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1. SARS-COV-2 Omicron variants conformationally escape a rare quaternary antibody binding mode

Author

Goike, Jule, Hsieh, Ching-Lin, Horton, Andrew P., Gardner, Elizabeth C., Zhou, Ling, Bartzoka, Foteini, Wang, Nianshuang, Javanmardi, Kamyab, Herbert, Andrew, Abbassi, Shawn, Xie, Xuping, Xia, Hongjie, Shi, Pei-Yong, Renberg, Rebecca, Segall-Shapiro, Thomas H., Terrace, Cynthia I., Wu, Wesley, Shroff, Raghav, Byrom, Michelle, Ellington, Andrew D., Marcotte, Edward M., Musser, James M., Kuchipudi, Suresh V., Kapur, Vivek, Georgiou, George, Weaver, Scott C., Dye, John M., Boutz, Daniel R., McLellan, Jason S., and Gollihar, Jimmy D.

Published
2023
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2. Author Correction: Two point mutations in protocadherin-1 disrupt hantavirus recognition and afford protection against lethal infection

Author

Slough, Megan M., Li, Rong, Herbert, Andrew S., Lasso, Gorka, Kuehne, Ana I., Monticelli, Stephanie R., Bakken, Russell R., Liu, Yanan, Ghosh, Agnidipta, Moreau, Alicia M., Zeng, Xiankun, Rey, Félix A., Guardado-Calvo, Pablo, Almo, Steven C., Dye, John M., Jangra, Rohit K., Wang, Zhongde, and Chandran, Kartik

Published
2023
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4. Crimean-Congo hemorrhagic fever survivors elicit protective non-neutralizing antibodies that target 11 overlapping regions on glycoprotein GP38

Author

Shin, Olivia S., Monticelli, Stephanie R., Hjorth, Christy K., Hornet, Vladlena, Doyle, Michael, Abelson, Dafna, Kuehne, Ana I., Wang, Albert, Bakken, Russell R., Mishra, Akaash K., Middlecamp, Marissa, Champney, Elizabeth, Stuart, Lauran, Maurer, Daniel P., Li, Jiannan, Berrigan, Jacob, Barajas, Jennifer, Balinandi, Stephen, Lutwama, Julius J., Lobel, Leslie, Zeitlin, Larry, Walker, Laura M., Dye, John M., Chandran, Kartik, Herbert, Andrew S., Pauli, Noel T., and McLellan, Jason S.

Published
2024
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5. Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects

Author

Saul, Sirle, Karim, Marwah, Ghita, Luca, Huang, Pei-Tzu, Chiu, Winston, Duran, Veronica, Lo, Chieh-Wen, Kumar, Sathish, Bhalla, Nishank, Leyssen, Pieter, Alem, Farhang, Boghdeh, Niloufar A., Tran, Do H.N., Cohen, Courtney A., Brown, Jacquelyn A., Huie, Kathleen E., Tindle, Courtney, Sibai, Mamdouh, Ye, Chengjin, Khalil, Ahmed Magdy, Chiem, Kevin, Martinez-Sobrido, Luis, Dye, John M., Pinsky, Benjamin A., Ghosh, Pradipta, Das, Soumita, Solow-Cordero, David E., Jin, Jing, Wikswo, John P., Jochmans, Dirk, Neyts, Johan, De Jonghe, Steven, Narayanan, Aarthi, and Einav, Shirit

Subjects
Inflammation -- Drug therapy, Antiviral agents -- Research, Drug discovery, Pharmaceutical research, Health care industry
Abstract

Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family of receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the directacting antiviral nirmatrelvir. We discovered that ErbB1, ErbB2, and ErbB4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARSCoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, proinflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production, and disruption of bloodbrain barrier integrity in microfluidics-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof of principle for a repurposed, ErbB-targeted approach to combat emerging viruses., Introduction Acute emerging viral infections can cause epidemics and pandemics and thus pose major threats to human health. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread Authorship note: SS [...]

Published
2023
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6. 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 B. H., 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., Hüttner, Florian, Hyndman, Timothy H., Ilyas, M., Jalkanen, Risto, Jiāng, Dàohóng, Jonson, Gilda B., Junglen, Sandra, Kadono, Fujio, Kaukinen, Karia H., Kawate, Michael, Klempa, Boris, Klingström, Jonas, Kobinger, Gary, Koloniuk, Igor, Kondō, Hideki, Koonin, Eugene V., Krupovic, Mart, Kubota, Kenji, Kurath, Gael, Laenen, Lies, Lambert, Amy J., Langevin, Stanley L., Lee, Benhur, Lefkowitz, Elliot J., Leroy, Eric M., Li, Shaorong, Li, Longhui, Lǐ, Jiànróng, Liu, Huazhen, Lukashevich, Igor S., Maes, Piet, de Souza, William Marciel, Marklewitz, Marco, Marshall, Sergio H., Marzano, Shin-Yi L., Massart, Sebastien, McCauley, John W., Melzer, Michael, Mielke-Ehret, Nicole, Miller, Kristina M., Ming, Tobi J., Mirazimi, Ali, Mordecai, Gideon J., Mühlbach, Hans-Peter, Mühlberger, Elke, Naidu, Rayapati, Natsuaki, Tomohide, Navarro, José A., Netesov, Sergey V., Neumann, Gabriele, Nowotny, Norbert, Nunes, Márcio R. T., Olmedo-Velarde, Alejandro, Palacios, Gustavo, Pallás, Vicente, Pályi, Bernadett, Papa, Anna, Paraskevopoulou, Sofia, Park, Adam C., Parrish, Colin R., Patterson, David A., Pauvolid-Corrêa, Alex, Pawęska, Janusz T., Payne, Susan, Peracchio, Carlotta, Pérez, Daniel R., Postler, Thomas S., Qi, Liying, Radoshitzky, Sheli R., Resende, Renato O., Reyes, Carina A., Rima, Bertus K., Luna, Gabriel Robles, Romanowski, Víctor, Rota, Paul, Rubbenstroth, Dennis, Rubino, Luisa, Runstadler, Jonathan A., Sabanadzovic, Sead, Sall, Amadou Alpha, Salvato, Maria S., Sang, Rosemary, Sasaya, Takahide, Schulze, Angela D., Schwemmle, Martin, Shi, Mang, Shí, Xiǎohóng, Shí, Zhènglì, Shimomoto, Yoshifumi, Shirako, Yukio, Siddell, Stuart G., Simmonds, Peter, Sironi, Manuela, Smagghe, Guy, Smither, Sophie, Song, Jin-Won, Spann, Kirsten, Spengler, Jessica R., Stenglein, Mark D., Stone, David M., Sugano, Jari, Suttle, Curtis A., Tabata, Amy, Takada, Ayato, Takeuchi, Shigeharu, Tchouassi, David P., Teffer, Amy, Tesh, Robert B., Thornburg, Natalie J., Tomitaka, Yasuhiro, Tomonaga, Keizō, Tordo, Noël, Torto, Baldwyn, Towner, Jonathan S., Tsuda, Shinya, Tu, Changchun, Turina, Massimo, Tzanetakis, Ioannis E., Uchida, Janice, Usugi, Tomio, Vaira, Anna Maria, Vallino, Marta, van den Hoogen, Bernadette, Varsani, Arvind, Vasilakis, Nikos, Verbeek, Martin, von Bargen, Susanne, Wada, Jiro, Wahl, Victoria, Walker, Peter J., Wang, Lin-Fa, Wang, Guoping, Wang, Yanxiang, Wang, Yaqin, Waqas, Muhammad, Wèi, Tàiyún, Wen, Shaohua, Whitfield, Anna E., Williams, John V., Wolf, Yuri I., Wu, Jiangxiang, Xu, Lei, Yanagisawa, Hironobu, Yang, Caixia, Yang, Zuokun, Zerbini, F. Murilo, Zhai, Lifeng, Zhang, Yong-Zhen, Zhang, Song, Zhang, Jinguo, Zhang, Zhe, and Zhou, Xueping

