Towers, Greg J., additional, and Jolly, Clare, additional
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- 2023
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10. SARS-CoV-2 Variants Evolve Convergent Strategies to Remodel the Host Response
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Bouhaddou, Mehdi, primary, Reuschl, Ann-Kathrin, additional, Polacco, Benjamin J., additional, Thorne, Lucy G., additional, Ummadi, Manisha R., additional, Ye, Chengjin, additional, Rosales, Romel, additional, Pelin, Adrian, additional, Batra, Jyoti, additional, Jang, Gwendolyn, additional, Xu, Jiewei, additional, Moen, Jack M., additional, Richards, Alicia L., additional, Zhou, Yuan, additional, Harjai, Bhavya, additional, Stevenson, Erica, additional, Rojc, Ajda, additional, Ragazzini, Roberta, additional, Whelan, Matthew V.X., additional, Furnon, Wilhelm, additional, De Lorenzo, Giuditta, additional, Cowton, Vanessa, additional, Syed, Abdullah M., additional, Ciling, Alison, additional, Deutsch, Noa, additional, Pirak, Daniel, additional, Dowgier, Giulia, additional, Mesner, Dejan, additional, Turner, Jane L., additional, McGovern, Briana L., additional, Rodriguez, M. Luis, additional, Leiva-Rebollo, Rocio, additional, Dunham, Alistair S., additional, Zhong, Xiaofang, additional, Eckhardt, Manon, additional, Fossati, Andrea, additional, Liotta, Nicholas, additional, Kehrer, Thomas, additional, Cupic, Anastasija, additional, Rutkowska, Magda, additional, Mena, Nacho, additional, Aslam, Sadaf, additional, Hoffert, Alyssa, additional, Foussard, Helene, additional, Olwal, Charles, additional, Huang, Weiqing, additional, Zwaka, Thomas, additional, Pham, John, additional, Lyons, Molly, additional, Donahue, Laura, additional, Griffin, Aliesha, additional, Nugent, Rebecca, additional, Holden, Kevin, additional, Deans, Robert, additional, Aviles, Pablo, additional, López, José Antonio, additional, Jimeno Doñaque, José María, additional, Obernier, Kirsten, additional, Fabius, Jacqueline M., additional, Soucheray, Margaret, additional, Hüttenhain, Ruth, additional, Jungreis, Irwin, additional, Kellis, Manolis, additional, Echeverria, Ignacia, additional, Verba, Kliment, additional, Bonfanti, Paola, additional, Beltrao, Pedro, additional, Sharan, Roded, additional, Doudna, Jennifer A., additional, Martinez-Sobrido, Luis, additional, Patel, Arvind, additional, Palmarini, Massimo, additional, Miorin, Lisa, additional, White, Kris, additional, Swaney, Danielle L., additional, Garcia-Sastre, Adolfo, additional, Jolly, Clare, additional, Zuliani-Alvarez, Lorena, additional, Towers, Greg J., additional, and Krogan, Nevan J., additional
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- 2023
- Full Text
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11. Global landscape of the host response to SARS-CoV-2 variants reveals viral evolutionary trajectories
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Bouhaddou, Mehdi, primary, Reuschl, Ann-Kathrin, additional, Polacco, Benjamin J., additional, Thorne, Lucy G., additional, Ummadi, Manisha R., additional, Ye, Chengjin, additional, Rosales, Romel, additional, Pelin, Adrian, additional, Batra, Jyoti, additional, Jang, Gwendolyn M., additional, Xu, Jiewei, additional, Moen, Jack M., additional, Richards, Alicia, additional, Zhou, Yuan, additional, Harjai, Bhavya, additional, Stevenson, Erica, additional, Rojc, Ajda, additional, Ragazzini, Roberta, additional, Whelan, Matthew V.X., additional, Furnon, Wilhelm, additional, De Lorenzo, Giuditta, additional, Cowton, Vanessa, additional, Syed, Abdullah M., additional, Ciling, Alison, additional, Deutsch, Noa, additional, Pirak, Daniel, additional, Dowgier, Giulia, additional, Mesner, Dejan, additional, Turner, Jane L., additional, McGovern, Briana L., additional, Rodriguez, M. Luis, additional, Leiva-Rebollo, Rocio, additional, Dunham, Alistair S., additional, Zhong, Xiaofang, additional, Eckhardt, Manon, additional, Fossati, Andrea, additional, Liotta, Nicholas, additional, Kehrer, Thomas, additional, Cupic, Anastasija, additional, Rutkowska, Magda, additional, Mena, Nacho, additional, Aslam, Sadaf, additional, Hoffert, Alyssa, additional, Foussard, Helene, additional, Pham, John, additional, Lyons, Molly, additional, Donahue, Laura, additional, Griffin, Aliesha, additional, Nugent, Rebecca, additional, Holden, Kevin, additional, Deans, Robert, additional, Aviles, Pablo, additional, López-Martín, José Antonio, additional, Jimeno, Jose M., additional, Obernier, Kirsten, additional, Fabius, Jacqueline M., additional, Soucheray, Margaret, additional, Hüttenhain, Ruth, additional, Jungreis, Irwin, additional, Kellis, Manolis, additional, Echeverria, Ignacia, additional, Verba, Kliment, additional, Bonfanti, Paola, additional, Beltrao, Pedro, additional, Sharan, Roded, additional, Doudna, Jennifer A., additional, Martinez-Sobrido, Luis, additional, Patel, Arvind, additional, Palmarini, Massimo, additional, Miorin, Lisa, additional, White, Kris, additional, Swaney, Danielle L., additional, García-Sastre, Adolfo, additional, Jolly, Clare, additional, Zuliani-Alvarez, Lorena, additional, Towers, Greg J., additional, and Krogan, Nevan J., additional
