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4. Sequential immunization with chimeric hemagglutinin ΔNS1 attenuated influenza vaccines induces broad humoral and cellular immunity

Author

Rathnasinghe, Raveen, Chang, Lauren A., Pearl, Rebecca, Jangra, Sonia, Aspelund, Amy, Hoag, Alaura, Yildiz, Soner, Mena, Ignacio, Sun, Weina, Loganathan, Madhumathi, Crossland, Nicholas Alexander, Gertje, Hans P., Tseng, Anna Elise, Aslam, Sadaf, Albrecht, Randy A., Palese, Peter, Krammer, Florian, Schotsaert, Michael, Muster, Thomas, and García-Sastre, Adolfo

Published
2024
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6. Monkeypox virus genomic accordion strategies

Author

Monzón, Sara, Varona, Sarai, Negredo, Anabel, Vidal-Freire, Santiago, Patiño-Galindo, Juan Angel, Ferressini-Gerpe, Natalia, Zaballos, Angel, Orviz, Eva, Ayerdi, Oskar, Muñoz-Gómez, Ana, Delgado-Iribarren, Alberto, Estrada, Vicente, García, Cristina, Molero, Francisca, Sánchez-Mora, Patricia, Torres, Montserrat, Vázquez, Ana, Galán, Juan-Carlos, Torres, Ignacio, Causse del Río, Manuel, Merino-Diaz, Laura, López, Marcos, Galar, Alicia, Cardeñoso, Laura, Gutiérrez, Almudena, Loras, Cristina, Escribano, Isabel, Alvarez-Argüelles, Marta E., del Río, Leticia, Simón, María, Meléndez, María Angeles, Camacho, Juan, Herrero, Laura, Jiménez, Pilar, Navarro-Rico, María Luisa, Jado, Isabel, Giannetti, Elaina, Kuhn, Jens H., Sanchez-Lockhart, Mariano, Di Paola, Nicholas, Kugelman, Jeffrey R., Guerra, Susana, García-Sastre, Adolfo, Cuesta, Isabel, Sánchez-Seco, Maripaz P., and Palacios, Gustavo

Published
2024
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7. SUMOylation modulates eIF5A activities in both yeast and pancreatic ductal adenocarcinoma cells

Author

Seoane, Rocío, Lama-Díaz, Tomás, Romero, Antonia María, El Motiam, Ahmed, Martínez-Férriz, Arantxa, Vidal, Santiago, Bouzaher, Yanis H., Blanquer, María, Tolosa, Rocío M., Castillo Mewa, Juan, Rodríguez, Manuel S., García-Sastre, Adolfo, Xirodimas, Dimitris, Sutherland, James D., Barrio, Rosa, Alepuz, Paula, Blanco, Miguel G., Farràs, Rosa, and Rivas, Carmen

Published
2024
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8. Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

Author

Kehrer, Thomas, Cupic, Anastasija, Ye, Chengjin, Yildiz, Soner, Bouhaddou, Mehdi, Crossland, Nicholas A, Barrall, Erika A, Cohen, Phillip, Tseng, Anna, Çağatay, Tolga, Rathnasinghe, Raveen, Flores, Daniel, Jangra, Sonia, Alam, Fahmida, Mena, Ignacio, Aslam, Sadaf, Saqi, Anjali, Rutkowska, Magdalena, Ummadi, Manisha R, Pisanelli, Giuseppe, Richardson, R Blake, Veit, Ethan C, Fabius, Jacqueline M, Soucheray, Margaret, Polacco, Benjamin J, Ak, Baran, Marin, Arturo, Evans, Matthew J, Swaney, Danielle L, Gonzalez-Reiche, Ana S, Sordillo, Emilia M, van Bakel, Harm, Simon, Viviana, Zuliani-Alvarez, Lorena, Fontoura, Beatriz MA, Rosenberg, Brad R, Krogan, Nevan J, Martinez-Sobrido, Luis, García-Sastre, Adolfo, and Miorin, Lisa

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Immunology, Coronaviruses, Infectious Diseases, Emerging Infectious Diseases, Biodefense, Genetics, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Infection, Humans, COVID-19, Immunity, Innate, Interferons, SARS-CoV-2, Viral Proteins, ORF6, Omicron variant, SARS-CoV-2 pathogenesis, interferon, mRNA export, nuclear import, nucleocytoplasmic trafficking, virus-host interaction, Microbiology, Biochemistry and cell biology, Medical microbiology
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.

Published
2023

9. Annual (2023) taxonomic update of RNA-directed RNA polymerase-encoding negative-sense RNA viruses (realm Riboviria: kingdom Orthornavirae: phylum Negarnaviricota).

Author

Bukreyev, Alexander, Burt, Felicity, Büttner, Carmen, Calisher, Charles, Cao, Mengji, Casas, Inmaculada, Chandran, Kartik, Charrel, Rémi, Kumar Chaturvedi, Krishna, Chooi, Kar, Crane, Anya, Dal Bó, Elena, Carlos de la Torre, Juan, de Souza, William, de Swart, Rik, Debat, Humberto, Dheilly, Nolwenn, Di Paola, Nicholas, Di Serio, Francesco, Dietzgen, Ralf, Digiaro, Michele, Drexler, J, Duprex, W, Dürrwald, Ralf, Easton, Andrew, Elbeaino, Toufic, Ergünay, Koray, Feng, Guozhong, Firth, Andrew, Fooks, Anthony, Formenty, Pierre, Freitas-Astúa, Juliana, Gago-Zachert, Selma, Laura García, María, García-Sastre, Adolfo, Garrison, Aura, Gaskin, Thomas, Gong, Wenjie, Gonzalez, Jean-Paul, de Bellocq, JoëlleGoüy, Griffiths, Anthony, Groschup, Martin, Günther, Ines, Günther, Stephan, Hammond, John, Hasegawa, Yusuke, Hayashi, Kazusa, Hepojoki, Jussi, Higgins, Colleen, Hongō, Seiji, Horie, Masayuki, Hughes, Holly, Hume, Adam, Hyndman, Timothy, Ikeda, Kenichi, Jiāng, Dàohóng, Jonson, Gilda, Junglen, Sandra, Klempa, Boris, Klingström, Jonas, Kondō, Hideki, Koonin, Eugene, Krupovic, Mart, Kubota, Kenji, Kurath, Gael, Laenen, Lies, Lambert, Amy, Lǐ, Jiànróng, Li, Jun-Min, Liu, Ran, Lukashevich, Igor, MacDiarmid, Robin, Maes, Piet, Marklewitz, Marco, Marshall, Sergio, Marzano, Shin-Yi, McCauley, John, Mirazimi, Ali, Mühlberger, Elke, Nabeshima, Tomoyuki, Naidu, Rayapati, Natsuaki, Tomohide, Navarro, Beatriz, Navarro, José, Neriya, Yutaro, Netesov, Sergey, Neumann, Gabriele, Nowotny, Norbert, Nunes, Márcio, Ochoa-Corona, Francisco, Okada, Tomoyuki, Palacios, Gustavo, Pallás, Vicente, Papa, Anna, Paraskevopoulou, Sofia, Parrish, Colin, Pauvolid-Corrêa, Alex, Pawęska, Janusz, Pérez, Daniel, and Pfaff, Florian