Published
2021
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7. Correction to: 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 B. H., 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., Hüttner, Florian, Hyndman, Timothy H., Ilyas, M., Jalkanen, Risto, Jiāng, Dàohóng, Jonson, Gilda B., Junglen, Sandra, Kadono, Fujio, Kaukinen, Karia H., Kawate, Michael, Klempa, Boris, Klingström, Jonas, Kobinger, Gary, Koloniuk, Igor, Kondō, Hideki, Koonin, Eugene V., Krupovic, Mart, Kubota, Kenji, Kurath, Gael, Laenen, Lies, Lambert, Amy J., Langevin, Stanley L., Lee, Benhur, Lefkowitz, Elliot J., Leroy, Eric M., Li, Shaorong, Li, Longhui, Lǐ, Jiànróng, Liu, Huazhen, Lukashevich, Igor S., Maes, Piet, de Souza, William Marciel, Marklewitz, Marco, Marshall, Sergio H., Marzano, Shin-Yi L., Massart, Sebastien, McCauley, John W., Melzer, Michael, Mielke-Ehret, Nicole, Miller, Kristina M., Ming, Tobi J., Mirazimi, Ali, Mordecai, Gideon J., Mühlbach, Hans-Peter, Mühlberger, Elke, Naidu, Rayapati, Natsuaki, Tomohide, Navarro, José A., Netesov, Sergey V., Neumann, Gabriele, Nowotny, Norbert, Nunes, Márcio R. T., Olmedo-Velarde, Alejandro, Palacios, Gustavo, Pallás, Vicente, Pályi, Bernadett, Papa, Anna, Paraskevopoulou, Sofia, Park, Adam C., Parrish, Colin R., Patterson, David A., Pauvolid-Corrêa, Alex, Pawęska, Janusz T., Payne, Susan, Peracchio, Carlotta, Pérez, Daniel R., Postler, Thomas S., Qi, Liying, Radoshitzky, Sheli R., Resende, Renato O., Reyes, Carina A., Rima, Bertus K., Luna, Gabriel Robles, Romanowski, Víctor, Rota, Paul, Rubbenstroth, Dennis, Rubino, Luisa, Runstadler, Jonathan A., Sabanadzovic, Sead, Sall, Amadou Alpha, Salvato, Maria S., Sang, Rosemary, Sasaya, Takahide, Schulze, Angela D., Schwemmle, Martin, Shi, Mang, Shí, Xiǎohóng, Shí, Zhènglì, Shimomoto, Yoshifumi, Shirako, Yukio, Siddell, Stuart G., Simmonds, Peter, Sironi, Manuela, Smagghe, Guy, Smither, Sophie, Song, Jin-Won, Spann, Kirsten, Spengler, Jessica R., Stenglein, Mark D., Stone, David M., Sugano, Jari, Suttle, Curtis A., Tabata, Amy, Takada, Ayato, Takeuchi, Shigeharu, Tchouassi, David P., Teffer, Amy, Tesh, Robert B., Thornburg, Natalie J., Tomitaka, Yasuhiro, Tomonaga, Keizō, Tordo, Noël, Torto, Baldwyn, Towner, Jonathan S., Tsuda, Shinya, Tu, Changchun, Turina, Massimo, Tzanetakis, Ioannis E., Uchida, Janice, Usugi, Tomio, Vaira, Anna Maria, Vallino, Marta, van den Hoogen, Bernadette, Varsani, Arvind, Vasilakis, Nikos, Verbeek, Martin, von Bargen, Susanne, Wada, Jiro, Wahl, Victoria, Walker, Peter J., Wang, Lin-Fa, Wang, Guoping, Wang, Yanxiang, Wang, Yaqin, Waqas, Muhammad, Wèi, Tàiyún, Wen, Shaohua, Whitfield, Anna E., Williams, John V., Wolf, Yuri I., Wu, Jiangxiang, Xu, Lei, Yanagisawa, Hironobu, Yang, Caixia, Yang, Zuokun, Zerbini, F. Murilo, Zhai, Lifeng, Zhang, Yong-Zhen, Zhang, Song, Zhang, Jinguo, Zhang, Zhe, and Zhou, Xueping

Published
2021
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8. Long-term Sudan Virus Ebola Survivors Maintain Multiple Antiviral Defense Mechanisms.

Author

Sobarzo, Ariel, Moné, Yves, Lang, Steven, Gelkop, Sigal, Brangel, Polina, Kuehne, Ana I, McKendry, Rachel A, Mell, Joshua Chang, Ahmed, Azad, Davis, Claytus, Dye, John M, Lutwama, Julius Julian, Lobel, Leslie, Veas, Francisco, and Ehrlich, Garth D

Subjects
MONONUCLEAR leukocytes, IMMUNOLOGIC memory, IMMUNE response, EBOLA virus, NATURAL immunity
Abstract

Background The critical issues of sustained memory immunity following ebolavirus disease among long-term survivors are still unclear. Methods Here, we examine virus-specific immune and inflammatory responses following in vitro challengd in 12 Sudan virus (SUDV) long-term survivors from Uganda's 2000–2001 Gulu outbreak, 15 years after recovery. Total RNA from isolated SUDV-stimulated and unstimulated peripheral blood mononuclear cells was extracted and analyzed. Matched serum samples were also collected to determine SUDV IgG levels and functionality. Results We detected persistent humoral (58%, 7 of 12) and cellular (33%, 4 of 12) immune responses in SUDV long-term survivors and identified critical molecular mechanisms of innate and adaptive immunity. Gene expression in immune pathways, the interferon signaling system, antiviral defense response, and activation and regulation of T- and B-cell responses were observed. SUDV long-term survivors also maintained robust virus-specific IgG antibodies capable of polyfunctional responses, including neutralizing and innate Fc effector functions. Conclusions Data integration identified significant correlations among humoral and cellular immune responses and pinpointed a specific innate and adaptive gene expression signature associated with long-lasting immunity. This could help identify natural and vaccine correlates of protection against ebolavirus disease. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Development of an antibody cocktail for treatment of Sudan virus infection

Author

Herbert, Andrew S., Froude, Jeffery W., Ortiz, Ramon A., Kuehne, Ana I., Dorosky, Danielle E., Bakken, Russell R., Zak, Samantha E., Josleyn, Nicole M., Musiychuk, Konstantin, Jones, R. Mark, Green, Brian, Streatfield, Stephen J., Wec, Anna Z., Bohorova, Natasha, Bohorov, Ognian, Kim, Do H., Pauly, Michael H., Velasco, Jesus, Whaley, Kevin J., Stonier, Spencer W., Bornholdt, Zachary A., Chandran, Kartik, Zeitlin, Larry, Sampey, Darryl, Yusibov, Vidadi, and Dye, John M.

Published
2020

10. Convalescent plasma anti-SARS-CoV-2 spike protein ectodomain and receptor-binding domain IgG correlate with virus neutralization

Author

Salazar, Eric, Kuchipudi, Suresh V., Christensen, Paul A., Eagar, Todd, Yi, Xin, Zhao, Picheng, Jin, Zhicheng, Long, S. Wesley, Olsen, Randall J., Chen, Jian, Castillo, Brian, Leveque, Christopher, Towers, Dalton, Lavinder, Jason, Gollihar, Jimmy, Cardona, Jose, Ippolito, Gregory, Nissly, Ruth, Bird, Ian, Greenawalt, Denver, Rossi, Randall M., Gontu, Abhinay, Srinivasan, Sreenidhi, Poojary, Indira, Cattadori, Isabella M., Hudson, Peter J., Josleyn, Nicole M., Prugar, Laura, Huie, Kathleen, Herbert, Andrew, Bernard, David W., Dye, John M., Kapur, Vivek, and Musser, James M.