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- 2022
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12. Evolutionary remodelling of N‐terminal domain loops fine‐tunes SARS‐CoV‐2 spike
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Cantoni, Diego, primary, Murray, Matthew J, additional, Kalemera, Mphatso D, additional, Dicken, Samuel J, additional, Stejskal, Lenka, additional, Brown, Georgina, additional, Lytras, Spyros, additional, Coey, Jonathon D, additional, McKenna, James, additional, Bridgett, Stephen, additional, Simpson, David, additional, Fairley, Derek, additional, Thorne, Lucy G, additional, Reuschl, Ann‐Kathrin, additional, Forrest, Calum, additional, Ganeshalingham, Maaroothen, additional, Muir, Luke, additional, Palor, Machaela, additional, Jarvis, Lisa, additional, Willett, Brian, additional, Power, Ultan F, additional, McCoy, Laura E, additional, Jolly, Clare, additional, Towers, Greg J, additional, Doores, Katie J, additional, Robertson, David L, additional, Shepherd, Adrian J, additional, Reeves, Matthew B, additional, Bamford, Connor G G, additional, and Grove, Joe, additional
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- 2022
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13. Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants
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Reuschl, Ann-Kathrin, primary, Thorne, Lucy G., additional, Whelan, Matthew V.X., additional, Ragazzini, Roberta, additional, Furnon, Wilhelm, additional, Cowton, Vanessa M., additional, de Lorenzo, Giuditta, additional, Mesner, Dejan, additional, Turner, Jane L. E., additional, Dowgier, Giulia, additional, Bogoda, Nathasha, additional, Bonfanti, Paola, additional, Palmarini, Massimo, additional, Patel, Arvind H., additional, Jolly, Clare, additional, and Towers, Greg. J., additional
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- 2022
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14. SARS-CoV-2 Spike evolution influences GBP and IFITM sensitivity
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Mesner, Dejan, primary, Reuschl, Ann-Kathrin, additional, Whelan, Matthew V.X, additional, Bronzovich, Taylor, additional, Haider, Tafhima, additional, Thorne, Lucy G., additional, Towers, Greg J., additional, and Jolly, Clare, additional
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- 2022
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15. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19
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Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Vergara-Alert, Júlia, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, Belgrano, Álvaro, Sopesén, Belén, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, Enjuanes Sánchez, Luis CSIC ORCID, Fernández-Sousa, José M., Plitidepsin – COVID - 19 Study Group, Krogan, Nevan J., Jimeno, José M., García-Sastre, Adolfo, McGovern, Briana L., Rodríguez, M. Luis, Enjuanes Sánchez, Luis, Producció Animal, Sanitat Animal, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), National Institute of Allergy and Infectious Diseases (US), and Swiss National Science Foundation
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Adult ,Male ,Neutropenia ,Health, Toxicology and Mutagenesis ,Clinical Trials and Supportive Activities ,Plant Science ,Kaplan-Meier Estimate ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Cell Line ,Clinical Research ,Depsipeptides ,Humans ,Lung ,Aged ,Cancer ,Cyclic ,Tumor ,Ecology ,SARS-CoV-2 ,Prevention ,COVID-19 ,Evaluation of treatments and therapeutic interventions ,Length of Stay ,Viral Load ,Middle Aged ,Preclinical ,COVID-19 Drug Treatment ,Hospitalization ,Treatment Outcome ,Infectious Diseases ,Good Health and Well Being ,6.1 Pharmaceuticals ,Drug Evaluation ,Female ,Patient Safety ,Peptides - Abstract
Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19., This work was supported by grants from the Government of Spain (PIE_INTRAMURAL_ LINEA 1 - 202020E079; PIE_INTRAMURAL_CSIC-202020E043). The research of CBIG consortium (constituted by IRTA-CReSA, BSC, & IrsiCaixa) is supported by Grifols pharmaceutical. We also acknowledge the crowdfunding initiative #Yomecorono (https://www.yomecorono.com). N Izquierdo-Useros has nonrestrictive funding from PharmaMar to study the antiviral effect of Plitidepsin. NJ Krogan was funded by grants from the National Institutes of Health (P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, and P01AI063302); by the Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR), a collaboration between the University of California, San Francisco (UCSF), University of California, Berkley (UCB), and GlaxoSmithKline (GSK) (#133122P); by the Roddenberry Foundation, and gifts from QCRG philanthropic donors. This work was supported by the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement #HR0011-19-2-0020. The views, opinions, and/or findings contained in this material are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. This research was partly funded by Center for Research for Influenza Pathogenesis and Transmission (CRIPT), a National Institute of Allergy and Infectious Diseases (NIAID) supported Center of Excellence for Influenza Research and Response (CEIRS, contract # 75N93021C00014), by DARPA grant HR0011-19-2-0020, by supplements to NIAID grants U19AI142733, U19AI135972, and DoD grant W81XWH-20-1-0270, and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384)), and anonymous donors to A García-Sastre. S Yildiz received funding from a Swiss National Foundation Early Postdoc Mobility fellowship (P2GEP3_184202).
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- 2022
16. Evolution of enhanced innate immune evasion by SARS-CoV-2
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Thorne, Lucy G., primary, Bouhaddou, Mehdi, additional, Reuschl, Ann-Kathrin, additional, Zuliani-Alvarez, Lorena, additional, Polacco, Ben, additional, Pelin, Adrian, additional, Batra, Jyoti, additional, Whelan, Matthew V. X., additional, Hosmillo, Myra, additional, Fossati, Andrea, additional, Ragazzini, Roberta, additional, Jungreis, Irwin, additional, Ummadi, Manisha, additional, Rojc, Ajda, additional, Turner, Jane, additional, Bischof, Marie L., additional, Obernier, Kirsten, additional, Braberg, Hannes, additional, Soucheray, Margaret, additional, Richards, Alicia, additional, Chen, Kuei-Ho, additional, Harjai, Bhavya, additional, Memon, Danish, additional, Hiatt, Joseph, additional, Rosales, Romel, additional, McGovern, Briana L., additional, Jahun, Aminu, additional, Fabius, Jacqueline M., additional, White, Kris, additional, Goodfellow, Ian G., additional, Takeuchi, Yasu, additional, Bonfanti, Paola, additional, Shokat, Kevan, additional, Jura, Natalia, additional, Verba, Klim, additional, Noursadeghi, Mahdad, additional, Beltrao, Pedro, additional, Kellis, Manolis, additional, Swaney, Danielle L., additional, García-Sastre, Adolfo, additional, Jolly, Clare, additional, Towers, Greg J., additional, and Krogan, Nevan J., additional
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- 2021
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17. SARS‐CoV‐2 sensing by RIG‐I and MDA5 links epithelial infection to macrophage inflammation
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Thorne, Lucy G, primary, Reuschl, Ann‐Kathrin, additional, Zuliani‐Alvarez, Lorena, additional, Whelan, Matthew V X, additional, Turner, Jane, additional, Noursadeghi, Mahdad, additional, Jolly, Clare, additional, and Towers, Greg J, additional
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- 2021
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18. Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant
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Thorne, Lucy G, primary, Bouhaddou, Mehdi, additional, Reuschl, Ann-Kathrin, additional, Zuliani-Alvarez, Lorena, additional, Polacco, Ben, additional, Pelin, Adrian, additional, Batra, Jyoti, additional, Whelan, Matthew V.X., additional, Ummadi, Manisha, additional, Rojc, Ajda, additional, Turner, Jane, additional, Obernier, Kirsten, additional, Braberg, Hannes, additional, Soucheray, Margaret, additional, Richards, Alicia, additional, Chen, Kuei-Ho, additional, Harjai, Bhavya, additional, Memon, Danish, additional, Hosmillo, Myra, additional, Hiatt, Joseph, additional, Jahun, Aminu, additional, Goodfellow, Ian G., additional, Fabius, Jacqueline M., additional, Shokat, Kevan, additional, Jura, Natalia, additional, Verba, Klim, additional, Noursadeghi, Mahdad, additional, Beltrao, Pedro, additional, Swaney, Danielle L., additional, Garcia-Sastre, Adolfo, additional, Jolly, Clare, additional, Towers, Greg J., additional, and Krogan, Nevan J., additional
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- 2021
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19. Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization
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PharmaMar, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), Centers of Excellence for Influenza Research and Surveillance (US), JPB Foundation, Swiss National Science Foundation, López-Martín, José A. [0000-0001-7530-3207], Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Sopesén, Belén, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Plitidepsin – COVID - 19 Study Group, Krogan, Nevan J., Jimeno, José M., García-Sastre, Adolfo, PharmaMar, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), Centers of Excellence for Influenza Research and Surveillance (US), JPB Foundation, Swiss National Science Foundation, López-Martín, José A. [0000-0001-7530-3207], Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Sopesén, Belén, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Plitidepsin – COVID - 19 Study Group, Krogan, Nevan J., Jimeno, José M., and García-Sastre, Adolfo
- Abstract
Plitidepsin is a marine-derived cyclic-peptide that inhibits SARS-CoV-2 replication at low nanomolar concentrations by the targeting of host protein eEF1A (eukaryotic translation-elongation-factor-1A). We evaluated a model of intervention with plitidepsin in hospitalized COVID-19 adult patients where three doses were assessed (1.5, 2 and 2.5 mg/day for 3 days, as a 90-minute intravenous infusion) in 45 patients (15 per dose-cohort). Treatment was well tolerated, with only two Grade 3 treatment-related adverse events observed (hypersensitivity and diarrhea). The discharge rates by Days 8 and 15 were 56.8% and 81.8%, respectively, with data sustaining dose-effect. A mean 4.2 log10 viral load reduction was attained by Day 15. Improvement in inflammation markers was also noted in a seemingly dose-dependent manner. These results suggest that plitidepsin impacts the outcome of patients with COVID-19.
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- 2021
20. Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2
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Dicken, Samuel J., primary, Murray, Matthew J., additional, Thorne, Lucy G., additional, Reuschl, Ann-Kathrin, additional, Forrest, Calum, additional, Ganeshalingham, Maaroothen, additional, Muir, Luke, additional, Kalemera, Mphatso D., additional, Palor, Machaela, additional, McCoy, Laura E., additional, Jolly, Clare, additional, Towers, Greg J., additional, Reeves, Matthew B., additional, and Grove, Joe, additional
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- 2021
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21. Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant
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Reuschl, Ann-Kathrin, primary, Thorne, Lucy G., additional, Zuliani-Alvarez, Lorena, additional, Bouhaddou, Mehdi, additional, Obernier, Kirsten, additional, Hiatt, Joseph, additional, Soucheray, Margaret, additional, Turner, Jane, additional, Fabius, Jacqueline M., additional, Nguyen, Gina T., additional, Swaney, Danielle L., additional, Rosales, Romel, additional, White, Kris M., additional, Avilés, Pablo, additional, Kirby, Ilsa T., additional, Melnyk, James E., additional, Shi, Ying, additional, Zhang, Ziyang, additional, Shokat, Kevan M., additional, García-Sastre, Adolfo, additional, Jolly, Clare, additional, Towers, Gregory J., additional, and Krogan, Nevan J., additional
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- 2021
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22. SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation
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Thorne, Lucy G, primary, Reuschl, Ann-Kathrin, additional, Zuliani-Alvarez, Lorena, additional, Whelan, Matthew V.X., additional, Noursadeghi, Mahdad, additional, Jolly, Clare, additional, and Towers, Greg J, additional
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- 2020
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23. Cyclosporine H Overcomes Innate Immune Restrictions to Improve Lentiviral Transduction and Gene Editing In Human Hematopoietic Stem Cells
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Petrillo, Carolina, primary, Thorne, Lucy G., additional, Unali, Giulia, additional, Schiroli, Giulia, additional, Giordano, Anna M.S., additional, Piras, Francesco, additional, Cuccovillo, Ivan, additional, Petit, Sarah J., additional, Ahsan, Fatima, additional, Noursadeghi, Mahdad, additional, Clare, Simon, additional, Genovese, Pietro, additional, Gentner, Bernhard, additional, Naldini, Luigi, additional, Towers, Greg J., additional, and Kajaste-Rudnitski, Anna, additional
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- 2018
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24. Are Evolution and the Intracellular Innate Immune System Key Determinants in HIV Transmission?
