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2,047 results on '"Rice, Charles M."'

1. Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase

Author

Meyer, Cindy, Garzia, Aitor, Miller, Michael W., Huggins, David J., Myers, Robert W., Hoffmann, Hans-Heinrich, Ashbrook, Alison W., Jannath, Syeda Y., Liverton, Nigel, Kargman, Stacia, Zimmerman, Matthew, Nelson, Andrew M., Sharma, Vijeta, Dolgov, Enriko, Cangialosi, Julianna, Penalva-Lopez, Suyapa, Alvarez, Nadine, Chang, Ching-Wen, Oswal, Neelam, Gonzalez, Irene, Rasheed, Risha, Goldgirsh, Kira, Davis, Jada A., Ramos-Espiritu, Lavoisier, Menezes, Miriam-Rose, Larson, Chloe, Nitsche, Julius, Ganichkin, Oleg, Alwaseem, Hanan, Molina, Henrik, Steinbacher, Stefan, Glickman, J. Fraser, Perlin, David S., Rice, Charles M., Meinke, Peter T., and Tuschl, Thomas

Published
2024
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2. Virology—the path forward

Author

Rasmussen, Angela L, Gronvall, Gigi K, Lowen, Anice C, Goodrum, Felicia, Alwine, James, Andersen, Kristian G, Anthony, Simon J, Baines, Joel, Banerjee, Arinjay, Broadbent, Andrew J, Brooke, Christopher B, Campos, Samuel K, Caposio, Patrizia, Casadevall, Arturo, Chan, Gary C, Cliffe, Anna R, Collins-McMillen, Donna, Connell, Nancy, Damania, Blossom, Daugherty, Matthew D, Debbink, Kari, Dermody, Terence S, DiMaio, Daniel, Duprex, W Paul, Emerman, Michael, Galloway, Denise A, Garry, Robert F, Goldstein, Stephen A, Greninger, Alexander L, Hartman, Amy L, Hogue, Brenda G, Horner, Stacy M, Hotez, Peter J, Jung, Jae U, Kamil, Jeremy P, Karst, Stephanie M, Laimins, Lou, Lakdawala, Seema S, Landais, Igor, Letko, Michael, Lindenbach, Brett, Liu, Shan-Lu, Luftig, Micah, McFadden, Grant, Mehle, Andrew, Morrison, Juliet, Moscona, Anne, Mühlberger, Elke, Munger, Joshua, Münger, Karl, Murphy, Eain, Neufeldt, Christopher J, Nikolich, Janko Z, O'Connor, Christine M, Pekosz, Andrew, Permar, Sallie R, Pfeiffer, Julie K, Popescu, Saskia V, Purdy, John G, Racaniello, Vincent R, Rice, Charles M, Runstadler, Jonathan A, Sapp, Martin J, Scott, Rona S, Smith, Gregory A, Sorrell, Erin M, Speranza, Emily, Streblow, Daniel, Tibbetts, Scott A, Toth, Zsolt, Van Doorslaer, Koenraad, Weiss, Susan R, White, Elizabeth A, White, Timothy M, Wobus, Christiane E, Worobey, Michael, Yamaoka, Satoko, and Yurochko, Andrew

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Biomedical and Clinical Sciences, Coronaviruses, Prevention, Emerging Infectious Diseases, Infectious Diseases, Good Health and Well Being, Humans, Containment of Biohazards, COVID-19, United States, Viruses, Virology, Biomedical Research, virology, SARS-CoV-2, oversight, biosafety, emergence, Agricultural and Veterinary Sciences, Medical and Health Sciences, Agricultural, veterinary and food sciences, Biological sciences, Biomedical and clinical sciences
Abstract

In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is a vital part of protecting the health, economy, and security of US citizens. Herein, we offer our perspectives on priorities for revised rules governing virology research in the US.

Published
2024

3. WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma

Author

Rialdi, Alex, Duffy, Mary, Scopton, Alex P, Fonseca, Frank, Zhao, Julia Nanyi, Schwarz, Megan, Molina-Sanchez, Pedro, Mzoughi, Slim, Arceci, Elisa, Abril-Fornaguera, Jordi, Meadows, Austin, Ruiz de Galarreta, Marina, Torre, Denis, Reyes, Kyna, Lim, Yan Ting, Rosemann, Felix, Khan, Zaigham M, Mohammed, Kevin, Wang, Xuedi, Yu, Xufen, Lakshmanan, Manikandan, Rajarethinam, Ravisankar, Tan, Soo Yong, Jin, Jian, Villanueva, Augusto, Michailidis, Eleftherios, De Jong, Ype P, Rice, Charles M, Marazzi, Ivan, Hasson, Dan, Llovet, Josep M, Sobota, Radoslaw M, Lujambio, Amaia, Guccione, Ernesto, and Dar, Arvin C

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Rare Diseases, Liver Disease, Biotechnology, Liver Cancer, Genetics, Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Humans, Mice, Animals, Carcinoma, Hepatocellular, beta Catenin, Liver Neoplasms, Transcription Factors, Antineoplastic Agents, Protein Kinase Inhibitors, Immunology, Oncology and carcinogenesis
Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. β-Catenin (CTNNB1)-mutated HCC represents 30% of cases of the disease with no precision therapeutics available. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffolds, we screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multiomic and target engagement analyses, combined with rescue experiments and in vitro and in vivo efficacy studies, revealed that WNTinib is superior to clinical KIs and inhibits KIT/mitogen-activated protein kinase (MAPK) signaling at multiple nodes. Moreover, we demonstrate that reduced engagement on BRAF and p38α kinases by WNTinib relative to several multi-KIs is necessary to avoid compensatory feedback signaling-providing a durable and selective transcriptional repression of mutant β-catenin/Wnt targets through nuclear translocation of the EZH2 transcriptional repressor. Our studies uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index.