Subjects
Aliusviridae, Arenaviridae, Articulavirales, Artoviridae, Aspiviridae, Bornaviridae, Bunyavirales, Crepuscuviridae, Discoviridae, Filoviridae, Fimoviridae, Goujianvirales, Hantaviridae, ICTV, International Committee on Taxonomy of Viruses, Jingchuvirales, Lispiviridae, Mononegavirales, Muvirales, Mymonaviridae, Myriaviridae, Nairoviridae, Natareviridae, Negarnaviricota, Nyamiviridae, Orthomyxoviridae, Orthornavirae, Paramyxoviridae, Peribunyaviridae, Phasmaviridae, Phenuiviridae, Pneumoviridae, Rhabdoviridae, Riboviria, Serpentovirales, Sunviridae, Tenuivirus, Tosoviridae, Tospoviridae, Tulasviridae, articulaviral, bunyaviral, bunyavirus, goujianviral, megaclassification, megataxonomy, mononegaviral, muviral, negarnaviricot, serpentoviral, virus classification, virus nomenclature, virus taxonomy, Negative-Sense RNA Viruses, RNA Viruses, RNA-Dependent RNA Polymerase
Abstract

In April 2023, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by one new family, 14 new genera, and 140 new species. Two genera and 538 species were renamed. One species was moved, and four were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.

Published
2023

10. Large library docking for novel SARS‐CoV‐2 main protease non‐covalent and covalent inhibitors

Author

Fink, Elissa A, Bardine, Conner, Gahbauer, Stefan, Singh, Isha, Detomasi, Tyler C, White, Kris, Gu, Shuo, Wan, Xiaobo, Chen, Jun, Ary, Beatrice, Glenn, Isabella, O'Connell, Joseph, O'Donnell, Henry, Fajtová, Pavla, Lyu, Jiankun, Vigneron, Seth, Young, Nicholas J, Kondratov, Ivan S, Alisoltani, Arghavan, Simons, Lacy M, Lorenzo‐Redondo, Ramon, Ozer, Egon A, Hultquist, Judd F, O'Donoghue, Anthony J, Moroz, Yurii S, Taunton, Jack, Renslo, Adam R, Irwin, John J, García‐Sastre, Adolfo, Shoichet, Brian K, and Craik, Charles S

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, Emerging Infectious Diseases, Infectious Diseases, Coronaviruses, 5.1 Pharmaceuticals, Good Health and Well Being, Humans, COVID-19, SARS-CoV-2, Pandemics, Protease Inhibitors, Molecular Docking Simulation, Viral Nonstructural Proteins, Antiviral Agents, major protease, SARS-COV-2, structure-based inhibitor, discoverydockinganti-viral, Biochemistry and Cell Biology, Computation Theory and Mathematics, Other Information and Computing Sciences, Biophysics, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Antiviral therapeutics to treat SARS-CoV-2 are needed to diminish the morbidity of the ongoing COVID-19 pandemic. A well-precedented drug target is the main viral protease (MPro ), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure-based approach, we docked 1.2 billion non-covalent lead-like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 and 20 μM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of MPro inhibitors for SARS-CoV-2, the modest success rate also reveals weaknesses in our approach for challenging targets like MPro versus other targets where it has been more successful, and versus other structure-based techniques against MPro itself.

Published
2023

11. Structure-Based Discovery of Inhibitors of the SARS-CoV‑2 Nsp14 N7-Methyltransferase

Author

Singh, Isha, Li, Fengling, Fink, Elissa A, Chau, Irene, Li, Alice, Rodriguez-Hernández, Annía, Glenn, Isabella, Zapatero-Belinchón, Francisco J, Rodriguez, M Luis, Devkota, Kanchan, Deng, Zhijie, White, Kris, Wan, Xiaobo, Tolmachova, Nataliya A, Moroz, Yurii S, Kaniskan, H Ümit, Ott, Melanie, García-Sastre, Adolfo, Jin, Jian, Fujimori, Danica Galonić, Irwin, John J, Vedadi, Masoud, and Shoichet, Brian K

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, Emerging Infectious Diseases, Infectious Diseases, Humans, Methyltransferases, SARS-CoV-2, Viral Nonstructural Proteins, COVID-19, RNA, Viral, Exoribonucleases, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, Pharmacology and pharmaceutical sciences, Medicinal and biomolecular chemistry, Organic chemistry
Abstract

An under-explored target for SARS-CoV-2 is the S-adenosyl methionine (SAM)-dependent methyltransferase Nsp14, which methylates the N7-guanosine of viral RNA at the 5'-end, allowing the virus to evade host immune response. We sought new Nsp14 inhibitors with three large library docking strategies. First, up to 1.1 billion lead-like molecules were docked against the enzyme's SAM site, leading to three inhibitors with IC50 values from 6 to 50 μM. Second, docking a library of 16 million fragments revealed 9 new inhibitors with IC50 values from 12 to 341 μM. Third, docking a library of 25 million electrophiles to covalently modify Cys387 revealed 7 inhibitors with IC50 values from 3.5 to 39 μM. Overall, 32 inhibitors encompassing 11 chemotypes had IC50 values < 50 μM and 5 inhibitors in 4 chemotypes had IC50 values < 10 μM. These molecules are among the first non-SAM-like inhibitors of Nsp14, providing starting points for future optimization.