Subjects
Viral proteins -- Health aspects, Epidemics -- Control -- United States, COVID-19 -- Control, Immunoglobulin G -- Health aspects, Health care industry
Abstract

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the urgent need for assays that detect protective levels of neutralizing antibodies. We studied the relationship among anti-spike ectodomain (anti-ECD), antireceptor-binding domain (anti-RBD) IgG titers, and SARS-CoV-2 virus neutralization (VN) titers generated by 2 in vitro assays using convalescent plasma samples from 68 patients with COVID-19. We report a strong positive correlation between both plasma anti-RBD and anti-ECD IgG titers and in vitro VN titers. The probability of a VN titer of [greater than or equal to] 160, the FDA-recommended level for convalescent plasma used for COVID-19 treatment, was [greater than or equal to] 80% when anti-RBD or anti-ECD titers were [greater than or equal to] 1:1350. Of all donors, 37% lacked VN titers of [greater than or equal to] 160. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease VN or IgG titers. Analysis of 2814 asymptomatic adults found 73 individuals with anti-ECD IgG titers of [greater than or equal to] 1:50 and strong positive correlation with anti-RBD and VN titers. Fourteen of these individuals had VN titers of [greater than or equal to] 1:160, and all of them had anti-RBD titers of [greater than or equal to] 1:1350. We conclude that anti-RBD or anti-ECD IgG titers can serve as a surrogate for VN titers to identify suitable plasma donors. Plasma anti-RBD or anti-ECD titers of [greater than or equal to] 1:1350 may provide critical information about protection against COVID-19 disease., Introduction The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus that causes coronavirus disease 2019 (COVID-19) disease, has spread globally and is now responsible for massive [...]

Published
2020
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11. Design and characterization of protective pan-ebolavirus and pan-filovirus bispecific antibodies.

Author

Wirchnianski, Ariel S., Nyakatura, Elisabeth K., Herbert, Andrew S., Kuehne, Ana I., Abbasi, Shawn A., Florez, Catalina, Storm, Nadia, McKay, Lindsay G. A., Dailey, Leandrew, Kuang, Erin, Abelson, Dafna M., Wec, Anna Z., Chakraborti, Srinjoy, Holtsberg, Frederick W., Shulenin, Sergey, Bornholdt, Zachary A., Aman, M. Javad, Honko, Anna N., Griffiths, Anthony, and Dye, John M.

Subjects
BISPECIFIC antibodies, MARBURG virus, EBOLA virus, HEMORRHAGIC fever, FILOVIRIDAE, PROTEIN engineering
Abstract

Monoclonal antibodies (mAbs) are an important class of antiviral therapeutics. MAbs are highly selective, well tolerated, and have long in vivo half-life as well as the capacity to induce immune-mediated virus clearance. Their activities can be further enhanced by integration of their variable fragments (Fvs) into bispecific antibodies (bsAbs), affording simultaneous targeting of multiple epitopes to improve potency and breadth and/or to mitigate against viral escape by a single mutation. Here, we explore a bsAb strategy for generation of pan-ebolavirus and pan-filovirus immunotherapeutics. Filoviruses, including Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV), cause severe hemorrhagic fever. Although there are two FDA-approved mAb therapies for EBOV infection, these do not extend to other filoviruses. Here, we combine Fvs from broad ebolavirus mAbs to generate novel pan-ebolavirus bsAbs that are potently neutralizing, confer protection in mice, and are resistant to viral escape. Moreover, we combine Fvs from pan-ebolavirus mAbs with those of protective MARV mAbs to generate pan-filovirus protective bsAbs. These results provide guidelines for broad antiviral bsAb design and generate new immunotherapeutic candidates. Author summary: Filoviruses, such as Ebola virus and Marburg virus (EBOV and MARV, respectively), cause severe hemorrhagic fever with a high mortality rate in humans. Monoclonal antibodies (mAbs) are effective treatments for filovirus infection, but current therapies have limited breadth. Furthermore, a single mAb is susceptible to development of resistance. Here, we used protein engineering to create "bispecific" antibodies in which activities of two different mAbs were combined into one. These bispecific antibodies had broad activity, in one case providing protection against lethal challenge by two distant clades of filoviruses (EBOV and MARV). The bispecific antibodies were also less susceptible to resistance mutations. This work provides a roadmap for development of new bispecific antibody therapies for filoviruses. [ABSTRACT FROM AUTHOR]

Published
2024
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12. 2020 taxonomic update for phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales

Author

Kuhn, Jens H., Adkins, Scott, Alioto, Daniela, Alkhovsky, Sergey V., Amarasinghe, Gaya K., Anthony, Simon J., Avšič-Županc, Tatjana, Ayllón, María A., Bahl, Justin, Balkema-Buschmann, Anne, Ballinger, Matthew J., Bartonička, Tomáš, Basler, Christopher, Bavari, Sina, Beer, Martin, Bente, Dennis A., Bergeron, Éric, Bird, Brian H., Blair, Carol, Blasdell, Kim R., Bradfute, Steven B., Breyta, Rachel, Briese, Thomas, Brown, Paul A., Buchholz, Ursula J., Buchmeier, Michael J., Bukreyev, Alexander, Burt, Felicity, Buzkan, Nihal, Calisher, Charles H., Cao, Mengji, Casas, Inmaculada, Chamberlain, John, Chandran, Kartik, Charrel, Rémi N., Chen, Biao, Chiumenti, Michela, Choi, Il-Ryong, Clegg, J. Christopher S., Crozier, Ian, da Graça, John V., Dal Bó, Elena, Dávila, Alberto M. R., de la Torre, Juan Carlos, de Lamballerie, Xavier, de Swart, Rik L., Di Bello, Patrick L., Di Paola, Nicholas, Di Serio, Francesco, Dietzgen, Ralf G., Digiaro, Michele, Dolja, Valerian V., Dolnik, Olga, Drebot, Michael A., Drexler, Jan Felix, Dürrwald, Ralf, Dufkova, Lucie, Dundon, William G., Duprex, W. Paul, Dye, John M., Easton, Andrew J., Ebihara, Hideki, Elbeaino, Toufic, Ergünay, Koray, Fernandes, Jorlan, Fooks, Anthony R., Formenty, Pierre B. H., Forth, Leonie F., Fouchier, Ron A. M., Freitas-Astúa, Juliana, Gago-Zachert, Selma, Gāo, George Fú, García, María Laura, García-Sastre, Adolfo, Garrison, Aura R., Gbakima, Aiah, Goldstein, Tracey, Gonzalez, Jean-Paul J., Griffiths, Anthony, Groschup, Martin H., Günther, Stephan, Guterres, Alexandro, Hall, Roy A., Hammond, John, Hassan, Mohamed, Hepojoki, Jussi, Hepojoki, Satu, Hetzel, Udo, Hewson, Roger, Hoffmann, Bernd, Hongo, Seiji, Höper, Dirk, Horie, Masayuki, Hughes, Holly R., Hyndman, Timothy H., Jambai, Amara, Jardim, Rodrigo, Jiāng, Dàohóng, Jin, Qi, Jonson, Gilda B., Junglen, Sandra, Karadağ, Serpil, Keller, Karen E., Klempa, Boris, Klingström, Jonas, Kobinger, Gary, Kondō, Hideki, Koonin, Eugene V., Krupovic, Mart, Kurath, Gael, Kuzmin, Ivan V., Laenen, Lies, Lamb, Robert A., Lambert, Amy J., Langevin, Stanley L., Lee, Benhur, Lemos, Elba R. S., Leroy, Eric M., Li, Dexin, Lǐ, Jiànróng, Liang, Mifang, Liú, Wénwén, Liú, Yàn, Lukashevich, Igor S., Maes, Piet, Marciel de Souza, William, Marklewitz, Marco, Marshall, Sergio H., Martelli, Giovanni P., Martin, Robert R., Marzano, Shin-Yi L., Massart, Sébastien, McCauley, John W., Mielke-Ehret, Nicole, Minafra, Angelantonio, Minutolo, Maria, Mirazimi, Ali, Mühlbach, Hans-Peter, Mühlberger, Elke, Naidu, Rayapati, Natsuaki, Tomohide, Navarro, Beatriz, Navarro, José A., Netesov, Sergey V., Neumann, Gabriele, Nowotny, Norbert, Nunes, Márcio R. T., Nylund, Are, Økland, Arnfinn L., Oliveira, Renata C., Palacios, Gustavo, Pallas, Vicente, Pályi, Bernadett, Papa, Anna, Parrish, Colin R., Pauvolid-Corrêa, Alex, Pawęska, Janusz T., Payne, Susan, Pérez, Daniel R., Pfaff, Florian, Radoshitzky, Sheli R., Rahman, Aziz-ul, Ramos-González, Pedro L., Resende, Renato O., Reyes, Carina A., Rima, Bertus K., Romanowski, Víctor, Robles Luna, Gabriel, Rota, Paul, Rubbenstroth, Dennis, Runstadler, Jonathan A., Ruzek, Daniel, Sabanadzovic, Sead, Salát, Jiří, Sall, Amadou Alpha, Salvato, Maria S., Sarpkaya, Kamil, Sasaya, Takahide, Schwemmle, Martin, Shabbir, Muhammad Z., Shí, Xiǎohóng, Shí, Zhènglì, Shirako, Yukio, Simmonds, Peter, Širmarová, Jana, Sironi, Manuela, Smither, Sophie, Smura, Teemu, Song, Jin-Won, Spann, Kirsten M., Spengler, Jessica R., Stenglein, Mark D., Stone, David M., Straková, Petra, Takada, Ayato, Tesh, Robert B., Thornburg, Natalie J., Tomonaga, Keizō, Tordo, Noël, Towner, Jonathan S., Turina, Massimo, Tzanetakis, Ioannis, Ulrich, Rainer G., Vaira, Anna Maria, van den Hoogen, Bernadette, Varsani, Arvind, Vasilakis, Nikos, Verbeek, Martin, Wahl, Victoria, Walker, Peter J., Wang, Hui, Wang, Jianwei, Wang, Xifeng, Wang, Lin-Fa, Wèi, Tàiyún, Wells, Heather, Whitfield, Anna E., Williams, John V., Wolf, Yuri I., Wú, Zhìqiáng, Yang, Xin, Yáng, Xīnglóu, Yu, Xuejie, Yutin, Natalya, Zerbini, F. Murilo, Zhang, Tong, Zhang, Yong-Zhen, Zhou, Guohui, and Zhou, Xueping

Published
2020
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15. SARS-CoV-2 Aerosol and Intranasal Exposure Models in Ferrets.

Author

Zumbrun, Elizabeth E., Zak, Samantha E., Lee, Eric D., Bowling, Philip A., Ruiz, Sara I., Zeng, Xiankun, Koehler, Jeffrey W., Delp, Korey L., Bakken, Russel R., Hentschel, Shannon S., Bloomfield, Holly A., Ricks, Keersten M., Clements, Tamara L., Babka, April M., Dye, John M., and Herbert, Andrew S.

Subjects
SARS-CoV-2, MICROBIOLOGICAL aerosols, FERRET, TURBINATE bones, VIRAL antigens
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the worldwide COVID-19 pandemic. Animal models are extremely helpful for testing vaccines and therapeutics and for dissecting the viral and host factors that contribute to disease severity and transmissibility. Here, we report the assessment and comparison of intranasal and small particle (~3 µm) aerosol SARS-CoV-2 exposure in ferrets. The primary endpoints for analysis were clinical signs of disease, recovery of the virus in the upper respiratory tract, and the severity of damage within the respiratory tract. This work demonstrated that ferrets were productively infected with SARS-CoV-2 following either intranasal or small particle aerosol exposure. SARS-CoV-2 infection of ferrets resulted in an asymptomatic disease course following either intranasal or small particle aerosol exposure, with no clinical signs, significant weight loss, or fever. In both aerosol and intranasal ferret models, SARS-CoV-2 replication, viral genomes, and viral antigens were detected within the upper respiratory tract, with little to no viral material detected in the lungs. The ferrets exhibited a specific IgG immune response to the SARS-CoV-2 full spike protein. Mild pathological findings included inflammation, necrosis, and edema within nasal turbinates, which correlated to positive immunohistochemical staining for the SARS-CoV-2 virus. Environmental sampling was performed following intranasal exposure of ferrets, and SARS-CoV-2 genomic material was detected on the feeders and nesting areas from days 2–10 post-exposure. We conclude that both intranasal and small particle aerosol ferret models displayed measurable parameters that could be utilized for future studies, including transmission studies and testing SARS-CoV-2 vaccines and therapeutics. [ABSTRACT FROM AUTHOR]

Published
2023
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19. Taxonomy of the order Mononegavirales: update 2019

Author

Amarasinghe, Gaya K., Ayllón, María A., Bào, Yīmíng, Basler, Christopher F., Bavari, Sina, Blasdell, Kim R., Briese, Thomas, Brown, Paul A., Bukreyev, Alexander, Balkema-Buschmann, Anne, Buchholz, Ursula J., Chabi-Jesus, Camila, Chandran, Kartik, Chiapponi, Chiara, Crozier, Ian, de Swart, Rik L., Dietzgen, Ralf G., Dolnik, Olga, Drexler, Jan F., Dürrwald, Ralf, Dundon, William G., Duprex, W. Paul, Dye, John M., Easton, Andrew J., Fooks, Anthony R., Formenty, Pierre B. H., Fouchier, Ron A. M., Freitas-Astúa, Juliana, Griffiths, Anthony, Hewson, Roger, Horie, Masayuki, Hyndman, Timothy H., Jiāng, Dàohóng, Kitajima, Elliott W., Kobinger, Gary P., Kondō, Hideki, Kurath, Gael, Kuzmin, Ivan V., Lamb, Robert A., Lavazza, Antonio, Lee, Benhur, Lelli, Davide, Leroy, Eric M., Lǐ, Jiànróng, Maes, Piet, Marzano, Shin-Yi L., Moreno, Ana, Mühlberger, Elke, Netesov, Sergey V., Nowotny, Norbert, Nylund, Are, Økland, Arnfinn L., Palacios, Gustavo, Pályi, Bernadett, Pawęska, Janusz T., Payne, Susan L., Prosperi, Alice, Ramos-González, Pedro Luis, Rima, Bertus K., Rota, Paul, Rubbenstroth, Dennis, Shī, Mǎng, Simmonds, Peter, Smither, Sophie J., Sozzi, Enrica, Spann, Kirsten, Stenglein, Mark D., Stone, David M., Takada, Ayato, Tesh, Robert B., Tomonaga, Keizō, Tordo, Noël, Towner, Jonathan S., van den Hoogen, Bernadette, Vasilakis, Nikos, Wahl, Victoria, Walker, Peter J., Wang, Lin-Fa, Whitfield, Anna E., Williams, John V., Zerbini, F. Murilo, Zhāng, Tāo, Zhang, Yong-Zhen, and Kuhn, Jens H.