Published
2023

6. Human antibodies in Mexico and Brazil neutralizing tick-borne flaviviruses

Author

Cervantes Rincón, Tomás, Kapoor, Tania, Keeffe, Jennifer R., Simonelli, Luca, Hoffmann, Hans-Heinrich, Agudelo, Marianna, Jurado, Andrea, Peace, Avery, Lee, Yu E., Gazumyan, Anna, Guidetti, Francesca, Cantergiani, Jasmine, Cena, Benedetta, Bianchini, Filippo, Tamagnini, Elia, Moro, Simone G., Svoboda, Pavel, Costa, Federico, Reis, Mitermayer G., Ko, Albert I., Fallon, Brian A., Avila-Rios, Santiago, Reyes-Téran, Gustavo, Rice, Charles M., Nussenzweig, Michel C., Bjorkman, Pamela J., Ruzek, Daniel, Varani, Luca, MacDonald, Margaret R., and Robbiani, Davide F.

Published
2024
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10. The HLA-II immunopeptidome of SARS-CoV-2

Author

Weingarten-Gabbay, Shira, Chen, Da-Yuan, Sarkizova, Siranush, Taylor, Hannah B., Gentili, Matteo, Hernandez, Gabrielle M., Pearlman, Leah R., Bauer, Matthew R., Rice, Charles M., Clauser, Karl R., Hacohen, Nir, Carr, Steven A., Abelin, Jennifer G., Saeed, Mohsan, and Sabeti, Pardis C.

Published
2024
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11. The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

Author

Manry, Jérémy, Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Michailidis, Eleftherios, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martínez, Alba, Yang, Rui, Haljasmägi, Liis, Migaud, Mélanie, Särekannu, Karita, Maslovskaja, Julia, de Prost, Nicolas, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesús, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garçon, Pierre, Rivière, Jacques G., Lagier, Jean-Christophe, Gentile, Stéphanie, Rosen, Lindsey B., Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Louis, Sene, Damien, Stepanian, Alain, Mégarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James R., Franco, José Luis, Anaya, Juan-Manuel, Solé-Violán, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia M., Zhang, Yu, Snow, Andrew L., Holland, Steven M., Biggs, Catherine M., Moncada-Vélez, Marcela, Arias, Andrés Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Anglicheau, Dany, Planas, Anna M., Haerynck, Filomeen, Duvlis, Sotirija, Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed A., Bakkouri, Jalila El, Ramirez-Santana, Carolina, Paul, Stéphane, Pan-Hammarström, Qiang, Hammarström, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine N., Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila A., Dominguez-Garrido, Elena, Vidigal, Mateus, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart G., Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Lluis, Klocperk, Adam, Kann, Nelli Y., Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angélique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel C., Arrestier, Romain, Boudhabhay, Idris, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam H., Kennelly, Sean P., Bourke, Nollaig M., Halwani, Rabih, Sharif-Askari, Fatemeh Saheb, Dorgham, Karim, Sallette, Jérôme, Sedkaoui, Souad Mehlal, AlKhater, Suzan, Rigo-Bonnin, Raúl, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald C., Erikstrup, Christian, Condino-Neto, Antonio, Prando, Carolina, Bondarenko, Anastasiia, Spaan, András N., Gilardin, Laurent, Fellay, Jacques, Lyonnet, Stanislas, Bilguvar, Kaya, Lifton, Richard P., Mane, Shrikant, Anderson, Mark S., Boisson, Bertrand, Béziat, Vivien, Zhang, Shen-Ying, Andreakos, Evangelos, Hermine, Olivier, Pujol, Aurora, Peterson, Pärt, Mogensen, Trine H., Rowen, Lee, Mond, James, Debette, Stéphanie, de Lamballerie, Xavier, Burdet, Charles, Bouadma, Lila, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter K., Piemonti, Lorenzo, Rodríguez-Gallego, Carlos, Notarangelo, Luigi D., Su, Helen C., Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles M., Tiberghien, Pierre, Zhang, Qian, Casanova, Jean-Laurent, Abel, Laurent, and Cobat, Aurélie

Published
2022

12. Epigenetic memory of coronavirus infection in innate immune cells and their progenitors

Author

Cheong, Jin-Gyu, Ravishankar, Arjun, Sharma, Siddhartha, Parkhurst, Christopher N., Grassmann, Simon A., Wingert, Claire K., Laurent, Paoline, Ma, Sai, Paddock, Lucinda, Miranda, Isabella C., Karakaslar, Emin Onur, Nehar-Belaid, Djamel, Thibodeau, Asa, Bale, Michael J., Kartha, Vinay K., Yee, Jim K., Mays, Minh Y., Jiang, Chenyang, Daman, Andrew W., Martinez de Paz, Alexia, Ahimovic, Dughan, Ramos, Victor, Lercher, Alexander, Nielsen, Erik, Alvarez-Mulett, Sergio, Zheng, Ling, Earl, Andrew, Yallowitz, Alisha, Robbins, Lexi, LaFond, Elyse, Weidman, Karissa L., Racine-Brzostek, Sabrina, Yang, He S., Price, David R., Leyre, Louise, Rendeiro, André F., Ravichandran, Hiranmayi, Kim, Junbum, Borczuk, Alain C., Rice, Charles M., Jones, R. Brad, Schenck, Edward J., Kaner, Robert J., Chadburn, Amy, Zhao, Zhen, Pascual, Virginia, Elemento, Olivier, Schwartz, Robert E., Buenrostro, Jason D., Niec, Rachel E., Barrat, Franck J., Lief, Lindsay, Sun, Joseph C., Ucar, Duygu, and Josefowicz, Steven Z.