Published
2023

12. Virology under the Microscope-a Call for Rational Discourse.

Author

Goodrum, Felicia, Lowen, Anice C, Lakdawala, Seema, Alwine, James, Casadevall, Arturo, Imperiale, Michael J, Atwood, Walter, Avgousti, Daphne, Baines, Joel, Banfield, Bruce, Banks, Lawrence, Bhaduri-McIntosh, Sumita, Bhattacharya, Deepta, Blanco-Melo, Daniel, Bloom, David, Boon, Adrianus, Boulant, Steeve, Brandt, Curtis, Broadbent, Andrew, Brooke, Christopher, Cameron, Craig, Campos, Samuel, Caposio, Patrizia, Chan, Gary, Cliffe, Anna, Coffin, John, Collins, Kathleen, Damania, Blossom, Daugherty, Matthew, Debbink, Kari, DeCaprio, James, Dermody, Terence, Dikeakos, Jimmy, DiMaio, Daniel, Dinglasan, Rhoel, Duprex, W Paul, Dutch, Rebecca, Elde, Nels, Emerman, Michael, Enquist, Lynn, Fane, Bentley, Fernandez-Sesma, Ana, Flenniken, Michelle, Frappier, Lori, Frieman, Matthew, Frueh, Klaus, Gack, Michaela, Gaglia, Marta, Gallagher, Tom, Galloway, Denise, García-Sastre, Adolfo, Geballe, Adam, Glaunsinger, Britt, Goff, Stephen, Greninger, Alexander, Hancock, Meaghan, Harris, Eva, Heaton, Nicholas, Heise, Mark, Heldwein, Ekaterina, Hogue, Brenda, Horner, Stacy, Hutchinson, Edward, Hyser, Joseph, Jackson, William, Kalejta, Robert, Kamil, Jeremy, Karst, Stephanie, Kirchhoff, Frank, Knipe, David, Kowalik, Timothy, Lagunoff, Michael, Laimins, Laimonis, Langlois, Ryan, Lauring, Adam, Lee, Benhur, Leib, David, Liu, Shan-Lu, Longnecker, Richard, Lopez, Carolina, Luftig, Micah, Lund, Jennifer, Manicassamy, Balaji, McFadden, Grant, McIntosh, Michael, Mehle, Andrew, Miller, W Allen, Mohr, Ian, Moody, Cary, Moorman, Nathaniel, Moscona, Anne, Mounce, Bryan, Munger, Joshua, Münger, Karl, Murphy, Eain, Naghavi, Mojgan, Nelson, Jay, Neufeldt, Christopher, Nikolich, Janko, and O'Connor, Christine

Subjects
COVID-19, Coronavirus, DURC, Gain of function, SARS-CoV-2, biosafety, influenza, pandemic, vaccines, zoonosis, Infectious Diseases, Prevention, Vaccine Related, Immunization, Infection, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

Published
2023

13. Phase II study on the safety and immunogenicity of single-dose intramuscular or intranasal administration of the AVX/COVID-12 “Patria” recombinant Newcastle disease virus vaccine as a heterologous booster against COVID-19 in Mexico

Author

López-Macías, Constantino, Torres, Martha, Armenta-Copca, Brenda, Wacher, Niels H., Castro-Castrezana, Laura, Colli-Domínguez, Andrea Alicia, Rivera-Hernández, Tania, Torres-Flores, Alejandro, Damián-Hernández, Matilde, Ramírez-Martínez, Luis, la Rosa, Georgina Paz-De, Rojas-Martínez, Oscar, Suárez-Martínez, Alejandro, Peralta-Sánchez, Gustavo, Carranza, Claudia, Juárez, Esmeralda, Zamudio-Meza, Horacio, Carreto-Binaghi, Laura E., Viettri, Mercedes, Romero-Rodríguez, Damaris, Palencia, Andrea, Reyna-Rosas, Edgar, Márquez-García, José E., Sarfati-Mizrahi, David, Sun, Weina, Chagoya-Cortés, Héctor Elías, Castro-Peralta, Felipa, Palese, Peter, Krammer, Florian, García-Sastre, Adolfo, and Lozano-Dubernard, Bernardo

Published
2025
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14. Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets

Author

Haas, Kelsey M, McGregor, Michael J, Bouhaddou, Mehdi, Polacco, Benjamin J, Kim, Eun-Young, Nguyen, Thong T, Newton, Billy W, Urbanowski, Matthew, Kim, Heejin, Williams, Michael AP, Rezelj, Veronica V, Hardy, Alexandra, Fossati, Andrea, Stevenson, Erica J, Sukerman, Ellie, Kim, Tiffany, Penugonda, Sudhir, Moreno, Elena, Braberg, Hannes, Zhou, Yuan, Metreveli, Giorgi, Harjai, Bhavya, Tummino, Tia A, Melnyk, James E, Soucheray, Margaret, Batra, Jyoti, Pache, Lars, Martin-Sancho, Laura, Carlson-Stevermer, Jared, Jureka, Alexander S, Basler, Christopher F, Shokat, Kevan M, Shoichet, Brian K, Shriver, Leah P, Johnson, Jeffrey R, Shaw, Megan L, Chanda, Sumit K, Roden, Dan M, Carter, Tonia C, Kottyan, Leah C, Chisholm, Rex L, Pacheco, Jennifer A, Smith, Maureen E, Schrodi, Steven J, Albrecht, Randy A, Vignuzzi, Marco, Zuliani-Alvarez, Lorena, Swaney, Danielle L, Eckhardt, Manon, Wolinsky, Steven M, White, Kris M, Hultquist, Judd F, Kaake, Robyn M, García-Sastre, Adolfo, and Krogan, Nevan J

Subjects
Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Influenza, Biotechnology, Genetics, Lung, Biodefense, Pneumonia & Influenza, Emerging Infectious Diseases, Infectious Diseases, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Infection, Humans, Influenza A virus, Influenza, Human, Influenza A Virus, H5N1 Subtype, Influenza A Virus, H3N2 Subtype, Proteomics, Virus Replication, COVID-19, SARS-CoV-2, Antiviral Agents, Host-Pathogen Interactions
Abstract

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

Published
2023

16. 2022 taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales.