Published
2019
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20. Taxonomy of the order Mononegavirales: second update 2018

Author

Maes, Piet, Amarasinghe, Gaya K., Ayllón, María A., Basler, Christopher F., Bavari, Sina, Blasdell, Kim R., Briese, Thomas, Brown, Paul A., Bukreyev, Alexander, Balkema-Buschmann, Anne, Buchholz, Ursula J., Chandran, Kartik, Crozier, Ian, de Swart, Rik L., Dietzgen, Ralf G., Dolnik, Olga, Domier, Leslie L., Drexler, Jan F., Dürrwald, Ralf, Dundon, William G., Duprex, W. Paul, Dye, John M., Easton, Andrew J., Fooks, Anthony R., Formenty, Pierre B. H., Fouchier, Ron A. M., Freitas-Astúa, Juliana, Ghedin, Elodie, Griffiths, Anthony, Hewson, Roger, Horie, Masayuki, Hurwitz, Julia L., Hyndman, Timothy H., Jiāng, Dàohóng, Kobinger, Gary P., Kondō, Hideki, Kurath, Gael, Kuzmin, Ivan V., Lamb, Robert A., Lee, Benhur, Leroy, Eric M., Lǐ, Jiànróng, Marzano, Shin-Yi L., Mühlberger, Elke, Netesov, Sergey V., Nowotny, Norbert, Palacios, Gustavo, Pályi, Bernadett, Pawęska, Janusz T., Payne, Susan L., Rima, Bertus K., Rota, Paul, Rubbenstroth, Dennis, Simmonds, Peter, Smither, Sophie J., Song, Qisheng, Song, Timothy, Spann, Kirsten, Stenglein, Mark D., Stone, David M., Takada, Ayato, Tesh, Robert B., Tomonaga, Keizō, Tordo, Noël, Towner, Jonathan S., van den Hoogen, Bernadette, Vasilakis, Nikos, Wahl, Victoria, Walker, Peter J., Wang, David, Wang, Lin-Fa, Whitfield, Anna E., Williams, John V., Yè, Gōngyín, Zerbini, F. Murilo, Zhang, Yong-Zhen, and Kuhn, Jens H.

Published
2019
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22. Protocadherin-1 is essential for cell entry by New World hantaviruses

Author

Jangra, Rohit K., Herbert, Andrew S., Li, Rong, Jae, Lucas T., Kleinfelter, Lara M., Slough, Megan M., Barker, Sarah L., Guardado-Calvo, Pablo, Román-Sosa, Gleyder, Dieterle, M. Eugenia, Kuehne, Ana I., Muena, Nicolás A., Wirchnianski, Ariel S., Nyakatura, Elisabeth K., Fels, J. Maximilian, Ng, Melinda, Mittler, Eva, Pan, James, Bharrhan, Sushma, Wec, Anna Z., Lai, Jonathan R., Sidhu, Sachdev S., Tischler, Nicole D., Rey, Félix A., Moffat, Jason, Brummelkamp, Thijn R., Wang, Zhongde, Dye, John M., and Chandran, Kartik

Published
2018
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23. Possibility and Challenges of Conversion of Current Virus Species Names to Linnaean Binomials

Author

Postler, Thomas S., Clawson, Anna N., Amarasinghe, Gaya K., Basler, Christopher F., Bavari, Sbina, Benkő, Mária, Blasdell, Kim R., Briese, Thomas, Buchmeier, Michael J., Bukreyev, Alexander, Calisher, Charles H., Chandran, Kartik, Charrel, Rémi, Clegg, Christopher S., Collins, Peter L., de la Torre, Juan Carlos, DeRisi, Joseph L., Dietzgen, Ralf G., Dolnik, Olga, Dürrwald, Ralf, Dye, John M., Easton, Andrew J., Emonet, Sébastian, Formenty, Pierre, Fouchier, Ron A. M., Ghedin, Elodie, Gonzalez, Jean-Paul, Harrach, Balázs, Hewson, Roger, Horie, Masayuki, Jiāng, Dàohóng, Kobinger, Gary, Kondo, Hideki, Kropinski, Andrew M., Krupovic, Mart, Kurath, Gael, Lamb, Robert A., Leroy, Eric M., Lukashevich, Igor S., Maisner, Andrea, Mushegian, Arcady R., Netesov, Sergey V., Nowotny, Norbert, Patterson, Jean L., Payne, Susan L., Paweska, Janusz T., Peters, Clarence J., Radoshitzky, Sheli R., Rima, Bertus K., Romanowski, Victor, Rubbenstroth, Dennis, Sabanadzovic, Sead, Sanfaçon, Hélène, Salvato, Maria S., Schwemmle, Martin, Smither, Sophie J., Stenglein, Mark D., Stone, David M., Takada, Ayato, Tesh, Robert B., Tomonaga, Keizo, Tordo, Noël, Towner, Jonathan S., Vasilakis, Nikos, Volchkov, Viktor E., Wahl-Jensen, Victoria, Walker, Peter J., Wang, Lin-Fa, Varsani, Arvind, Whitfield, Anna E., Zerbini, F. Murilo, and Kuhn, Jens H.

Published
2017

24. A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses

Author

Wec, Anna Z., Nyakatura, Elisabeth K., Herbert, Andrew S., Howell, Katie A., Holtsberg, Frederick W., Bakken, Russell R., Mittler, Eva, Christin, John R., Shulenin, Sergey, Jangra, Rohit K., Bharrhan, Sushma, Kuehne, Ana I., Bornholdt, Zachary A., Flyak, Andrew I., Saphire, Erica Ollmann, Crowe, James E., Aman, M. Javad, Dye, John M., Lai, Jonathan R., and Chandran, Kartik

Published
2016

27. Taxonomy of the order Mononegavirales: update 2018

Author

Amarasinghe, Gaya K., Aréchiga Ceballos, Nidia G., Banyard, Ashley C., Basler, Christopher F., Bavari, Sina, Bennett, Andrew J., Blasdell, Kim R., Briese, Thomas, Bukreyev, Alexander, Caì, Yíngyún, Calisher, Charles H., Campos Lawson, Cristine, Chandran, Kartik, Chapman, Colin A., Chiu, Charles Y., Choi, Kang-Seuk, Collins, Peter L., Dietzgen, Ralf G., Dolja, Valerian V., Dolnik, Olga, Domier, Leslie L., Dürrwald, Ralf, Dye, John M., Easton, Andrew J., Ebihara, Hideki, Echevarría, Juan E., Fooks, Anthony R., Formenty, Pierre B. H., Fouchier, Ron A. M., Freuling, Conrad M., Ghedin, Elodie, Goldberg, Tony L., Hewson, Roger, Horie, Masayuki, Hyndman, Timothy H., Jiāng, Dàohóng, Kityo, Robert, Kobinger, Gary P., Kondō, Hideki, Koonin, Eugene V., Krupovic, Mart, Kurath, Gael, Lamb, Robert A., Lee, Benhur, Leroy, Eric M., Maes, Piet, Maisner, Andrea, Marston, Denise A., Mor, Sunil Kumar, Müller, Thomas, Mühlberger, Elke, Ramírez, Víctor Manuel Neira, Netesov, Sergey V., Ng, Terry Fei Fan, Nowotny, Norbert, Palacios, Gustavo, Patterson, Jean L., Pawęska, Janusz T., Payne, Susan L., Prieto, Karla, Rima, Bertus K., Rota, Paul, Rubbenstroth, Dennis, Schwemmle, Martin, Siddell, Stuart, Smither, Sophie J., Song, Qisheng, Song, Timothy, Stenglein, Mark D., Stone, David M., Takada, Ayato, Tesh, Robert B., Thomazelli, Luciano Matsumiya, Tomonaga, Keizō, Tordo, Noël, Towner, Jonathan S., Vasilakis, Nikos, Vázquez-Morón, Sonia, Verdugo, Claudio, Volchkov, Viktor E., Wahl, Victoria, Walker, Peter J., Wang, David, Wang, Lin-Fa, Wellehan, James F. X., Wiley, Michael R., Whitfield, Anna E., Wolf, Yuri I., Yè, Gōngyín, Zhāng, Yǒng-Zhèn, and Kuhn, Jens H.