Published
2023
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13. A combination of two human monoclonal antibodies limits fetal damage by Zika virus in macaques

Author

Van Rompay, Koen KA, Coffey, Lark L, Kapoor, Tania, Gazumyan, Anna, Keesler, Rebekah I, Jurado, Andrea, Peace, Avery, Agudelo, Marianna, Watanabe, Jennifer, Usachenko, Jodie, Singapuri, Anil, Immareddy, Ramya, Ardeshir, Amir, Stuart, Jackson B, Bournazos, Stylianos, Ravetch, Jeffrey V, Balderes, Paul J, Lorenz, Ivo C, Esswein, Shannon R, Keeffe, Jennifer R, Bjorkman, Pamela J, Wang, Qiao, Rice, Charles M, MacDonald, Margaret R, Nussenzweig, Michel C, and Robbiani, Davide F

Subjects
Medical Microbiology, Reproductive Medicine, Biomedical and Clinical Sciences, Immunology, Vector-Borne Diseases, Women's Health, Perinatal Period - Conditions Originating in Perinatal Period, Biodefense, Maternal Health, Prevention, Emerging Infectious Diseases, Pregnancy, Vaccine Related, Immunization, Rare Diseases, Infectious Diseases, Pediatric, 5.1 Pharmaceuticals, Reproductive health and childbirth, Infection, Good Health and Well Being, Animals, Animals, Newborn, Antibodies, Monoclonal, Antibodies, Neutralizing, Disease Models, Animal, Drug Therapy, Combination, Female, Fetus, HEK293 Cells, Humans, Immunoglobulin Fc Fragments, Immunoglobulin G, Infectious Disease Transmission, Vertical, Pregnancy Complications, Infectious, Protein Engineering, RNA, Viral, Recombinant Proteins, Zika Virus, Zika Virus Infection, Fc domain modifications, Zika virus, macaque pregnancy model, antibody-dependent enhancement, congenital Zika syndrome
Abstract

Human infection by Zika virus (ZIKV) during pregnancy can lead to vertical transmission and fetal aberrations, including microcephaly. Prophylactic administration of antibodies can diminish or prevent ZIKV infection in animal models, but whether passive immunization can protect nonhuman primates and their fetuses during pregnancy has not been determined. Z004 and Z021 are neutralizing monoclonal antibodies to domain III of the envelope (EDIII) of ZIKV. Together the two antibodies protect nonpregnant macaques against infection even after Fc modifications to prevent antibody-dependent enhancement (ADE) in vitro and extend their half-lives. Here we report on prophylactic coadministration of the Fc-modified antibodies to pregnant rhesus macaques challenged three times with ZIKV during first and second trimester. The two antibodies did not entirely eliminate maternal viremia but limited vertical transmission, protecting the fetus from neurologic damage. Thus, maternal passive immunization with two antibodies to EDIII can shield primate fetuses from the harmful effects of ZIKV.

Published
2020

16. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Author

Rosain, Jérémie, Neehus, Anna-Lena, Manry, Jérémy, Yang, Rui, Le Pen, Jérémie, Daher, Wassim, Liu, Zhiyong, Chan, Yi-Hao, Tahuil, Natalia, Türel, Özden, Bourgey, Mathieu, Ogishi, Masato, Doisne, Jean-Marc, Izquierdo, Helena M., Shirasaki, Takayoshi, Le Voyer, Tom, Guérin, Antoine, Bastard, Paul, Moncada-Vélez, Marcela, Han, Ji Eun, Khan, Taushif, Rapaport, Franck, Hong, Seon-Hui, Cheung, Andrew, Haake, Kathrin, Mindt, Barbara C., Pérez, Laura, Philippot, Quentin, Lee, Danyel, Zhang, Peng, Rinchai, Darawan, Al Ali, Fatima, Ahmad Ata, Manar Mahmoud, Rahman, Mahbuba, Peel, Jessica N., Heissel, Søren, Molina, Henrik, Kendir-Demirkol, Yasemin, Bailey, Rasheed, Zhao, Shuxiang, Bohlen, Jonathan, Mancini, Mathieu, Seeleuthner, Yoann, Roelens, Marie, Lorenzo, Lazaro, Soudée, Camille, Paz, María Elvira Josefina, González, María Laura, Jeljeli, Mohamed, Soulier, Jean, Romana, Serge, L’Honneur, Anne-Sophie, Materna, Marie, Martínez-Barricarte, Rubén, Pochon, Mathieu, Oleaga-Quintas, Carmen, Michev, Alexandre, Migaud, Mélanie, Lévy, Romain, Alyanakian, Marie-Alexandra, Rozenberg, Flore, Croft, Carys A., Vogt, Guillaume, Emile, Jean-François, Kremer, Laurent, Ma, Cindy S., Fritz, Jörg H., Lemon, Stanley M., Spaan, András N., Manel, Nicolas, Abel, Laurent, MacDonald, Margaret R., Boisson-Dupuis, Stéphanie, Marr, Nico, Tangye, Stuart G., Di Santo, James P., Zhang, Qian, Zhang, Shen-Ying, Rice, Charles M., Béziat, Vivien, Lachmann, Nico, Langlais, David, Casanova, Jean-Laurent, Gros, Philippe, and Bustamante, Jacinta

Published
2023
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18. Risk of Zika microcephaly correlates with features of maternal antibodies

