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5. 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

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

Author

Frumkin, Lyn R., primary, Lucas, Michaela, additional, Scribner, Curtis L., additional, Ortega-Heinly, Nastassja, additional, Rogers, Jayden, additional, Yin, Gang, additional, Hallam, Trevor J., additional, Yam, Alice, additional, Bedard, Kristin, additional, Begley, Rebecca, additional, Cohen, Courtney A., additional, Badger, Catherine V., additional, Abbasi, Shawn A., additional, Dye, John M., additional, McMillan, Brian, additional, Wallach, Michael, additional, Bricker, Traci L., additional, Joshi, Astha, additional, Boon, Adrianus C. M., additional, Pokhrel, Suman, additional, Kraemer, Benjamin R., additional, Lee, Lucia, additional, Kargotich, Stephen, additional, Agochiya, Mahima, additional, John, Tom St., additional, and Mochly-Rosen, Daria, additional

Published
2022
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7. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

Author

Westendorf, Kathryn, primary, Žentelis, Stefanie, additional, Wang, Lingshu, additional, Foster, Denisa, additional, Vaillancourt, Peter, additional, Wiggin, Matthew, additional, Lovett, Erica, additional, van der Lee, Robin, additional, Hendle, Jörg, additional, Pustilnik, Anna, additional, Sauder, J. Michael, additional, Kraft, Lucas, additional, Hwang, Yuri, additional, Siegel, Robert W., additional, Chen, Jinbiao, additional, Heinz, Beverly A., additional, Higgs, Richard E., additional, Kallewaard, Nicole L., additional, Jepson, Kevin, additional, Goya, Rodrigo, additional, Smith, Maia A., additional, Collins, David W., additional, Pellacani, Davide, additional, Xiang, Ping, additional, de Puyraimond, Valentine, additional, Ricicova, Marketa, additional, Devorkin, Lindsay, additional, Pritchard, Caitlin, additional, O’Neill, Aoise, additional, Dalal, Kush, additional, Panwar, Pankaj, additional, Dhupar, Harveer, additional, Garces, Fabian A., additional, Cohen, Courtney A., additional, Dye, John M., additional, Huie, Kathleen E., additional, Badger, Catherine V., additional, Kobasa, Darwyn, additional, Audet, Jonathan, additional, Freitas, Joshua J., additional, Hassanali, Saleema, additional, Hughes, Ina, additional, Munoz, Luis, additional, Palma, Holly C., additional, Ramamurthy, Bharathi, additional, Cross, Robert W., additional, Geisbert, Thomas W., additional, Menachery, Vineet, additional, Lokugamage, Kumari, additional, Borisevich, Viktoriya, additional, Lanz, Iliana, additional, Anderson, Lisa, additional, Sipahimalani, Payal, additional, Corbett, Kizzmekia S., additional, Yang, Eun Sung, additional, Zhang, Yi, additional, Shi, Wei, additional, Zhou, Tongqing, additional, Choe, Misook, additional, Misasi, John, additional, Kwong, Peter D., additional, Sullivan, Nancy J., additional, Graham, Barney S., additional, Fernandez, Tara L., additional, Hansen, Carl L., additional, Falconer, Ester, additional, Mascola, John R., additional, Jones, Bryan E., additional, and Barnhart, Bryan C., additional

Published
2022
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8. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