Published
2018
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28. Novel Small Molecule Entry Inhibitors of Ebola Virus

Author

Basu, Arnab, Mills, Debra M., Mitchell, Daniel, Ndungo, Esther, Williams, John D., Herbert, Andrew S., Dye, John M., Moir, Donald T., Chandran, Kartik, Patterson, Jean L., Rong, Lijun, and Bowlin, Terry L.

Published
2015

30. Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody.

Author

Mittler, Eva, Serris, Alexandra, Esterman, Emma S., Florez, Catalina, Polanco, Laura C., O'Brien, Cecilia M., Slough, Megan M., Tynell, Janne, Gröning, Remigius, Sun, Yan, Abelson, Dafna M., Wec, Anna Z., Haslwanter, Denise, Keller, Markus, Ye, Chunyan, Bakken, Russel R., Jangra, Rohit K., Dye, John M., Ahlm, Clas, and Rappazzo, C. Garrett

Subjects
MONOCLONAL antibodies, HANTAVIRUS diseases, VACCINE approval, HETERODIMERS, IMMUNOGLOBULINS, HANTAVIRUSES, VIRUS diseases
Abstract

Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus–experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic. Editor's summary: Infection with hantaviruses can cause severe disease in humans, and virus-specific therapeutics and vaccines are urgently needed. Neutralizing antibodies represent a promising therapeutic option, but most antibodies fail to neutralize evolutionarily divergent hantaviruses, limiting their utility. To address this, Mittler et al. performed structural analysis on a recently identified broadly neutralizing antibody isolated from an individual who recovered from infection with an Old World hantavirus, Puumala virus. Using structural information and complementary binding, neutralization, and functional studies, the authors engineered an optimized variant of this patient-derived antibody that could protect against infection by Puumala virus and lethal challenge by Andes virus, a New World hantavirus, in rodent models. This broadly neutralizing antibody, ADI-65534, represents a potential therapeutic candidate to treat hantavirus infections. —Courtney Malo [ABSTRACT FROM AUTHOR]

Published
2023
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31. Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects

Author

Bekerman, Elena, Neveu, Gregory, Shulla, Ana, Brannan, Jennifer, Pu, Szu-Yuan, Wang, Stanley, Xiao, Fei, Barouch-Bentov, Rina, Bakken, Russell R., Mateo, Roberto, Govero, Jennifer, Nagamine, Claude M., Diamond, Michael S., De Jonghe, Steven, Herdewijn, Piet, Dye, John M., Randall, Glenn, and Einav, Shirit

Subjects
Host-virus relationships, Enzyme regulation -- Health aspects, Virus diseases -- Drug therapy, Antineoplastic agents -- Patient outcomes, Health care industry
Abstract

Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infection, sunitinib/erlotinib combination protected against morbidity and mortality. We validated sunitinib- and erlotinib-mediated inhibition of AAK1 and GAK activity as an important mechanism of antiviral action. Additionally, we revealed potential roles for additional kinase targets. These findings advance our understanding of virus-host interactions and establish a proof of principle for a repurposed, host-targeted approach to combat emerging viruses., Introduction A major threat to human health is posed by emerging viruses, such as dengue (DENV) and Ebola (EBOV). Dengue is estimated to infect 390 million people annually in over [...]

Published
2017
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32. Taxonomy of the order Mononegavirales: update 2017

Author

Amarasinghe, Gaya K., Bào, Yīmíng, Basler, Christopher F., Bavari, Sina, Beer, Martin, Bejerman, Nicolás, Blasdell, Kim R., Bochnowski, Alisa, Briese, Thomas, Bukreyev, Alexander, Calisher, Charles H., Chandran, Kartik, Collins, Peter L., Dietzgen, Ralf G., Dolnik, Olga, Dürrwald, Ralf, Dye, John M., Easton, Andrew J., Ebihara, Hideki, Fang, Qi, Formenty, Pierre, Fouchier, Ron A. M., Ghedin, Elodie, Harding, Robert M., Hewson, Roger, Higgins, Colleen M., Hong, Jian, Horie, Masayuki, James, Anthony P., Jiāng, Dàohóng, Kobinger, Gary P., Kondo, Hideki, Kurath, Gael, Lamb, Robert A., Lee, Benhur, Leroy, Eric M., Li, Ming, Maisner, Andrea, Mühlberger, Elke, Netesov, Sergey V., Nowotny, Norbert, Patterson, Jean L., Payne, Susan L., Paweska, Janusz T., Pearson, Michael N., Randall, Rick E., Revill, Peter A., Rima, Bertus K., Rota, Paul, Rubbenstroth, Dennis, Schwemmle, Martin, Smither, Sophie J., Song, Qisheng, Stone, David M., Takada, Ayato, Terregino, Calogero, Tesh, Robert B., Tomonaga, Keizo, Tordo, Noël, Towner, Jonathan S., Vasilakis, Nikos, Volchkov, Viktor E., Wahl-Jensen, Victoria, Walker, Peter J., Wang, Beibei, Wang, David, Wang, Fei, Wang, Lin-Fa, Werren, John H., Whitfield, Anna E., Yan, Zhichao, Ye, Gongyin, and Kuhn, Jens H.

Published
2017
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33. Lassa virus entry requires a trigger-induced receptor switch

Author

Jae, Lucas T., Raaben, Matthijs, Herbert, Andrew S., Kuehne, Ana I., Wirchnianski, Ariel S., Soh, Timothy K., Stubbs, Sarah H., Janssen, Hans, Damme, Markus, Saftig, Paul, Whelan, Sean P., Dye, John M., and Brummelkamp, Thijn R.

Published
2014

34. Taxonomy of the order Mononegavirales: update 2016

Author

Afonso, Claudio L., Amarasinghe, Gaya K., Bányai, Krisztián, Bào, Yīmíng, Basler, Christopher F., Bavari, Sina, Bejerman, Nicolás, Blasdell, Kim R., Briand, François-Xavier, Briese, Thomas, Bukreyev, Alexander, Calisher, Charles H., Chandran, Kartik, Chéng, Jiāsēn, Clawson, Anna N., Collins, Peter L., Dietzgen, Ralf G., Dolnik, Olga, Domier, Leslie L., Dürrwald, Ralf, Dye, John M., Easton, Andrew J., Ebihara, Hideki, Farkas, Szilvia L., Freitas-Astúa, Juliana, Formenty, Pierre, Fouchier, Ron A. M., Fù, Yànpíng, Ghedin, Elodie, Goodin, Michael M., Hewson, Roger, Horie, Masayuki, Hyndman, Timothy H., Jiāng, Dàohóng, Kitajima, Elliot W., Kobinger, Gary P., Kondo, Hideki, Kurath, Gael, Lamb, Robert A., Lenardon, Sergio, Leroy, Eric M., Li, Ci-Xiu, Lin, Xian-Dan, Liú, Lìjiāng, Longdon, Ben, Marton, Szilvia, Maisner, Andrea, Mühlberger, Elke, Netesov, Sergey V., Nowotny, Norbert, Patterson, Jean L., Payne, Susan L., Paweska, Janusz T., Randall, Rick E., Rima, Bertus K., Rota, Paul, Rubbenstroth, Dennis, Schwemmle, Martin, Shi, Mang, Smither, Sophie J., Stenglein, Mark D., Stone, David M., Takada, Ayato, Terregino, Calogero, Tesh, Robert B., Tian, Jun-Hua, Tomonaga, Keizo, Tordo, Noël, Towner, Jonathan S., Vasilakis, Nikos, Verbeek, Martin, Volchkov, Viktor E., Wahl-Jensen, Victoria, Walsh, John A., Walker, Peter J., Wang, David, Wang, Lin-Fa, Wetzel, Thierry, Whitfield, Anna E., Xiè, Jiǎtāo, Yuen, Kwok-Yung, Zhang, Yong-Zhen, and Kuhn, Jens H.