Author

Robbiani, Davide F, Olsen, Priscilla C, Costa, Federico, Wang, Qiao, Oliveira, Thiago Y, Nery, Nivison, Aromolaran, Adeolu, do Rosário, Mateus S, Sacramento, Gielson A, Cruz, Jaqueline S, Khouri, Ricardo, Wunder, Elsio A, Mattos, Adriana, de Paula Freitas, Bruno, Sarno, Manoel, Archanjo, Gracinda, Daltro, Dina, Carvalho, Gustavo BS, Pimentel, Kleber, de Siqueira, Isadora C, de Almeida, João RM, Henriques, Daniele F, Lima, Juliana A, Vasconcelos, Pedro FC, Schaefer-Babajew, Dennis, Azzopardi, Stephanie A, Bozzacco, Leonia, Gazumyan, Anna, Belfort, Rubens, Alcântara, Ana P, Carvalho, Gustavo, Moreira, Licia, Araujo, Katiaci, Reis, Mitermayer G, Keesler, Rebekah I, Coffey, Lark L, Tisoncik-Go, Jennifer, Gale, Michael, Rajagopal, Lakshmi, Waldorf, Kristina M Adams, Dudley, Dawn M, Simmons, Heather A, Mejia, Andres, O’Connor, David H, Steinbach, Rosemary J, Haese, Nicole, Smith, Jessica, Lewis, Anne, Colgin, Lois, Roberts, Victoria, Frias, Antonio, Kelleher, Meredith, Hirsch, Alec, Streblow, Daniel N, Rice, Charles M, MacDonald, Margaret R, de Almeida, Antonio RP, Van Rompay, Koen KA, Ko, Albert I, and Nussenzweig, Michel C

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Women's Health, Pediatric, Prevention, Vector-Borne Diseases, Rare Diseases, Neurosciences, Emerging Infectious Diseases, Biodefense, Infectious Diseases, Maternal Health, Congenital Structural Anomalies, Pregnancy, Infection, Reproductive health and childbirth, Good Health and Well Being, Animals, Antibodies, Viral, Brain, Female, Fetus, Humans, K562 Cells, Macaca mulatta, Macaca nemestrina, Maternal-Fetal Exchange, Microcephaly, Pregnancy Complications, Infectious, Zika Virus, Zika Virus Infection, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Zika virus (ZIKV) infection during pregnancy causes congenital abnormalities, including microcephaly. However, rates vary widely, and the contributing risk factors remain unclear. We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015-2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P < 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly.

Published
2019

19. Characterization of Novel Splice Variants of Zinc Finger Antiviral Protein (ZAP).

Author

Li, Melody MH, Aguilar, Eduardo G, Michailidis, Eleftherios, Pabon, Jonathan, Park, Paul, Wu, Xianfang, de Jong, Ype P, Schneider, William M, Molina, Henrik, Rice, Charles M, and MacDonald, Margaret R

Subjects
Infectious Diseases, Vaccine Related, Prevention, Hepatitis, Biodefense, Emerging Infectious Diseases, Digestive Diseases, Liver Disease, Genetics, 2.1 Biological and endogenous factors, Aetiology, Infection, Good Health and Well Being, A549 Cells, Alphavirus, Alternative Splicing, Cell Line, HEK293 Cells, Haplotypes, HeLa Cells, Hepatitis B virus, Humans, Protein Isoforms, RNA Splicing, RNA, Viral, RNA-Binding Proteins, Virus Replication, Zinc Fingers, Ebola virus, PARP13, ZAP, alphavirus, alternative splice variants, hepatitis B virus, interferon, Hela Cells, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Virology
Abstract

Given the unprecedented scale of the recent Ebola and Zika viral epidemics, it is crucial to understand the biology of host factors with broad antiviral action in order to develop novel therapeutic approaches. Here, we look into one such factor: zinc finger antiviral protein (ZAP) inhibits a variety of RNA and DNA viruses. Alternative splicing results in two isoforms that differ at their C termini: ZAPL (long) encodes a poly(ADP-ribose) polymerase (PARP)-like domain that is missing in ZAPS (short). Previously, it has been shown that ZAPL is more antiviral than ZAPS, while the latter is more induced by interferon (IFN). In this study, we discovered and confirmed the expression of two additional splice variants of human ZAP: ZAPXL (extralong) and ZAPM (medium). We also found two haplotypes of human ZAP. Since ZAPL and ZAPS have differential activities, we hypothesize that all four ZAP isoforms have evolved to mediate distinct antiviral and/or cellular functions. By taking a gene-knockout-and-reconstitution approach, we have characterized the antiviral, translational inhibition, and IFN activation activities of individual ZAP isoforms. Our work demonstrates that ZAPL and ZAPXL are more active against alphaviruses and hepatitis B virus (HBV) than ZAPS and ZAPM and elucidates the effects of splice variants on the action of a broad-spectrum antiviral factor.IMPORTANCE ZAP is an IFN-induced host factor that can inhibit a wide range of viruses, and there is great interest in fully characterizing its antiviral mechanism. This is the first study that defines the antiviral capacities of individual ZAP isoforms in the absence of endogenous ZAP expression and, hence, cross talk with other isoforms. Our data demonstrate that ZAP is expressed as four different forms: ZAPS, ZAPM, ZAPL, and ZAPXL. The longer ZAP isoforms better inhibit alphaviruses and HBV, while all isoforms equally inhibit Ebola virus transcription and replication. In addition, there is no difference in the abilities of ZAP isoforms to enhance the induction of type I IFN expression. Our results show that the full spectrum of ZAP activities can change depending on the virus target and the relative levels of basal expression and induction by IFN or infection.