Author

Bukreyev, Alexander, Burt, Felicity, Büttner, Carmen, Calisher, Charles, Candresse, Thierry, Carson, Jeremy, Casas, Inmaculada, Chandran, Kartik, Charrel, Rémi, Chiaki, Yuya, Crane, Anya, Crane, Mark, Dacheux, Laurent, Bó, Elena, de la Torre, Juan, de Lamballerie, Xavier, de Souza, William, de Swart, Rik, Dheilly, Nolwenn, Di Paola, Nicholas, Di Serio, Francesco, Dietzgen, Ralf, Digiaro, Michele, Drexler, J, Duprex, W, Dürrwald, Ralf, Easton, Andrew, Elbeaino, Toufic, Ergünay, Koray, Feng, Guozhong, Feuvrier, Claudette, Firth, Andrew, Fooks, Anthony, Formenty, Pierre, Freitas-Astúa, Juliana, Gago-Zachert, Selma, García, María, García-Sastre, Adolfo, Garrison, Aura, Godwin, Scott, Gonzalez, Jean-Paul, de Bellocq, Joëlle, Griffiths, Anthony, Groschup, Martin, Günther, Stephan, Hammond, John, Hepojoki, Jussi, Hierweger, Melanie, Hongō, Seiji, Horie, Masayuki, Horikawa, Hidenori, Hughes, Holly, Hume, Adam, Hyndman, Timothy, Jiāng, Dàohóng, Jonson, Gilda, Junglen, Sandra, Kadono, Fujio, Karlin, David, Klempa, Boris, Klingström, Jonas, Koch, Michel, Kondō, Hideki, Koonin, Eugene, Krásová, Jarmila, Krupovic, Mart, Kubota, Kenji, Kuzmin, Ivan, Laenen, Lies, Lambert, Amy, Lǐ, Jiànróng, Li, Jun-Min, Lieffrig, François, Lukashevich, Igor, Luo, Dongsheng, Maes, Piet, Marklewitz, Marco, Marshall, Sergio, Marzano, Shin-Yi, McCauley, John, Mirazimi, Ali, Mohr, Peter, Moody, Nick, Morita, Yasuaki, Morrison, Richard, Mühlberger, Elke, Naidu, Rayapati, Natsuaki, Tomohide, Navarro, José, Neriya, Yutaro, Netesov, Sergey, Neumann, Gabriele, Nowotny, Norbert, Ochoa-Corona, Francisco, Palacios, Gustavo, Pallandre, Laurane, Pallás, Vicente, Papa, Anna, Paraskevopoulou, Sofia, and Parrish, Colin

Subjects
Humans, Mononegavirales, Phylogeny, Viruses
Abstract

In March 2022, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by two new families (bunyaviral Discoviridae and Tulasviridae), 41 new genera, and 98 new species. Three hundred forty-nine species were renamed and/or moved. The accidentally misspelled names of seven species were corrected. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.

Published
2022

17. Inhibition of SARS-CoV-2 growth in the lungs of mice by a peptide-conjugated morpholino oligomer targeting viral RNA

Author

Sakai, Alexandra, Singh, Gagandeep, Khoshbakht, Mahsa, Bittner, Scott, Löhr, Christiane V., Diaz-Tapia, Randy, Warang, Prajakta, White, Kris, Luo, Luke Le, Tolbert, Blanton, Blanco, Mario, Chow, Amy, Guttman, Mitchell, Li, Cuiping, Bao, Yiming, Ho, Joses, Maurer-Stroh, Sebastian, Chatterjee, Arnab, Chanda, Sumit, García-Sastre, Adolfo, Schotsaert, Michael, Teijaro, John R., Moulton, Hong M., and Stein, David A.

Published
2024
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20. Characteristics of Lung Cancer Patients With Asymptomatic or Undiagnosed SARS-CoV-2 Infections

Author

Somisetty, Medha, Mack, Philip C., Hsu, Chih-Yuan, Huang, Yuanhui, Gomez, Jorge E., Rodilla, Ananda M., Cagan, Jazz, Tavolacci, Sooyun C., Carreño, Juan Manuel, Brody, Rachel, Moore, Amy C., King, Jennifer C., Rohs, Nicholas C., Rolfo, Christian, Bunn, Paul A., Minna, John D., Bhalla, Sheena, Krammer, Florian, García-Sastre, Adolfo, Figueiredo, Jane C., Kazemian, Elham, Reckamp, Karen L., Merchant, Akil A., Nadri, Maimoona, Ahmed, Rafi, Ramalingam, Suresh S., Shyr, Yu, Hirsch, Fred R., and Gerber, David E.

Published
2024
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22. Fungal microbiota sustains lasting immune activation of neutrophils and their progenitors in severe COVID-19

Author

Kusakabe, Takato, Lin, Woan-Yu, Cheong, Jin-Gyu, Singh, Gagandeep, Ravishankar, Arjun, Yeung, Stephen T., Mesko, Marissa, DeCelie, Meghan Bialt, Carriche, Guilhermina, Zhao, Zhen, Rand, Sophie, Doron, Itai, Putzel, Gregory G., Worgall, Stefan, Cushing, Melissa, Westblade, Lars, Inghirami, Giorgio, Parkhurst, Christopher N., Guo, Chun-Jun, Schotsaert, Michael, García-Sastre, Adolfo, Josefowicz, Steven Z., Salvatore, Mirella, and Iliev, Iliyan D.