Published
2016
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35. Toll-like receptor 4 mediates blood-brain barrier permeability and disease in C3H mice during Venezuelan equine encephalitis virus infection

Author

Hollidge, Bradley S., Cohen, Courtney A., Akuoku Frimpong, Justice, Badger, Catherine V., Dye, John M., and Schmaljohn, Connie S.

Subjects
veev, Mice, Inbred C3H, Venezuelan equine encephalitis virus, toll-like receptor 4, Brain, Encephalomyelitis, Venezuelan Equine, blood-brain barrier, tlr4, Virus Replication, Permeability, Encephalitis Virus, Venezuelan Equine, Disease Models, Animal, Mice, Animals, Female, Research Article, Research Paper
Abstract

Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus that can cause debilitating, acute febrile illness and potentially result in encephalitis. Currently, there are no FDA-licensed vaccines or specific therapeutics for VEEV. Previous studies have demonstrated that VEEV infection results in increased blood-brain barrier (BBB) permeability that is mediated by matrix metalloproteinases (MMPs). Furthermore, after subarachnoid hemorrhage in mice, MMP-9 is upregulated in the brain and mediates BBB permeability in a toll-like receptor 4 (TLR4)-dependent manner. Here, we demonstrate that disease in C3H mice during VEEV TC-83 infection is dependent on TLR4 because intranasal infection of C3H/HeN (TLR4WT) mice with VEEV TC-83 resulted in mortality as opposed to survival of TLR4-defective C3H/HeJ (TLR4mut) mice. In addition, BBB permeability was induced to a lesser extent in TLR4mut mice compared with TLR4WT mice during VEEV TC-83 infection as determined by sodium fluorescein and fluorescently-conjugated dextran extravasation. Moreover, MMP-9, MMP-2, ICAM-1, CCL2 and IFN-γ were all induced to significantly lower levels in the brains of infected TLR4mut mice compared with infected TLR4WT mice despite the absence of significantly different viral titers or immune cell populations in the brains of infected TLR4WT and TLR4mut mice. These data demonstrate the critical role of TLR4 in mediating BBB permeability and disease in C3H mice during VEEV TC-83 infection, which suggests that TLR4 is a potential target for the development of therapeutics for VEEV.

Published
2021

42. Discovery of pan-ErbB inhibitors protecting from SARS-CoV-2 replication, inflammation, and lung injury by a drug repurposing screen

Author

Saul, Sirle, Karim, Marwah, Huang, Pei-Tzu, Ghita, Luca, Chiu, Winston, Kumar, Sathish, Bhalla, Nishank, Leyssen, Pieter, Cohen, Courtney A., Huie, Kathleen, Tindle, Courtney, Sibai, Mamdouh, Pinsky, Benjamin A., Das, Soumita, Ghosh, Pradipta, Dye, John M., Solow-Cordero, David E., Jin, Jing, Jochmans, Dirk, Neyts, Johan, Narayanan, Aarthi, De Jonghe, Steven, and Einav, Shirit

Subjects
viruses, skin and connective tissue diseases, Article
Abstract

Effective therapies are needed to combat emerging viruses. Seventeen candidates that rescue cells from SARS-CoV-2-induced lethality and target diverse functions emerged in a screen of 4,413 compounds. Among the hits was lapatinib, an approved inhibitor of the ErbB family of receptor tyrosine kinases. Lapatinib and other pan-ErbB inhibitors suppress replication of SARS-CoV-2 and unrelated viruses with a high barrier to resistance. ErbB4, but not lapatinib's cancer targets ErbB1 and ErbB2, is required for SARS-CoV-2 entry and encephalitis alphavirus infection and is a molecular target mediating lapatinib's antiviral effect. In human lung organoids, lapatinib protects from SARS-CoV-2-induced activation of pathways implicated in non-infectious acute lung injury and fibrosis downstream of ErbBs (p38-MAPK, MEK/ERK, and AKT/mTOR), pro-inflammatory cytokine production, and epithelial barrier injury. These findings reveal regulation of viral infection, inflammation, and lung injury via ErbBs and propose approved candidates to counteract these effects with implications for pandemic coronaviruses and unrelated viruses.

Published
2021

43. Virus nomenclature below the species level: a standardized nomenclature for filovirus strains and variants rescued from cDNA

Author

Kuhn, Jens H., Bào, Yīmíng, Bavari, Sina, Becker, Stephan, Bradfute, Steven, Brauburger, Kristina, Rodney Brister, J., Bukreyev, Alexander A., Caì, Yíngyún, Chandran, Kartik, Davey, Robert A., Dolnik, Olga, Dye, John M., Enterlein, Sven, Gonzalez, Jean-Paul, Formenty, Pierre, Freiberg, Alexander N., Hensley, Lisa E., Hoenen, Thomas, Honko, Anna N., Ignatyev, Georgy M., Jahrling, Peter B., Johnson, Karl M., Klenk, Hans-Dieter, Kobinger, Gary, Lackemeyer, Matthew G., Leroy, Eric M., Lever, Mark S., Mühlberger, Elke, Netesov, Sergey V., Olinger, Gene G., Palacios, Gustavo, Patterson, Jean L., Paweska, Janusz T., Pitt, Louise, Radoshitzky, Sheli R., Ryabchikova, Elena I., Saphire, Erica Ollmann, Shestopalov, Aleksandr M., Smither, Sophie J., Sullivan, Nancy J., Swanepoel, Robert, Takada, Ayato, Towner, Jonathan S., van der Groen, Guido, Volchkov, Viktor E., Volchkova, Valentina A., Wahl-Jensen, Victoria, Warren, Travis K., Warfield, Kelly L., Weidmann, Manfred, and Nichol, Stuart T.

Published
2014
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44. Discussions and decisions of the 2012–2014 International Committee on Taxonomy of Viruses (ICTV) Filoviridae Study Group, January 2012–June 2013

Author

Bukreyev, Alexander A., Chandran, Kartik, Dolnik, Olga, Dye, John M., Ebihara, Hideki, Leroy, Eric M., Mühlberger, Elke, Netesov, Sergey V., Patterson, Jean L., Paweska, Janusz T., Saphire, Erica Ollmann, Smither, Sophie J., Takada, Ayato, Towner, Jonathan S., Volchkov, Viktor E., Warren, Travis K., and Kuhn, Jens H.

Published
2014
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45. Phosphatidylserine clustering by the Ebola virus matrix protein is a critical step in viral budding.