Published
2019

20. ZAP's stress granule localization is correlated with its antiviral activity and induced by virus replication.

Author

Law, Lok Man John, Razooky, Brandon S, Li, Melody MH, You, Shihyun, Jurado, Andrea, Rice, Charles M, and MacDonald, Margaret R

Subjects
Tumor Cells, Cultured, Cytoplasmic Granules, Humans, Sindbis Virus, Alphavirus Infections, Osteosarcoma, Bone Neoplasms, RNA-Binding Proteins, RNA, Messenger, Antiviral Agents, Virus Replication, RNA Interference, Protein Transport, Stress, Physiological, RNA, Messenger, Stress, Physiological, Tumor Cells, Cultured, Virology, Microbiology, Immunology, Medical Microbiology
Abstract

Cellular antiviral programs encode molecules capable of targeting multiple steps in the virus lifecycle. Zinc-finger antiviral protein (ZAP) is a central and general regulator of antiviral activity that targets pathogen mRNA stability and translation. ZAP is diffusely cytoplasmic, but upon infection ZAP is targeted to particular cytoplasmic structures, termed stress granules (SGs). However, it remains unclear if ZAP's antiviral activity correlates with SG localization, and what molecular cues are required to induce this localization event. Here, we use Sindbis virus (SINV) as a model infection and find that ZAP's localization to SGs can be transient. Sometimes no apparent viral infection follows ZAP SG localization but ZAP SG localization always precedes accumulation of SINV non-structural protein, suggesting virus replication processes trigger SG formation and ZAP recruitment. Data from single-molecule RNA FISH corroborates this finding as the majority of cells with ZAP localization in SGs contain low levels of viral RNA. Furthermore, ZAP recruitment to SGs occurred in ZAP-expressing cells when co-cultured with cells replicating full-length SINV, but not when co-cultured with cells replicating a SINV replicon. ZAP recruitment to SGs is functionally important as a panel of alanine ZAP mutants indicate that the anti-SINV activity is correlated with ZAP's ability to localize to SGs. As ZAP is a central component of the cellular antiviral programs, these data provide further evidence that SGs are an important cytoplasmic antiviral hub. These findings provide insight into how antiviral components are regulated upon virus infection to inhibit virus spread.

Published
2019

21. A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants

Author

Han, Yuling, Tan, Lei, Zhou, Ting, Yang, Liuliu, Carrau, Lucia, Lacko, Lauretta A., Saeed, Mohsan, Zhu, Jiajun, Zhao, Zeping, Nilsson-Payant, Benjamin E., Lira Neto, Filipe Tenorio, Cahir, Clare, Giani, Alice Maria, Chai, Jin Chou, Li, Yang, Dong, Xue, Moroziewicz, Dorota, Paull, Daniel, Zhang, Tuo, Koo, Soyeon, Tan, Christina, Danziger, Ron, Ba, Qian, Feng, Lingling, Chen, Zhengming, Zhong, Aaron, Wise, Gilbert J., Xiang, Jenny Z., Wang, Hui, Schwartz, Robert E., tenOever, Benjamin R., Noggle, Scott A., Rice, Charles M., Qi, Qibin, Evans, Todd, and Chen, Shuibing

Published
2022
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22. Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

Author

Kabbani, Mohammad, Michailidis, Eleftherios, Steensels, Sandra, Fulmer, Clifton G., Luna, Joseph M., Le Pen, Jérémie, Tardelli, Matteo, Razooky, Brandon, Ricardo-Lax, Inna, Zou, Chenhui, Zeck, Briana, Stenzel, Ansgar F., Quirk, Corrine, Foquet, Lander, Ashbrook, Alison W., Schneider, William M., Belkaya, Serkan, Lalazar, Gadi, Liang, Yupu, Pittman, Meredith, Devisscher, Lindsey, Suemizu, Hiroshi, Theise, Neil D., Chiriboga, Luis, Cohen, David E., Copenhaver, Robert, Grompe, Markus, Meuleman, Philip, Ersoy, Baran A., Rice, Charles M., and de Jong, Ype P.

Published
2022
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23. Analysis of memory B cells identifies conserved neutralizing epitopes on the N-terminal domain of variant SARS-Cov-2 spike proteins

Author

Wang, Zijun, Muecksch, Frauke, Cho, Alice, Gaebler, Christian, Hoffmann, Hans-Heinrich, Ramos, Victor, Zong, Shuai, Cipolla, Melissa, Johnson, Briana, Schmidt, Fabian, DaSilva, Justin, Bednarski, Eva, Ben Tanfous, Tarek, Raspe, Raphael, Yao, Kaihui, Lee, Yu E., Chen, Teresia, Turroja, Martina, Milard, Katrina G., Dizon, Juan, Kaczynska, Anna, Gazumyan, Anna, Oliveira, Thiago Y., Rice, Charles M., Caskey, Marina, Bieniasz, Paul D., Hatziioannou, Theodora, Barnes, Christopher O., and Nussenzweig, Michel C.

Published
2022
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25. Distinct pathways for evolution of enhanced receptor binding and cell entry in SARS-like bat coronaviruses.