Author

Westendorf, Kathryn, primary, Žentelis, Stefanie, additional, Wang, Lingshu, additional, Foster, Denisa, additional, Vaillancourt, Peter, additional, Wiggin, Matthew, additional, Lovett, Erica, additional, van der Lee, Robin, additional, Hendle, Jörg, additional, Pustilnik, Anna, additional, Sauder, J. Michael, additional, Kraft, Lucas, additional, Hwang, Yuri, additional, Siegel, Robert W., additional, Chen, Jinbiao, additional, Heinz, Beverly A., additional, Higgs, Richard E., additional, Kallewaard, Nicole L., additional, Jepson, Kevin, additional, Goya, Rodrigo, additional, Smith, Maia A., additional, Collins, David W., additional, Pellacani, Davide, additional, Xiang, Ping, additional, de Puyraimond, Valentine, additional, Ricicova, Marketa, additional, Devorkin, Lindsay, additional, Pritchard, Caitlin, additional, O’Neill, Aoise, additional, Dalal, Kush, additional, Panwar, Pankaj, additional, Dhupar, Harveer, additional, Garces, Fabian A., additional, Cohen, Courtney A., additional, Dye, John M., additional, Huie, Kathleen E., additional, Badger, Catherine V., additional, Kobasa, Darwyn, additional, Audet, Jonathan, additional, Freitas, Joshua J., additional, Hassanali, Saleema, additional, Hughes, Ina, additional, Munoz, Luis, additional, Palma, Holly C., additional, Ramamurthy, Bharathi, additional, Cross, Robert W., additional, Geisbert, Thomas W., additional, Menacherry, Vineet, additional, Lokugamage, Kumari, additional, Borisevich, Viktoriya, additional, Lanz, Iliana, additional, Anderson, Lisa, additional, Sipahimalani, Payal, additional, Corbett, Kizzmekia S., additional, Yang, Eun Sung, additional, Zhang, Yi, additional, Shi, Wei, additional, Zhou, Tongqing, additional, Choe, Misook, additional, Misasi, John, additional, Kwong, Peter D., additional, Sullivan, Nancy J., additional, Graham, Barney S., additional, Fernandez, Tara L., additional, Hansen, Carl L., additional, Falconer, Ester, additional, Mascola, John R., additional, Jones, Bryan E., additional, and Barnhart, Bryan C., additional

Published
2021
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9. Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease

Author

Golden, Joseph W., primary, Cline, Curtis R., additional, Zeng, Xiankun, additional, Garrison, Aura R., additional, Carey, Brian D., additional, Mucker, Eric M., additional, White, Lauren E., additional, Shamblin, Joshua D., additional, Brocato, Rebecca L., additional, Liu, Jun, additional, Babka, April M., additional, Rauch, Hypaitia B., additional, Smith, Jeffrey M., additional, Hollidge, Bradley S., additional, Fitzpatrick, Collin, additional, Badger, Catherine V., additional, and Hooper, Jay W., additional

Published
2020
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11. Virus-Like Particles and Magnetic Microspheres Provide a Flexible and Sustainable Multiplexed Alphavirus Immunodiagnostic Platform

Author

Ricks, Keersten M., primary, Shoemaker, Charles J., additional, Dupuy, Lesley C., additional, Flusin, Olivier, additional, Voorhees, Matthew A., additional, Fulmer, Ashley N., additional, Six, Carolyn M., additional, Badger, Catherine V., additional, Schmaljohn, Connie S., additional, and Schoepp, Randal J., additional

Published
2018
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12. A DNA vaccine for Crimean-Congo hemorrhagic fever protects against disease and death in two lethal mouse models

Author

Garrison, Aura R., primary, Shoemaker, Charles J., additional, Golden, Joseph W., additional, Fitzpatrick, Collin J., additional, Suschak, John J., additional, Richards, Michelle J., additional, Badger, Catherine V., additional, Six, Carolyn M., additional, Martin, Jacqueline D., additional, Hannaman, Drew, additional, Zivcec, Marko, additional, Bergeron, Eric, additional, Koehler, Jeffrey W., additional, and Schmaljohn, Connie S., additional

Published
2017
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13. Codon-optimized filovirus DNA vaccines delivered by intramuscular electroporation protect cynomolgus macaques from lethal Ebola and Marburg virus challenges

Author

Grant-Klein, Rebecca J, primary, Altamura, Louis A, additional, Badger, Catherine V, additional, Bounds, Callie E, additional, Van Deusen, Nicole M, additional, Kwilas, Steven A, additional, Vu, Hong A, additional, Warfield, Kelly L, additional, Hooper, Jay W, additional, Hannaman, Drew, additional, Dupuy, Lesley C, additional, and Schmaljohn, Connie S, additional

Published
2015
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14. A Fusion-Inhibiting Peptide against Rift Valley Fever Virus Inhibits Multiple, Diverse Viruses

Author

Koehler, Jeffrey W., primary, Smith, Jeffrey M., additional, Ripoll, Daniel R., additional, Spik, Kristin W., additional, Taylor, Shannon L., additional, Badger, Catherine V., additional, Grant, Rebecca J., additional, Ogg, Monica M., additional, Wallqvist, Anders, additional, Guttieri, Mary C., additional, Garry, Robert F., additional, and Schmaljohn, Connie S., additional

Published
2013
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15. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants.