Published
2023
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23. Nirmatrelvir and molnupiravir maintain potent in vitro and in vivo antiviral activity against circulating SARS-CoV-2 omicron subvariants

Author

Alshammary, Hala, Banu, R., Farrugia, K., Gonzalez-Reiche, Ana Silvia, Paniz-Mondolfi, A., Polanco, J., Rosales, Romel, McGovern, Briana L., Rodriguez, M. Luis, Leiva-Rebollo, Rocio, Diaz-Tapia, Randy, Benjamin, Jared, Rai, Devendra K., Cardin, Rhonda D., Anderson, Annaliesa S., Sordillo, Emilia Mia, van Bakel, Harm, Simon, Viviana, García-Sastre, Adolfo, and White, Kris M.

Published
2024
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25. 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

28. H19 influenza A virus exhibits species-specific MHC class II receptor usage

Author

Karakus, Umut, Mena, Ignacio, Kottur, Jithesh, El Zahed, Sara S., Seoane, Rocío, Yildiz, Soner, Chen, Leanne, Plancarte, Magdalena, Lindsay, LeAnn, Halpin, Rebecca, Stockwell, Timothy B., Wentworth, David E., Boons, Geert-Jan, Krammer, Florian, Stertz, Silke, Boyce, Walter, de Vries, Robert P., Aggarwal, Aneel K., and García-Sastre, Adolfo

Published
2024
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30. A chimeric haemagglutinin-based universal influenza virus vaccine boosts human cellular immune responses directed towards the conserved haemagglutinin stalk domain and the viral nucleoprotein

Author

Bliss, Carly M., Nachbagauer, Raffael, Mariottini, Chiara, Cuevas, Frans, Feser, Jodi, Naficy, Abdi, Bernstein, David I., Guptill, Jeffrey, Walter, Emmanuel B., Berlanda-Scorza, Francesco, Innis, Bruce L., García-Sastre, Adolfo, Palese, Peter, Krammer, Florian, and Coughlan, Lynda

Published
2024
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31. The IRE1α-XBP1 arm of the unfolded protein response is a host factor activated in SARS-CoV-2 infection

Author

Fernández, Jose Javier, Marín, Arturo, Rosales, Romel, Penrice-Randal, Rebekah, Mlcochova, Petra, Alvarez, Yolanda, Villalón-Letelier, Fernando, Yildiz, Soner, Pérez, Enrique, Rathnasinghe, Raveen, Cupic, Anastasija, Kehrer, Thomas, Uccellini, Melissa B., Alonso, Sara, Martínez, Fernando, McGovern, Briana Lynn, Clark, Jordan J., Sharma, Parul, Bayón, Yolanda, Alonso, Andrés, Albrecht, Randy A., White, Kris M., Schotsaert, Michael, Miorin, Lisa, Stewart, James P., Hiscox, Julian A., Gupta, Ravindra K., Irigoyen, Nerea, García-Sastre, Adolfo, Crespo, Mariano Sánchez, and Fernández, Nieves

Published
2024
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32. Mutations in SARS-CoV-2 variants of concern link to increased spike cleavage and virus transmission

Author

Escalera, Alba, Gonzalez-Reiche, Ana S, Aslam, Sadaf, Mena, Ignacio, Laporte, Manon, Pearl, Rebecca L, Fossati, Andrea, Rathnasinghe, Raveen, Alshammary, Hala, van de Guchte, Adriana, Farrugia, Keith, Qin, Yiren, Bouhaddou, Mehdi, Kehrer, Thomas, Zuliani-Alvarez, Lorena, Meekins, David A, Balaraman, Velmurugan, McDowell, Chester, Richt, Jürgen A, Bajic, Goran, Sordillo, Emilia Mia, Dejosez, Marion, Zwaka, Thomas P, Krogan, Nevan J, Simon, Viviana, Albrecht, Randy A, van Bakel, Harm, García-Sastre, Adolfo, and Aydillo, Teresa

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Coronaviruses, Emerging Infectious Diseases, Infectious Diseases, 2.2 Factors relating to the physical environment, Infection, Good Health and Well Being, COVID-19, Humans, Mutation, SARS-CoV-2, Spike Glycoprotein, Coronavirus, H655Y mutation, fusion, gamma, omicron, spike cleavage, syncytia formation, variants of concern, Microbiology, Immunology, Biochemistry and cell biology, Medical microbiology
Abstract

SARS-CoV-2 lineages have diverged into highly prevalent variants termed "variants of concern" (VOCs). Here, we characterized emerging SARS-CoV-2 spike polymorphisms in vitro and in vivo to understand their impact on transmissibility and virus pathogenicity and fitness. We demonstrate that the substitution S:655Y, represented in the gamma and omicron VOCs, enhances viral replication and spike protein cleavage. The S:655Y substitution was transmitted more efficiently than its ancestor S:655H in the hamster infection model and was able to outcompete S:655H in the hamster model and in a human primary airway system. Finally, we analyzed a set of emerging SARS-CoV-2 variants to investigate how different sets of mutations may impact spike processing. All VOCs tested exhibited increased spike cleavage and fusogenic capacity. Taken together, our study demonstrates that the spike mutations present in VOCs that become epidemiologically prevalent in humans are linked to an increase in spike processing and virus transmission.

Published
2022

33. Evolution of enhanced innate immune evasion by SARS-CoV-2

Author

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, Infectious Diseases, Coronaviruses, Emerging Infectious Diseases, Genetics, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, 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.