Author

Tse, Alexandra L., Acreman, Cory M., Ricardo-Lax, Inna, Berrigan, Jacob, Lasso, Gorka, Balogun, Toheeb, Kearns, Fiona L., Casalino, Lorenzo, McClain, Georgia L., Chandran, Amartya Mudry, Lemeunier, Charlotte, Amaro, Rommie E., Rice, Charles M., Jangra, Rohit K., McLellan, Jason S., Chandran, Kartik, and Miller, Emily Happy

Subjects
PANDEMIC preparedness, VESICULAR stomatitis, COVID-19 pandemic, CELL receptors, CORONAVIRUSES
Abstract

Understanding the zoonotic risks posed by bat coronaviruses (CoVs) is critical for pandemic preparedness. Herein, we generated recombinant vesicular stomatitis viruses (rVSVs) bearing spikes from divergent bat CoVs to investigate their cell entry mechanisms. Unexpectedly, the successful recovery of rVSVs bearing the spike from SHC014-CoV, a SARS-like bat CoV, was associated with the acquisition of a novel substitution in the S2 fusion peptide-proximal region (FPPR). This substitution enhanced viral entry in both VSV and coronavirus contexts by increasing the availability of the spike receptor-binding domain to recognize its cellular receptor, ACE2. A second substitution in the S1 N–terminal domain, uncovered through the rescue and serial passage of a virus bearing the FPPR substitution, further enhanced spike:ACE2 interaction and viral entry. Our findings identify genetic pathways for adaptation by bat CoVs during spillover and host-to-host transmission, fitness trade-offs inherent to these pathways, and potential Achilles' heels that could be targeted with countermeasures. Author summary: The recent emergence of several highly virulent human coronaviruses, SARS-CoV, MERS-CoV and SARS-CoV-2, underscores the risk coronaviruses can pose to the human population. Bat coronaviruses (CoVs) are of particular concern due to their potential to adapt to new hosts. Here, we attempted to generate recombinant vesicular stomatitis viruses (rVSVs) bearing the spike glycoproteins from several SARS-like bat CoVs to study their cell entry mechanisms. We identified two mutations in the SHC014-CoV spike that afforded successful recovery of an rVSV bearing this spike by greatly increasing viral entry. Interestingly, these mutations occur outside the receptor-binding domain (RBD) but enhance spike-receptor interaction nevertheless. These and other results herein establish that these mutations serve to "open" the spike and thereby augment virus-receptor engagement. Our work uncovers new genetic pathways that could contribute to the adaptation of bat CoVs during host spillover. However, these mutations also render the spike more susceptible to neutralizing antibodies that recognize the RBD, pointing to fitness tradeoffs associated with these pathways. [ABSTRACT FROM AUTHOR]

Published
2024
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27. A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

Author

Keeffe, Jennifer R, Van Rompay, Koen KA, Olsen, Priscilla C, Wang, Qiao, Gazumyan, Anna, Azzopardi, Stephanie A, Schaefer-Babajew, Dennis, Lee, Yu E, Stuart, Jackson B, Singapuri, Anil, Watanabe, Jennifer, Usachenko, Jodie, Ardeshir, Amir, Saeed, Mohsan, Agudelo, Marianna, Eisenreich, Thomas, Bournazos, Stylianos, Oliveira, Thiago Y, Rice, Charles M, Coffey, Lark L, MacDonald, Margaret R, Bjorkman, Pamela J, Nussenzweig, Michel C, and Robbiani, Davide F

Subjects
Biological Sciences, Rare Diseases, Prevention, Immunization, Vaccine Related, Biodefense, Biotechnology, Vector-Borne Diseases, Orphan Drug, Emerging Infectious Diseases, Infectious Diseases, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Dengue Virus, Epitopes, HEK293 Cells, Humans, Macaca, Mice, Knockout, Mutation, Protein Domains, Zika Virus, antibodies, antibody dependent enhancement, crystal structure, epitope, escape, flavivirus, macaques, prophylaxis, protection, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV.

Published
2018

31. Fc-engineered antibody therapeutics with improved anti-SARS-CoV-2 efficacy

Author

Yamin, Rachel, Jones, Andrew T., Hoffmann, Hans-Heinrich, Schäfer, Alexandra, Kao, Kevin S., Francis, Rebecca L., Sheahan, Timothy P., Baric, Ralph S., Rice, Charles M., Ravetch, Jeffrey V., and Bournazos, Stylianos

Subjects
Mathematical optimization -- Usage, Monoclonal antibodies -- Usage -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Monoclonal antibodies with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefits in cases of mild-to-moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease.sup.1-4. Treatment generally requires the administration of high doses of these monoclonal antibodies and has limited efficacy in preventing disease complications or mortality among hospitalized patients with COVID-19.sup.5. Here we report the development and evaluation of anti-SARS-CoV-2 monoclonal antibodies with optimized Fc domains that show superior potency for prevention or treatment of COVID-19. Using several animal disease models of COVID-19.sup.6,7, we demonstrate that selective engagement of activating Fc[gamma] receptors results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection against SARS-CoV-2 challenge and for treatment of pre-infected animals. Our results highlight the importance of Fc[gamma] receptor pathways in driving antibody-mediated antiviral immunity and exclude the possibility of pathogenic or disease-enhancing effects of Fc[gamma] receptor engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered monoclonal antibodies with optimal Fc-effector function and improved clinical efficacy against COVID-19 disease. Optimization of monoclonal antibodies against SARS-CoV-2 for enhanced Fc-effector function increase their effectiveness for prevention and treatment of COVID-19 in multiple animal models of SARS-CoV-2 infection., Author(s): Rachel Yamin [sup.1] , Andrew T. Jones [sup.1] , Hans-Heinrich Hoffmann [sup.2] , Alexandra Schäfer [sup.3] , Kevin S. Kao [sup.1] , Rebecca L. Francis [sup.1] , Timothy P. [...]