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Sumner, Rebecca P., primary, Thorne, Lucy G., additional, Fink, Doug L., additional, Khan, Hataf, additional, Milne, Richard S., additional, and Towers, Greg J., additional
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- 2017
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25. Norovirus gene expression and replication
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Thorne, Lucy G., primary and Goodfellow, Ian G., additional
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- 2014
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26. Interleukin 18 Coexpression during Respiratory Syncytial Virus Infection Results in Enhanced Disease Mediated by Natural Killer Cells
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Harker, James A., primary, Godlee, Alexandra, additional, Wahlsten, Jennifer L., additional, Lee, Debbie C. P., additional, Thorne, Lucy G., additional, Sawant, Devika, additional, Tregoning, John S., additional, Caspi, Rachel R., additional, Bukreyev, Alexander, additional, Collins, Peter L., additional, and Openshaw, Peter J. M., additional
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- 2010
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27. Evolution of enhanced innate immune evasion by SARS-CoV-2
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Lucy G. Thorne, Mehdi Bouhaddou, Ann-Kathrin Reuschl, Lorena Zuliani-Alvarez, Ben Polacco, Adrian Pelin, Jyoti Batra, Matthew V. X. Whelan, Myra Hosmillo, Andrea Fossati, Roberta Ragazzini, Irwin Jungreis, Manisha Ummadi, Ajda Rojc, Jane Turner, Marie L. Bischof, Kirsten Obernier, Hannes Braberg, Margaret Soucheray, Alicia Richards, Kuei-Ho Chen, Bhavya Harjai, Danish Memon, Joseph Hiatt, Romel Rosales, Briana L. McGovern, Aminu Jahun, Jacqueline M. Fabius, Kris White, Ian G. Goodfellow, Yasu Takeuchi, Paola Bonfanti, Kevan Shokat, Natalia Jura, Klim Verba, Mahdad Noursadeghi, Pedro Beltrao, Manolis Kellis, Danielle L. Swaney, Adolfo García-Sastre, Clare Jolly, Greg J. Towers, Nevan J. Krogan, Thorne, Lucy G [0000-0001-7358-6047], Polacco, Ben [0000-0003-1570-9234], Hosmillo, Myra [0000-0002-3514-7681], Fossati, Andrea [0000-0001-5170-4903], Ragazzini, Roberta [0000-0003-2186-293X], Jungreis, Irwin [0000-0002-3197-5367], Obernier, Kirsten [0000-0002-4025-1299], Braberg, Hannes [0000-0002-7070-2257], Chen, Kuei-Ho [0000-0001-6541-0578], Memon, Danish [0000-0002-1365-0710], McGovern, Briana L [0000-0002-0492-9904], Jahun, Aminu [0000-0002-4585-1701], White, Kris [0000-0003-0889-0506], Goodfellow, Ian [0000-0002-9483-510X], Bonfanti, Paola [0000-0001-9655-3766], Shokat, Kevan [0000-0001-8590-7741], Jura, Natalia [0000-0001-5129-641X], Verba, Klim [0000-0002-2238-8590], Noursadeghi, Mahdad [0000-0002-4774-0853], Kellis, Manolis [0000-0001-7113-9630], Swaney, Danielle L [0000-0001-6119-6084], García-Sastre, Adolfo [0000-0002-6551-1827], Jolly, Clare [0000-0002-4603-2281], Towers, Greg J [0000-0002-7707-0264], Krogan, Nevan J [0000-0003-4902-337X], Apollo - University of Cambridge Repository, and Goodfellow, Ian G [0000-0002-9483-510X]
- Subjects
Proteomics ,Evolution ,General Science & Technology ,Vaccine Related ,Evolution, Molecular ,Biodefense ,Mitochondrial Precursor Protein Import Complex Proteins ,Genetics ,Innate ,2.1 Biological and endogenous factors ,Coronavirus Nucleocapsid Proteins ,Humans ,Viral ,RNA-Seq ,Aetiology ,Phosphorylation ,Lung ,631/326/596/4130 ,Immune Evasion ,Multidisciplinary ,SARS-CoV-2 ,Prevention ,Stem Cells ,82/58 ,Immunity ,article ,Molecular ,COVID-19 ,Cell Biology ,Phosphoproteins ,Immunity, Innate ,Infectious Diseases ,Emerging Infectious Diseases ,RNA ,RNA, Viral ,Interferons ,631/553 ,Infection ,Developmental Biology - Abstract
The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6—all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants., Nature, 602 (7897), ISSN:0028-0836, ISSN:1476-4687
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- 2022
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28. Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant.