Published
2022

34. Author Correction: Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

Author

Riva, Laura, Yuan, Shuofeng, Yin, Xin, Martin-Sancho, Laura, Matsunaga, Naoko, Pache, Lars, Burgstaller-Muehlbacher, Sebastian, De Jesus, Paul D., Teriete, Peter, Hull, Mitchell V., Chang, Max W., Chan, Jasper Fuk-Woo, Cao, Jianli, Poon, Vincent Kwok-Man, Herbert, Kristina M., Cheng, Kuoyuan, Nguyen, Tu-Trinh H., Rubanov, Andrey, Pu, Yuan, Nguyen, Courtney, Choi, Angela, Rathnasinghe, Raveen, Schotsaert, Michael, Miorin, Lisa, Dejosez, Marion, Zwaka, Thomas P., Sit, Ko-Yung, Martinez-Sobrido, Luis, Liu, Wen-Chun, White, Kris M., Chapman, Mackenzie E., Lendy, Emma K., Glynne, Richard J., Albrecht, Randy, Ruppin, Eytan, Mesecar, Andrew D., Johnson, Jeffrey R., Benner, Christopher, Sun, Ren, Schultz, Peter G., Su, Andrew I., García-Sastre, Adolfo, Chatterjee, Arnab K., Yuen, Kwok-Yung, and Chanda, Sumit K.

Published
2024
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35. Human SUMOylation Pathway Is Critical for Influenza B Virus

Author

Dang, Runrui, Rodgers, Victor GJ, García-Sastre, Adolfo, and Liao, Jiayu

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biotechnology, Emerging Infectious Diseases, Infectious Diseases, 2.2 Factors relating to the physical environment, Aetiology, 2.1 Biological and endogenous factors, Infection, Cell Line, Host-Pathogen Interactions, Humans, Influenza B virus, Influenza, Human, Sumoylation, Ubiquitin-Protein Ligases, Viral Matrix Proteins, Virus Replication, influenza B virus or IBV, critical host factor, SUMOylation, therapeutics, Microbiology
Abstract

The identification and elucidation of host pathways for viral infection are critical for understanding the viral infection processes and novel therapeutics development. Here, for the first time, we discover that the human SUMOylation pathway is essential for the IBV viral life cycle. First, IBV viruses were completely inhibited by a novel SUMOylation specific inhibitor, STE025, discovered from our FRET-based high-throughput screening, and the inhibition was very potent, with IC50~ 0.1 µM in an IBV-induced cell death rescue assay; Second, we determined that the IBV M1 protein was SUMOylated, which was mediated by the SUMOylation E2 conjugation enzyme and the E3 ligase enzyme at very high affinities, of 0.20 µM and 0.22 µM, respectively; Third, the mutation of the IBV M1 SUMOylation site, K21R, completely abolished the viral particle generation, strongly suggesting the requirement of SUMOylation for the IBV life cycle. These results suggest that the blockage of the host human SUMOylation pathway is very effective for IBV inhibition. We therefore propose that the host SUMOylation pathway is a critical host factor for the IBV virus life cycle. The identification and inhibition of critical host factor(s) provide a novel strategy for future anti-viral therapeutics development, such as IBV and other viruses.

Published
2022

36. 2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales

Author

Kuhn, Jens H, Adkins, Scott, Agwanda, Bernard R, Al Kubrusli, Rim, Alkhovsky, Sergey V, Amarasinghe, Gaya K, Avšič-Županc, Tatjana, Ayllón, María A, Bahl, Justin, Balkema-Buschmann, Anne, Ballinger, Matthew J, Basler, Christopher F, Bavari, Sina, Beer, Martin, Bejerman, Nicolas, Bennett, Andrew J, Bente, Dennis A, Bergeron, Éric, Bird, Brian H, Blair, Carol D, Blasdell, Kim R, Blystad, Dag-Ragnar, Bojko, Jamie, Borth, Wayne B, Bradfute, Steven, Breyta, Rachel, Briese, Thomas, Brown, Paul A, Brown, Judith K, Buchholz, Ursula J, Buchmeier, Michael J, Bukreyev, Alexander, Burt, Felicity, Büttner, Carmen, Calisher, Charles H, Cao, Mengji, Casas, Inmaculada, Chandran, Kartik, Charrel, Rémi N, Cheng, Qi, Chiaki, Yuya, Chiapello, Marco, Choi, Il-Ryong, Ciuffo, Marina, Clegg, J Christopher S, Crozier, Ian, Dal Bó, Elena, de la Torre, Juan Carlos, de Lamballerie, Xavier, de Swart, Rik L, Debat, Humberto, Dheilly, Nolwenn M, Di Cicco, Emiliano, Di Paola, Nicholas, Di Serio, Francesco, Dietzgen, Ralf G, Digiaro, Michele, Dolnik, Olga, Drebot, Michael A, Drexler, J Felix, Dundon, William G, Duprex, W Paul, Dürrwald, Ralf, Dye, John M, Easton, Andrew J, Ebihara, Hideki, Elbeaino, Toufic, Ergünay, Koray, Ferguson, Hugh W, Fooks, Anthony R, Forgia, Marco, Formenty, Pierre BH, Fránová, Jana, Freitas-Astúa, Juliana, Fu, Jingjing, Fürl, Stephanie, Gago-Zachert, Selma, Gāo, George Fú, García, María Laura, García-Sastre, Adolfo, Garrison, Aura R, Gaskin, Thomas, Gonzalez, Jean-Paul J, Griffiths, Anthony, Goldberg, Tony L, Groschup, Martin H, Günther, Stephan, Hall, Roy A, Hammond, John, Han, Tong, Hepojoki, Jussi, Hewson, Roger, Hong, Jiang, Hong, Ni, Hongo, Seiji, Horie, Masayuki, Hu, John S, Hu, Tao, Hughes, Holly R, and Hüttner, Florian

Subjects
Biotechnology, Humans, Mononegavirales, Viruses, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Virology
Abstract

In March 2021, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by four families (Aliusviridae, Crepuscuviridae, Myriaviridae, and Natareviridae), three subfamilies (Alpharhabdovirinae, Betarhabdovirinae, and Gammarhabdovirinae), 42 genera, and 200 species. Thirty-nine species were renamed and/or moved and seven species were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.