Published
2021
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35. Intrinsic Immunity Shapes Viral Resistance of Stem Cells

Author

Wu, Xianfang, Thi, Viet Loan Dao, Huang, Yumin, Billerbeck, Eva, Saha, Debjani, Hoffmann, Hans-Heinrich, Wang, Yaomei, Silva, Luis A Vale, Sarbanes, Stephanie, Sun, Tony, Andrus, Linda, Yu, Yingpu, Quirk, Corrine, Li, Melody, MacDonald, Margaret R, Schneider, William M, An, Xiuli, Rosenberg, Brad R, and Rice, Charles M

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Biodefense, Infectious Diseases, Regenerative Medicine, Stem Cell Research - Nonembryonic - Human, Vaccine Related, Prevention, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Emerging Infectious Diseases, Genetics, Underpinning research, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, 1.1 Normal biological development and functioning, Inflammatory and immune system, Infection, Animals, Cells, Cultured, Female, HEK293 Cells, Humans, Immunity, Innate, Interferons, Male, Mice, Mice, Inbred NOD, Pluripotent Stem Cells, Species Specificity, Virus Diseases, antiviral mechanisms, interferon-stimulated genes, intrinsic immunity, stem cell differentiation, tissue stem cells, tissue tropism, viral infection, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Stem cells are highly resistant to viral infection compared to their differentiated progeny; however, the mechanism is mysterious. Here, we analyzed gene expression in mammalian stem cells and cells at various stages of differentiation. We find that, conserved across species, stem cells express a subset of genes previously classified as interferon (IFN) stimulated genes (ISGs) but that expression is intrinsic, as stem cells are refractory to interferon. This intrinsic ISG expression varies in a cell-type-specific manner, and many ISGs decrease upon differentiation, at which time cells become IFN responsive, allowing induction of a broad spectrum of ISGs by IFN signaling. Importantly, we show that intrinsically expressed ISGs protect stem cells against viral infection. We demonstrate the in vivo importance of intrinsic ISG expression for protecting stem cells and their differentiation potential during viral infection. These findings have intriguing implications for understanding stem cell biology and the evolution of pathogen resistance.

Published
2018

36. Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs

Author

Lavin-Parsons, Kendall, Parry, Blair, Lilley, Brendan, Lodenstein, Carl, McKaig, Brenna, Charland, Nicole, Khanna, Hargun, Margolin, Justin, Gonye, Anna, Gushterova, Irena, Lasalle, Tom, Sharma, Nihaarika, Russo, Brian C., Rojas-Lopez, Maricarmen, Sade-Feldman, Moshe, Manakongtreecheep, Kasidet, Tantivit, Jessica, Fisher Thomas, Molly, Weingarten-Gabbay, Shira, Klaeger, Susan, Sarkizova, Siranush, Pearlman, Leah R., Chen, Da-Yuan, Gallagher, Kathleen M.E., Bauer, Matthew R., Taylor, Hannah B., Dunn, W. Augustine, Tarr, Christina, Sidney, John, Rachimi, Suzanna, Conway, Hasahn L., Katsis, Katelin, Wang, Yuntong, Leistritz-Edwards, Del, Durkin, Melissa R., Tomkins-Tinch, Christopher H., Finkel, Yaara, Nachshon, Aharon, Gentili, Matteo, Rivera, Keith D., Carulli, Isabel P., Chea, Vipheaviny A., Chandrashekar, Abishek, Bozkus, Cansu Cimen, Carrington, Mary, Bhardwaj, Nina, Barouch, Dan H., Sette, Alessandro, Maus, Marcela V., Rice, Charles M., Clauser, Karl R., Keskin, Derin B., Pregibon, Daniel C., Hacohen, Nir, Carr, Steven A., Abelin, Jennifer G., Saeed, Mohsan, and Sabeti, Pardis C.

Published
2021
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38. Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico

Author

Robbiani, Davide F, Bozzacco, Leonia, Keeffe, Jennifer R, Khouri, Ricardo, Olsen, Priscilla C, Gazumyan, Anna, Schaefer-Babajew, Dennis, Avila-Rios, Santiago, Nogueira, Lilian, Patel, Roshni, Azzopardi, Stephanie A, Uhl, Lion FK, Saeed, Mohsan, Sevilla-Reyes, Edgar E, Agudelo, Marianna, Yao, Kai-Hui, Golijanin, Jovana, Gristick, Harry B, Lee, Yu E, Hurley, Arlene, Caskey, Marina, Pai, Joy, Oliveira, Thiago, Wunder, Elsio A, Sacramento, Gielson, Nery, Nivison, Orge, Cibele, Costa, Federico, Reis, Mitermayer G, Thomas, Neena M, Eisenreich, Thomas, Weinberger, Daniel M, de Almeida, Antonio RP, West, Anthony P, Rice, Charles M, Bjorkman, Pamela J, Reyes-Teran, Gustavo, Ko, Albert I, MacDonald, Margaret R, and Nussenzweig, Michel C

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Vector-Borne Diseases, Immunization, Vaccine Related, Prevention, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Animals, Antibodies, Neutralizing, Antibodies, Viral, B-Lymphocytes, Brazil, Female, Humans, Immunologic Memory, Leukocytes, Mononuclear, Male, Mexico, Mice, Zika Virus Infection, Zika virus, antibodies, dengue virus, flavivirus, structure, vaccine, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals who develop high titers of anti-ZIKV antibodies, we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with pre-existing reactivity to DENV1 in humans.

Published
2017

40. Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors

Author

Hoffmann, H.-Heinrich, Sánchez-Rivera, Francisco J., Schneider, William M., Luna, Joseph M., Soto-Feliciano, Yadira M., Ashbrook, Alison W., Le Pen, Jérémie, Leal, Andrew A., Ricardo-Lax, Inna, Michailidis, Eleftherios, Hao, Yuan, Stenzel, Ansgar F., Peace, Avery, Zuber, Johannes, Allis, C. David, Lowe, Scott W., MacDonald, Margaret R., Poirier, John T., and Rice, Charles M.