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Thorne LG, Bouhaddou M, Reuschl AK, Zuliani-Alvarez L, Polacco B, Pelin A, Batra J, Whelan MVX, Ummadi M, Rojc A, Turner J, Obernier K, Braberg H, Soucheray M, Richards A, Chen KH, Harjai B, Memon D, Hosmillo M, Hiatt J, Jahun A, Goodfellow IG, Fabius JM, Shokat K, Jura N, Verba K, Noursadeghi M, Beltrao P, Swaney DL, Garcia-Sastre A, Jolly C, Towers GJ, and Krogan NJ
- Abstract
Emergence of SARS-CoV-2 variants, including the globally successful B.1.1.7 lineage, suggests viral adaptations to host selective pressures resulting in more efficient transmission. Although much effort has focused on Spike adaptation for viral entry and adaptive immune escape, B.1.1.7 mutations outside Spike likely contribute to enhance transmission. Here we used unbiased abundance proteomics, phosphoproteomics, mRNA sequencing and viral replication assays to show that B.1.1.7 isolates more effectively suppress host innate immune responses in airway epithelial cells. We found that B.1.1.7 isolates have dramatically increased subgenomic RNA and protein levels of Orf9b and Orf6, both known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein required for RNA sensing adaptor MAVS activation, and Orf9b binding and activity was regulated via phosphorylation. We conclude that B.1.1.7 has evolved beyond the Spike coding region to more effectively antagonise host innate immune responses through upregulation of specific subgenomic RNA synthesis and increased protein expression of key innate immune antagonists. We propose that more effective innate immune antagonism increases the likelihood of successful B.1.1.7 transmission, and may increase in vivo replication and duration of infection.
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- 2021
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29. Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization.
- Author
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Varona JF, Landete P, Lopez-Martin JA, Estrada V, Paredes R, Guisado-Vasco P, de Orueta LF, Torralba M, Fortún J, Vates R, Barberán J, Clotet B, Ancochea J, Carnevali D, Cabello N, Porras L, Gijón P, Monereo A, Abad D, Zúñiga S, Sola I, Rodon J, Izquierdo-Useros N, Fudio S, Pontes MJ, de Rivas B, Girón de Velasco P, Sopesén B, Nieto A, Gómez J, Avilés P, Lubomirov R, White KM, Rosales R, Yildiz S, Reuschl AK, Thorne LG, Jolly C, Towers GJ, Zuliani-Alvarez L, Bouhaddou M, Obernier K, Enjuanes L, Fernández-Sousa JM, Krogan NJ, Jimeno JM, and García-Sastre A
- Abstract
Plitidepsin is a marine-derived cyclic-peptide that inhibits SARS-CoV-2 replication at low nanomolar concentrations by the targeting of host protein eEF1A (eukaryotic translation-elongation-factor-1A). We evaluated a model of intervention with plitidepsin in hospitalized COVID-19 adult patients where three doses were assessed (1.5, 2 and 2.5 mg/day for 3 days, as a 90-minute intravenous infusion) in 45 patients (15 per dose-cohort). Treatment was well tolerated, with only two Grade 3 treatment-related adverse events observed (hypersensitivity and diarrhea). The discharge rates by Days 8 and 15 were 56.8% and 81.8%, respectively, with data sustaining dose-effect. A mean 4.2 log10 viral load reduction was attained by Day 15. Improvement in inflammation markers was also noted in a seemingly dose-dependent manner. These results suggest that plitidepsin impacts the outcome of patients with COVID-19., One-Sentence Summary: Plitidepsin, an inhibitor of SARS-Cov-2 in vitro , is safe and positively influences the outcome of patients hospitalized with COVID-19.