Published
2021

41. Interim safety and immunogenicity results from an NDV-based COVID-19 vaccine phase I trial in Mexico

Author

Ponce-de-León, Samuel, Torres, Martha, Soto-Ramírez, Luis Enrique, Calva, Juan José, Santillán-Doherty, Patricio, Carranza-Salazar, Dora Eugenia, Carreño, Juan Manuel, Carranza, Claudia, Juárez, Esmeralda, Carreto-Binaghi, Laura E., Ramírez-Martínez, Luis, Paz De la Rosa, Georgina, Vigueras-Moreno, Rosalía, Ortiz-Stern, Alejandro, López-Vidal, Yolanda, Macías, Alejandro E., Torres-Flores, Jesús, Rojas-Martínez, Oscar, Suárez-Martínez, Alejandro, Peralta-Sánchez, Gustavo, Kawabata, Hisaaki, González-Domínguez, Irene, Martínez-Guevara, José Luis, Sun, Weina, Sarfati-Mizrahi, David, Soto-Priante, Ernesto, Chagoya-Cortés, Héctor Elías, López-Macías, Constantino, Castro-Peralta, Felipa, Palese, Peter, García-Sastre, Adolfo, Krammer, Florian, and Lozano-Dubernard, Bernardo

Published
2023
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42. Restriction factor compendium for influenza A virus reveals a mechanism for evasion of autophagy

Author

Martin-Sancho, Laura, Tripathi, Shashank, Rodriguez-Frandsen, Ariel, Pache, Lars, Sanchez-Aparicio, Maite, McGregor, Michael J, Haas, Kelsey M, Swaney, Danielle L, Nguyen, Thong T, Mamede, João I, Churas, Christopher, Pratt, Dexter, Rosenthal, Sara B, Riva, Laura, Nguyen, Courtney, Beltran-Raygoza, Nish, Soonthornvacharin, Stephen, Wang, Guojun, Jimenez-Morales, David, De Jesus, Paul D, Moulton, Hong M, Stein, David A, Chang, Max W, Benner, Chris, Ideker, Trey, Albrecht, Randy A, Hultquist, Judd F, Krogan, Nevan J, García-Sastre, Adolfo, and Chanda, Sumit K

Subjects
Microbiology, Biochemistry and Cell Biology, Biological Sciences, Influenza, Infectious Diseases, Emerging Infectious Diseases, Pneumonia & Influenza, Biodefense, 2.2 Factors relating to the physical environment, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Infection, Antiviral Agents, Autophagy, GTPase-Activating Proteins, Host-Pathogen Interactions, Humans, Immune Evasion, Influenza A virus, Lysosomes, Protein Binding, Viral Matrix Proteins, Virus Replication, rab GTP-Binding Proteins, rab7 GTP-Binding Proteins, Medical Microbiology
Abstract

The fate of influenza A virus (IAV) infection in the host cell depends on the balance between cellular defence mechanisms and viral evasion strategies. To illuminate the landscape of IAV cellular restriction, we generated and integrated global genetic loss-of-function screens with transcriptomics and proteomics data. Our multi-omics analysis revealed a subset of both IFN-dependent and independent cellular defence mechanisms that inhibit IAV replication. Amongst these, the autophagy regulator TBC1 domain family member 5 (TBC1D5), which binds Rab7 to enable fusion of autophagosomes and lysosomes, was found to control IAV replication in vitro and in vivo and to promote lysosomal targeting of IAV M2 protein. Notably, IAV M2 was observed to abrogate TBC1D5-Rab7 binding through a physical interaction with TBC1D5 via its cytoplasmic tail. Our results provide evidence for the molecular mechanism utilised by IAV M2 protein to escape lysosomal degradation and traffic to the cell membrane, where it supports IAV budding and growth.

Published
2021

43. Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2

Author

Tummino, Tia A, Rezelj, Veronica V, Fischer, Benoit, Fischer, Audrey, O'Meara, Matthew J, Monel, Blandine, Vallet, Thomas, White, Kris M, Zhang, Ziyang, Alon, Assaf, Schadt, Heiko, O'Donnell, Henry R, Lyu, Jiankun, Rosales, Romel, McGovern, Briana L, Rathnasinghe, Raveen, Jangra, Sonia, Schotsaert, Michael, Galarneau, Jean-René, Krogan, Nevan J, Urban, Laszlo, Shokat, Kevan M, Kruse, Andrew C, García-Sastre, Adolfo, Schwartz, Olivier, Moretti, Francesca, Vignuzzi, Marco, Pognan, Francois, and Shoichet, Brian K

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, Infectious Diseases, Orphan Drug, Rare Diseases, Clinical Research, Emerging Infectious Diseases, Clinical Trials and Supportive Activities, Coronaviruses, 5.1 Pharmaceuticals, Good Health and Well Being, A549 Cells, Animals, Antiviral Agents, COVID-19, Cations, Chlorocebus aethiops, Dose-Response Relationship, Drug, Drug Repositioning, Female, Humans, Lipidoses, Mice, Microbial Sensitivity Tests, Phospholipids, SARS-CoV-2, Surface-Active Agents, Vero Cells, Virus Replication, COVID-19 Drug Treatment, General Science & Technology
Abstract

Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities-rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.

Published
2021

44. Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19.

Author

Le, Brian L, Andreoletti, Gaia, Oskotsky, Tomiko, Vallejo-Gracia, Albert, Rosales, Romel, Yu, Katharine, Kosti, Idit, Leon, Kristoffer E, Bunis, Daniel G, Li, Christine, Kumar, G Renuka, White, Kris M, García-Sastre, Adolfo, Ott, Melanie, and Sirota, Marina

Subjects
Humans, Antiviral Agents, Computational Biology, Drug Repositioning, Transcriptome, COVID-19, SARS-CoV-2, Vaccine Related, Infectious Diseases, Biodefense, Pneumonia, Emerging Infectious Diseases, Lung, Prevention, 5.1 Pharmaceuticals, Infection
Abstract

The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov-Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated 16 of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.