Author

Husby, Monica L, Amiar, Souad, Prugar, Laura I, David, Emily A, Plescia, Caroline B, Huie, Kathleen E, Brannan, Jennifer M, Dye, John M, Pienaar, Elsje, and Stahelin, Robert V

Abstract

Phosphatidylserine (PS) is a critical lipid factor in the assembly and spread of numerous lipid‐enveloped viruses. Here, we describe the ability of the Ebola virus (EBOV) matrix protein eVP40 to induce clustering of PS and promote viral budding in vitro, as well as the ability of an FDA‐approved drug, fendiline, to reduce PS clustering and subsequent virus budding and entry. To gain mechanistic insight into fendiline inhibition of EBOV replication, multiple in vitro assays were run including imaging, viral budding and viral entry assays. Fendiline lowers PS content in mammalian cells and PS in the plasma membrane, where the ability of VP40 to form new virus particles is greatly lower. Further, particles that form from fendiline‐treated cells have altered particle morphology and cannot significantly infect/enter cells. These complementary studies reveal the mechanism by which EBOV matrix protein clusters PS to enhance viral assembly, budding, and spread from the host cell while also laying the groundwork for fundamental drug targeting strategies. Synopsis: The Ebola virus matrix protein VP40 clusters phosphatidylserine at the plasma membrane inner leaflet for efficient matrix layer formation and virus budding. The drug fendiline diminishes PS levels and clustering, reducing EBOV budding and spread. VP40 clusters phosphatidylserine (PS) in the plasma membrane of cells.VP40 PS clustering requires PS‐binding residues and VP40 oligomerization.FDA‐approved fendiline reduces PS levels and clustering.Fendiline greatly reduces VP40 oligomerization, EBOV budding and subsequent viral entry. [ABSTRACT FROM AUTHOR]

Published
2022
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46. An introduction to the Marburg virus vaccine consortium, MARVAC.

Author

Cross, Robert W., Longini, Ira M., Becker, Stephan, Bok, Karin, Boucher, David, Carroll, Miles W., Díaz, Janet V., Dowling, William E., Draghia-Akli, Ruxandra, Duworko, James T., Dye, John M., Egan, Michael A., Fast, Patricia, Finan, Amy, Finch, Courtney, Fleming, Thomas R., Fusco, Joan, Geisbert, Thomas W., Griffiths, Anthony, and Günther, Stephan

Subjects
MARBURG virus, VIRAL vaccines, CONSORTIA, VACCINE development, COMMUNICABLE diseases
Abstract

The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine "MARVAC" consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines. [ABSTRACT FROM AUTHOR]

Published
2022
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48. Egg-Derived Anti-SARS-CoV-2 Immunoglobulin Y (IgY) With Broad Variant Activity as Intranasal Prophylaxis Against COVID-19.

Author

Frumkin, Lyn R., Lucas, Michaela, Scribner, Curtis L., Ortega-Heinly, Nastassja, Rogers, Jayden, Yin, Gang, Hallam, Trevor J., Yam, Alice, Bedard, Kristin, Begley, Rebecca, Cohen, Courtney A., Badger, Catherine V., Abbasi, Shawn A., Dye, John M., McMillan, Brian, Wallach, Michael, Bricker, Traci L., Joshi, Astha, Boon, Adrianus C. M., and Pokhrel, Suman

Subjects
SARS-CoV-2, COVID-19, NEUTRALIZATION tests, SARS-CoV-2 Delta variant, SARS-CoV-2 Omicron variant, INTRANASAL administration
Abstract

COVID-19 emergency use authorizations and approvals for vaccines were achieved in record time. However, there remains a need to develop additional safe, effective, easy-to-produce, and inexpensive prevention to reduce the risk of acquiring SARS-CoV-2 infection. This need is due to difficulties in vaccine manufacturing and distribution, vaccine hesitancy, and, critically, the increased prevalence of SARS-CoV-2 variants with greater contagiousness or reduced sensitivity to immunity. Antibodies from eggs of hens (immunoglobulin Y; IgY) that were administered the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were developed for use as nasal drops to capture the virus on the nasal mucosa. Although initially raised against the 2019 novel coronavirus index strain (2019-nCoV), these anti-SARS-CoV-2 RBD IgY surprisingly had indistinguishable enzyme-linked immunosorbent assay binding against variants of concern that have emerged, including Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529). This is different from sera of immunized or convalescent patients. Culture neutralization titers against available Alpha, Beta, and Delta were also indistinguishable from the index SARS-CoV-2 strain. Efforts to develop these IgY for clinical use demonstrated that the intranasal anti-SARS-CoV-2 RBD IgY preparation showed no binding (cross-reactivity) to a variety of human tissues and had an excellent safety profile in rats following 28-day intranasal delivery of the formulated IgY. A double-blind, randomized, placebo-controlled phase 1 study evaluating single-ascending and multiple doses of anti-SARS-CoV-2 RBD IgY administered intranasally for 14 days in 48 healthy adults also demonstrated an excellent safety and tolerability profile, and no evidence of systemic absorption. As these antiviral IgY have broad selectivity against many variants of concern, are fast to produce, and are a low-cost product, their use as prophylaxis to reduce SARS-CoV-2 viral transmission warrants further evaluation. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT04567810 , identifier NCT04567810. [ABSTRACT FROM AUTHOR]

Published
2022
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49. Virus nomenclature below the species level: a standardized nomenclature for laboratory animal-adapted strains and variants of viruses assigned to the family Filoviridae

Author

Kuhn, Jens H., Bao, Yiming, Bavari, Sina, Becker, Stephan, Bradfute, Steven, Brister, J. Rodney, Bukreyev, Alexander A., Caì, Yíngyún, Chandran, Kartik, Davey, Robert A., Dolnik, Olga, Dye, John M., Enterlein, Sven, Gonzalez, Jean-Paul, Formenty, Pierre, Freiberg, Alexander N., Hensley, Lisa E., Honko, Anna N., Ignatyev, Georgy M., Jahrling, Peter B., Johnson, Karl M., Klenk, Hans-Dieter, Kobinger, Gary, Lackemeyer, Matthew G., Leroy, Eric M., Lever, Mark S., Lofts, Loreen L., Mühlberger, Elke, Netesov, Sergey V., Olinger, Gene G., Palacios, Gustavo, Patterson, Jean L., Paweska, Janusz T., Pitt, Louise, Radoshitzky, Sheli R., Ryabchikova, Elena I., Saphire, Erica Ollmann, Shestopalov, Aleksandr M., Smither, Sophie J., Sullivan, Nancy J., Swanepoel, Robert, Takada, Ayato, Towner, Jonathan S., van der Groen, Guido, Volchkov, Viktor E., Wahl-Jensen, Victoria, Warren, Travis K., Warfield, Kelly L., Weidmann, Manfred, and Nichol, Stuart T.

Published
2013
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50. Virus nomenclature below the species level: a standardized nomenclature for natural variants of viruses assigned to the family Filoviridae

Author

Kuhn, Jens H., Bao, Yiming, Bavari, Sina, Becker, Stephan, Bradfute, Steven, Brister, J. Rodney, Bukreyev, Alexander A., Chandran, Kartik, Davey, Robert A., Dolnik, Olga, Dye, John M., Enterlein, Sven, Hensley, Lisa E., Honko, Anna N., Jahrling, Peter B., Johnson, Karl M., Kobinger, Gary, Leroy, Eric M., Lever, Mark S., Mühlberger, Elke, Netesov, Sergey V., Olinger, Gene G., Palacios, Gustavo, Patterson, Jean L., Paweska, Janusz T., Pitt, Louise, Radoshitzky, Sheli R., Saphire, Erica Ollmann, Smither, Sophie J., Swanepoel, Robert, Towner, Jonathan S., van der Groen, Guido, Volchkov, Viktor E., Wahl-Jensen, Victoria, Warren, Travis K., Weidmann, Manfred, and Nichol, Stuart T.

Published
2013
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