- Published
- 2021
- Full Text
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30. Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2.
- Author
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Dicken SJ, Murray MJ, Thorne LG, Reuschl AK, Forrest C, Ganeshalingham M, Muir L, Kalemera MD, Palor M, McCoy LE, Jolly C, Towers GJ, Reeves MB, and Grove J
- Abstract
The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic. Determining the fundamental biology of viral variants and understanding their evolutionary trajectories will guide current mitigation measures, future genetic surveillance and vaccination strategies. Here we examine virus entry by the B.1.1.7 lineage, commonly referred to as the UK/Kent variant. Pseudovirus infection of model cell lines demonstrate that B.1.1.7 entry is enhanced relative to the Wuhan-Hu-1 reference strain, particularly under low expression of receptor ACE2. Moreover, the entry characteristics of B.1.1.7 were distinct from that of its predecessor strain containing the D614G mutation. These data suggest evolutionary tuning of spike protein function. Additionally, we found that amino acid deletions within the N-terminal domain (NTD) of spike were important for efficient entry by B.1.1.7. The NTD is a hotspot of diversity across sarbecoviruses, therefore, we further investigated this region by examining the entry of closely related CoVs. Surprisingly, Pangolin CoV spike entry was 50-100 fold enhanced relative to SARS-CoV-2; suggesting there may be evolutionary pathways by which SARSCoV-2 may further optimise entry. Swapping the NTD between Pangolin CoV and SARS-CoV-2 demonstrates that changes in this region alone have the capacity to enhance virus entry. Thus, the NTD plays a hitherto unrecognised role in modulating spike activity, warranting further investigation and surveillance of NTD mutations.
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- 2021
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31. Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant.
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Reuschl AK, Thorne LG, Zuliani-Alvarez L, Bouhaddou M, Obernier K, Hiatt J, Soucheray M, Turner J, Fabius JM, Nguyen GT, Swaney DL, Rosales R, White KM, Avilés P, Kirby IT, Melnyk JE, Shi Y, Zhang Z, Shokat KM, García-Sastre A, Jolly C, Towers GJ, and Krogan NJ
- Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide and massive societal and economic burden. Recently, a new variant of SARS-CoV-2, known as B.1.1.7, was first detected in the United Kingdom and is spreading in several other countries, heightening public health concern and raising questions as to the resulting effectiveness of vaccines and therapeutic interventions. We and others previously identified host-directed therapies with antiviral efficacy against SARS-CoV-2 infection. Less prone to the development of therapy resistance, host-directed drugs represent promising therapeutic options to combat emerging viral variants as host genes possess a lower propensity to mutate compared to viral genes. Here, in the first study of the full-length B.1.1.7 variant virus , we find two host-directed drugs, plitidepsin (aplidin; inhibits translation elongation factor eEF1A) and ralimetinib (inhibits p38 MAP kinase cascade), as well as remdesivir, to possess similar antiviral activity against both the early-lineage SARS-CoV-2 and the B.1.1.7 variant, evaluated in both human gastrointestinal and lung epithelial cell lines. We find that plitidepsin is over an order of magnitude more potent than remdesivir against both viruses. These results highlight the importance of continued development of host-directed therapeutics to combat current and future coronavirus variant outbreaks., Competing Interests: Competing Interests The García-Sastre Laboratory has received research support from Pfizer, Senhwa Biosciences and 7Hills Pharma. Adolfo García-Sastre has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Accurius and Esperovax. The Krogan Laboratory receives funding from Roche and VIR and Nevan Krogan has consulting agreements with Maze Therapeutics and Interline Therapeutics. Kevan Shokat has consulting agreements for the following companies involving cash and/or stock compensation: Black Diamond Therapeutics, BridGene Biosciences, Denali Therapeutics, Dice Molecules, eFFECTOR Therapeutics , Erasca, Genentech/Roche, Janssen Pharmaceuticals, Kumquat Biosciences, Kura Oncology, Merck, Mitokinin, Petra Pharma, Revolution Medicines, Type6 Therapeutics, Venthera, Wellspring Biosciences (Araxes Pharma), Turning Point Therapeutics, Ikena, Nextech. Pablo Avilés is an employee and shareholder of PharmaMar, SA (Madrid, Spain).
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- 2021
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