Published
2021
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42. TMEM41B Is a Pan-flavivirus Host Factor

Author

Hoffmann, H.-Heinrich, Schneider, William M., Rozen-Gagnon, Kathryn, Miles, Linde A., Schuster, Felix, Razooky, Brandon, Jacobson, Eliana, Wu, Xianfang, Yi, Soon, Rudin, Charles M., MacDonald, Margaret R., McMullan, Laura K., Poirier, John T., and Rice, Charles M.

Published
2021
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43. Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection

Author

Wang, Zijun, Muecksch, Frauke, Schaefer-Babajew, Dennis, Finkin, Shlomo, Viant, Charlotte, Gaebler, Christian, Hoffmann, Hans- Heinrich, Barnes, Christopher O., Cipolla, Melissa, Ramos, Victor, Oliveira, Thiago Y., Cho, Alice, Schmidt, Fabian, Da Silva, Justin, Bednarski, Eva, Aguado, Lauren, Yee, Jim, Daga, Mridushi, Turroja, Martina, Millard, Katrina G., Jankovic, Mila, Gazumyan, Anna, Zhao, Zhen, Rice, Charles M., Bieniasz, Paul D., Caskey, Marina, Hatziioannou, Theodora, and Nussenzweig, Michel C.

Published
2021
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46. Downregulation of IGF2 expression in third trimester placental tissues from Zika virus infected women in Brazil

Author

Suzukawa, Andréia A., Zanluca, Camila, Jorge, Natasha A.N., de Noronha, Lucia, Koishi, Andrea C., de Paula, Caroline B.V., Rebutini, Patrícia Z., Nagashima, Seigo, Hansel-Frose, Aruana F.F., Parreira, Vinícius S.C., Bordignon, Juliano, MacDonald, Margaret R., Rice, Charles M., Passetti, Fabio, and Duarte dos Santos, Claudia Nunes

Published
2020
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48. A Combination of Human Broadly Neutralizing Antibodies against Hepatitis B Virus HBsAg with Distinct Epitopes Suppresses Escape Mutations

Author

Wang, Qiao, Michailidis, Eleftherios, Yu, Yingpu, Wang, Zijun, Hurley, Arlene M., Oren, Deena A., Mayer, Christian T., Gazumyan, Anna, Liu, Zhenmi, Zhou, Yunjiao, Schoofs, Till, Yao, Kai-hui, Nieke, Jan P., Wu, Jianbo, Jiang, Qingling, Zou, Chenhui, Kabbani, Mohanmmad, Quirk, Corrine, Oliveira, Thiago, Chhosphel, Kalsang, Zhang, Qianqian, Schneider, William M., Jahan, Cyprien, Ying, Tianlei, Horowitz, Jill, Caskey, Marina, Jankovic, Mila, Robbiani, Davide F., Wen, Yumei, de Jong, Ype P., Rice, Charles M., and Nussenzweig, Michel C.

Published
2020
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49. TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP).

Author

Li, Melody MH, Lau, Zerlina, Cheung, Pamela, Aguilar, Eduardo G, Schneider, William M, Bozzacco, Leonia, Molina, Henrik, Buehler, Eugen, Takaoka, Akinori, Rice, Charles M, Felsenfeld, Dan P, and MacDonald, Margaret R

Subjects
Cell Line, Animals, Humans, Sindbis Virus, Alphavirus Infections, Ubiquitin-Protein Ligases, RNA-Binding Proteins, Interferon Type I, Protein Isoforms, Transcription Factors, RNA, Small Interfering, Antiviral Agents, RNA Interference, Cricetinae, Ubiquitination, HEK293 Cells, Tripartite Motif Proteins, Protein Domains, RNA, Small Interfering, Virology, Microbiology, Immunology, Medical Microbiology
Abstract

The host factor and interferon (IFN)-stimulated gene (ISG) product, zinc-finger antiviral protein (ZAP), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular pathways. To elucidate its antiviral mechanism, we perform a loss-of-function genome-wide RNAi screen to identify cellular cofactors required for ZAP antiviral activity against the prototype alphavirus, Sindbis virus (SINV). In order to exclude off-target effects, we carry out stringent confirmatory assays to verify the top hits. Important ZAP-liaising partners identified include proteins involved in membrane ion permeability, type I IFN signaling, and post-translational protein modification. The factor contributing most to the antiviral function of ZAP is TRIM25, an E3 ubiquitin and ISG15 ligase. We demonstrate here that TRIM25 interacts with ZAP through the SPRY domain, and TRIM25 mutants lacking the RING or coiled coil domain fail to stimulate ZAP's antiviral activity, suggesting that both TRIM25 ligase activity and its ability to form oligomers are critical for its cofactor function. TRIM25 increases the modification of both the short and long ZAP isoforms by K48- and K63-linked polyubiquitin, although ubiquitination of ZAP does not directly affect its antiviral activity. However, TRIM25 is critical for ZAP's ability to inhibit translation of the incoming SINV genome. Taken together, these data uncover TRIM25 as a bona fide ZAP cofactor that leads to increased ZAP modification enhancing its translational inhibition activity.

Published
2017

50. Autonomous circadian rhythms in the human hepatocyte regulate hepatic drug metabolism and inflammatory responses

Author

March, Sandra, primary, Nerurkar, Niketa, additional, Jain, Anisha, additional, Andrus, Linda, additional, Kim, Daniel, additional, Whittaker, Charles A., additional, Tan, Edward K.W., additional, Thiberge, Sabine, additional, Fleming, Heather E., additional, Mancio-Silva, Liliana, additional, Rice, Charles M., additional, and Bhatia, Sangeeta N., additional

Published
2024
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