Published
2021

45. Functional landscape of SARS-CoV-2 cellular restriction

Author

Martin-Sancho, Laura, Lewinski, Mary K, Pache, Lars, Stoneham, Charlotte A, Yin, Xin, Becker, Mark E, Pratt, Dexter, Churas, Christopher, Rosenthal, Sara B, Liu, Sophie, Weston, Stuart, De Jesus, Paul D, O'Neill, Alan M, Gounder, Anshu P, Nguyen, Courtney, Pu, Yuan, Curry, Heather M, Oom, Aaron L, Miorin, Lisa, Rodriguez-Frandsen, Ariel, Zheng, Fan, Wu, Chunxiang, Xiong, Yong, Urbanowski, Matthew, Shaw, Megan L, Chang, Max W, Benner, Christopher, Hope, Thomas J, Frieman, Matthew B, García-Sastre, Adolfo, Ideker, Trey, Hultquist, Judd F, Guatelli, John, and Chanda, Sumit K

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Coronaviruses Therapeutics and Interventions, Genetics, Emerging Infectious Diseases, Stem Cell Research, Coronaviruses, Infectious Diseases, Stem Cell Research - Embryonic - Human, Lung, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Infection, Good Health and Well Being, Animals, Antigens, CD, Binding Sites, Cell Line, Tumor, Chlorocebus aethiops, Endoplasmic Reticulum, GPI-Linked Proteins, Gene Expression Regulation, Golgi Apparatus, HEK293 Cells, Host-Pathogen Interactions, Humans, Immunity, Innate, Interferon Regulatory Factors, Interferon Type I, Molecular Docking Simulation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, SARS-CoV-2, Signal Transduction, Vero Cells, Viral Proteins, Virus Internalization, Virus Release, Virus Replication, BST2, ISG, Orf7a, innate immunity, interferon, viral evasion, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

A deficient interferon (IFN) response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated as a determinant of severe coronavirus disease 2019 (COVID-19). To identify the molecular effectors that govern IFN control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human IFN-stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors inhibiting viral entry, RNA binding proteins suppressing viral RNA synthesis, and a highly enriched cluster of endoplasmic reticulum (ER)/Golgi-resident ISGs inhibiting viral assembly/egress. These included broad-acting antiviral ISGs and eight ISGs that specifically inhibited SARS-CoV-2 and SARS-CoV-1 replication. Among the broad-acting ISGs was BST2/tetherin, which impeded viral release and is antagonized by SARS-CoV-2 Orf7a protein. Overall, these data illuminate a set of ISGs that underlie innate immune control of SARS-CoV-2/SARS-CoV-1 infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.

Published
2021

46. Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A

Author

White, Kris M, Rosales, Romel, Yildiz, Soner, Kehrer, Thomas, Miorin, Lisa, Moreno, Elena, Jangra, Sonia, Uccellini, Melissa B, Rathnasinghe, Raveen, Coughlan, Lynda, Martinez-Romero, Carles, Batra, Jyoti, Rojc, Ajda, Bouhaddou, Mehdi, Fabius, Jacqueline M, Obernier, Kirsten, Dejosez, Marion, Guillén, María José, Losada, Alejandro, Avilés, Pablo, Schotsaert, Michael, Zwaka, Thomas, Vignuzzi, Marco, Shokat, Kevan M, Krogan, Nevan J, and García-Sastre, Adolfo

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Emerging Infectious Diseases, Infectious Diseases, Biodefense, Biotechnology, Coronaviruses, Lung, Coronaviruses Therapeutics and Interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Adenosine Monophosphate, Alanine, Animals, Antiviral Agents, COVID-19, Coronavirus Nucleocapsid Proteins, Depsipeptides, Drug Evaluation, Preclinical, Female, HEK293 Cells, Humans, Mice, Inbred C57BL, Mutation, Peptide Elongation Factor 1, Peptides, Cyclic, Phosphoproteins, RNA, Viral, SARS-CoV-2, Virus Replication, COVID-19 Drug Treatment, Mice, General Science & Technology
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro by a factor of 27.5, with limited toxicity in cell culture. Through the use of a drug-resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A (eukaryotic translation elongation factor 1A). We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.

Published
2021

47. Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection

Author

Wei, Jin, Patil, Ajinkya, Collings, Clayton K., Alfajaro, Mia Madel, Liang, Yu, Cai, Wesley L., Strine, Madison S., Filler, Renata B., DeWeirdt, Peter C., Hanna, Ruth E., Menasche, Bridget L., Ökten, Arya, Peña-Hernández, Mario A., Klein, Jon, McNamara, Andrew, Rosales, Romel, McGovern, Briana L., Luis Rodriguez, M., García-Sastre, Adolfo, White, Kris M., Qin, Yiren, Doench, John G., Yan, Qin, Iwasaki, Akiko, Zwaka, Thomas P., Qi, Jun, Kadoch, Cigall, and Wilen, Craig B.

Published
2023
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48. Nuclear speckle integrity and function require TAO2 kinase

Author

Gao, Shengyan, Esparza, Matthew, Dehghan, Ishmael, Aksenova, Vasilisa, Zhang, Ke, Batten, Kimberly, Ferretti, Max B., Begg, Bridget E., Cagatay, Tolga, Shay, Jerry W., García-Sastre, Adolfo, Goldsmith, Elizabeth J., Chen, Zhijian J., Dasso, Mary, Lynch, Kristen W., Cobb, Melanie H., and Fontoura, Beatriz M. A.

Published
2022

49. SARS-CoV-2 variants evolve convergent strategies to remodel the host response

Author

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.

Published
2023
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50. Spatiotemporally organized immunomodulatory response to SARS-CoV-2 virus in primary human broncho-alveolar epithelia

Author

Castaneda, Diana Cadena, Jangra, Sonia, Yurieva, Marina, Martinek, Jan, Callender, Megan, Coxe, Matthew, Choi, Angela, García-Bernalt Diego, Juan, Lin, Jianan, Wu, Te-Chia, Marches, Florentina, Chaussabel, Damien, Yu, Peter, Salner, Andrew, Aucello, Gabrielle, Koff, Jonathan, Hudson, Briana, Church, Sarah E., Gorman, Kara, Anguiano, Esperanza, García-Sastre, Adolfo, Williams, Adam, Schotsaert, Michael, and Palucka, Karolina

Published
2023
Full Text
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