Author

Westendorf K, Žentelis S, Wang L, Foster D, Vaillancourt P, Wiggin M, Lovett E, van der Lee R, Hendle J, Pustilnik A, Sauder JM, Kraft L, Hwang Y, Siegel RW, Chen J, Heinz BA, Higgs RE, Kallewaard NL, Jepson K, Goya R, Smith MA, Collins DW, Pellacani D, Xiang P, de Puyraimond V, Ricicova M, Devorkin L, Pritchard C, O'Neill A, Dalal K, Panwar P, Dhupar H, Garces FA, Cohen CA, Dye JM, Huie KE, Badger CV, Kobasa D, Audet J, Freitas JJ, Hassanali S, Hughes I, Munoz L, Palma HC, Ramamurthy B, Cross RW, Geisbert TW, Menacherry V, Lokugamage K, Borisevich V, Lanz I, Anderson L, Sipahimalani P, Corbett KS, Yang ES, Zhang Y, Shi W, Zhou T, Choe M, Misasi J, Kwong PD, Sullivan NJ, Graham BS, Fernandez TL, Hansen CL, Falconer E, Mascola JR, Jones BE, and Barnhart BC

Abstract

SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization when administered early during COVID-19 disease. However, the emergence of variants of concern has negatively impacted the therapeutic use of some authorized mAbs. Using a high throughput B-cell screening pipeline, we isolated a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody called LY-CoV1404 (also known as bebtelovimab). LY-CoV1404 potently neutralizes authentic SARS-CoV-2 virus, including the prototype, B.1.1.7, B.1.351 and B.1.617.2). In pseudovirus neutralization studies, LY-CoV1404 retains potent neutralizing activity against numerous variants including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant and retains binding to spike proteins with a variety of underlying RBD mutations including K417N, L452R, E484K, and N501Y. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved with the exception of N439 and N501. Notably, the binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The breadth of reactivity to amino acid substitutions present among current VOC together with broad and potent neutralizing activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants causing COVID-19., In Brief: LY-CoV1404 is a potent SARS-CoV-2-binding antibody that neutralizes all known variants of concern and whose epitope is rarely mutated., Highlights: LY-CoV1404 potently neutralizes SARS-CoV-2 authentic virus and known variants of concern including the B.1.1.529 (Omicron), the BA.2 Omicron subvariant, and B.1.617.2 (Delta) variantsNo loss of potency against currently circulating variantsBinding epitope on RBD of SARS-CoV-2 is rarely mutated in GISAID databaseBreadth of neutralizing activity and potency supports clinical development.

Published
2022
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16. Enhanced Efficacy of a Codon-Optimized DNA Vaccine Encoding the Glycoprotein Precursor Gene of Lassa Virus in a Guinea Pig Disease Model When Delivered by Dermal Electroporation.

Author

Cashman KA, Broderick KE, Wilkinson ER, Shaia CI, Bell TM, Shurtleff AC, Spik KW, Badger CV, Guttieri MC, Sardesai NY, and Schmaljohn CS

Abstract

Lassa virus (LASV) causes a severe, often fatal, hemorrhagic fever endemic to West Africa. Presently, there are no FDA-licensed medical countermeasures for this disease. In a pilot study, we constructed a DNA vaccine (pLASV-GPC) that expressed the LASV glycoprotein precursor gene (GPC). This plasmid was used to vaccinate guinea pigs (GPs) using intramuscular electroporation as the delivery platform. Vaccinated GPs were protected from lethal infection (5/6) with LASV compared to the controls. However, vaccinated GPs experienced transient viremia after challenge, although lower than the mock-vaccinated controls. In a follow-on study, we developed a new device that allowed for both the vaccine and electroporation pulse to be delivered to the dermis. We also codon-optimized the GPC sequence of the vaccine to enhance expression in GPs. Together, these innovations resulted in enhanced efficacy of the vaccine. Unlike the pilot study where neutralizing titers were not detected until after virus challenge, modest neutralizing titers were detected in guinea pigs before challenge, with escalating titers detected after challenge. The vaccinated GPs were never ill and were not viremic at any timepoint. The combination of the codon-optimized vaccine and dermal electroporation delivery is a worthy candidate for further development.

Published
2013
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