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2. A measles-vectored vaccine candidate expressing prefusion-stabilized SARS-CoV-2 spike protein brought to phase I/II clinical trials: protection of African green monkeys from COVID-19 disease

Author

Nambulli, Sham, primary, Escriou, Nicolas, additional, Rennick, Linda J., additional, Demers, Matthew J., additional, Tilston‑Lunel, Natasha L., additional, McElroy, Anita K., additional, Barbeau, Dominique J., additional, Crossland, Nicholas A., additional, Hoehl, Ryan M., additional, Schrauf, Sabrina, additional, White, Alexander G., additional, Borish, H. Jacob, additional, Tomko, Jaime A., additional, Frye, Lonnie J., additional, Scanga, Charles A., additional, Flynn, JoAnne L., additional, Martin, Annette, additional, Gerke, Christiane, additional, Hartman, Amy L., additional, and Duprex, W. Paul, additional

Published
2024
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3. Rational attenuation of canine distemper virus (CDV) to develop a morbillivirus animal model that mimics measles in humans

Author

Schmitz, Katharina S., Rennick, Linda J., Tilston-Lunel, Natasha L., Comvalius, Anouskha D., Laksono, Brigitta M., Geers, Daryl, van Run, Peter, de Vries, Rory D., de Swart, Rik L., Duprex, W. Paul, Schmitz, Katharina S., Rennick, Linda J., Tilston-Lunel, Natasha L., Comvalius, Anouskha D., Laksono, Brigitta M., Geers, Daryl, van Run, Peter, de Vries, Rory D., de Swart, Rik L., and Duprex, W. Paul

Abstract

Morbilliviruses are members of the family Paramyxoviridae and are known for their ability to cause systemic disease in a variety of mammalian hosts. The prototypic morbillivirus, measles virus (MeV), infects humans and still causes morbidity and mortality in unvaccinated children and young adults. Experimental infection studies in non-human primates have contributed to the understanding of measles pathogenesis. However, ethical restrictions call for the development of new animal models. Canine distemper virus (CDV) infects a wide range of animals, including ferrets, and its pathogenesis shares many features with measles. However, wild-type CDV infection is almost always lethal, while MeV infection is usually self-limiting. Here, we made five recombinant CDVs, predicted to be attenuated, and compared their pathogenesis to the non-attenuated recombinant CDV in a ferret model. Three viruses were insufficiently attenuated based on clinical signs, fatality, and systemic infection, while one virus was too attenuated. The last candidate virus caused a self-limiting infection associated with transient viremia and viral dissemination to all lymphoid tissues, was shed transiently from the upper respiratory tract, and did not result in acute neurological signs. Additionally, an in-depth phenotyping of the infected white blood cells showed lower infection percentages in all lymphocyte subsets when compared to the non-attenuated CDV. In conclusion, infection models using this candidate virus mimic measles and can be used to study pathogenesis-related questions and to test interventions for morbilliviruses in a natural host species.IMPORTANCEMorbilliviruses are transmitted via the respiratory route but cause systemic disease. The viruses use two cellular receptors to infect myeloid, lymphoid, and epithelial cells. Measles virus (MeV) remains an important cause of morbidity and mortality in humans, requiring animal models to study pathogenesis or intervention strategies. Experimen

Published
2024

5. Multiplexed Metagenomic Deep Sequencing To Analyze the Composition of High-Priority Pathogen Reagents

Author

Wilson, Michael R, Fedewa, Greg, Stenglein, Mark D, Olejnik, Judith, Rennick, Linda J, Nambulli, Sham, Feldmann, Friederike, Duprex, W Paul, Connor, John H, Mühlberger, Elke, and DeRisi, Joseph L

Subjects
Microbiology, Biological Sciences, Bioinformatics and Computational Biology, Biodefense, Genetics, Emerging Infectious Diseases, Infectious Diseases, Biotechnology, 2.2 Factors relating to the physical environment, Infection, Good Health and Well Being, metagenomics, pathogen tracking, phylogenetic analysis
Abstract

Laboratories studying high-priority pathogens need comprehensive methods to confirm microbial species and strains while also detecting contamination. Metagenomic deep sequencing (MDS) inventories nucleic acids present in laboratory stocks, providing an unbiased assessment of pathogen identity, the extent of genomic variation, and the presence of contaminants. Double-stranded cDNA MDS libraries were constructed from RNA extracted from in vitro-passaged stocks of six viruses (La Crosse virus, Ebola virus, canine distemper virus, measles virus, human respiratory syncytial virus, and vesicular stomatitis virus). Each library was dual indexed and pooled for sequencing. A custom bioinformatics pipeline determined the organisms present in each sample in a blinded fashion. Single nucleotide variant (SNV) analysis identified viral isolates. We confirmed that (i) each sample contained the expected microbe, (ii) dual indexing of the samples minimized false assignments of individual sequences, (iii) multiple viral and bacterial contaminants were present, and (iv) SNV analysis of the viral genomes allowed precise identification of the viral isolates. MDS can be multiplexed to allow simultaneous and unbiased interrogation of mixed microbial cultures and (i) confirm pathogen identity, (ii) characterize the extent of genomic variation, (iii) confirm the cell line used for virus propagation, and (iv) assess for contaminating microbes. These assessments ensure the true composition of these high-priority reagents and generate a comprehensive database of microbial genomes studied in each facility. MDS can serve as an integral part of a pathogen-tracking program which in turn will enhance sample security and increase experimental rigor and precision. IMPORTANCE Both the integrity and reproducibility of experiments using select agents depend in large part on unbiased validation to ensure the correct identity and purity of the species in question. Metagenomic deep sequencing (MDS) provides the required level of validation by allowing for an unbiased and comprehensive assessment of all the microbes in a laboratory stock.

Published
2016

6. Targeting spike glycans to inhibit SARS-CoV2 viral entry

Author

Guseman, Alex J., primary, Rennick, Linda J., additional, Nambulli, Sham, additional, Roy, Chandra N., additional, Martinez, David R., additional, Yang, Darian T., additional, Bhinderwala, Fatema, additional, Vergara, Sandra, additional, Schaefer, Alexandra, additional, Baric, Ralph S., additional, Ambrose, Zandrea, additional, Duprex, W. Paul, additional, and Gronenborn, Angela M., additional

Published
2023
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7. Inoculation of raccoons with a wild-type-based recombinant canine distemper virus results in viremia, lymphopenia, fever, and widespread histological lesions

Author

Roelofs, Dagmar, primary, Schmitz, Katharina S., additional, van Amerongen, Geert, additional, Rijsbergen, Laurine C., additional, Laksono, Brigitta M., additional, Comvalius, Anouskha D., additional, Nambulli, Sham, additional, Rennick, Linda J., additional, van Run, Peter, additional, Duprex, W. Paul, additional, van den Brand, Judith M. A., additional, de Swart, Rik L., additional, and de Vries, Rory D., additional

Published
2023
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8. Inoculation of raccoons with a wild-type-based recombinant canine distemper virus results in viremia, lymphopenia, fever, and widespread histological lesions

Author

Roelofs, Dagmar, Schmitz, Katharina S, van Amerongen, Geert, Rijsbergen, Laurine C, Laksono, Brigitta M, Comvalius, Anouskha D, Nambulli, Sham, Rennick, Linda J, van Run, Peter, Duprex, W Paul, van den Brand, Judith M A, de Swart, Rik L, de Vries, Rory D, Roelofs, Dagmar, Schmitz, Katharina S, van Amerongen, Geert, Rijsbergen, Laurine C, Laksono, Brigitta M, Comvalius, Anouskha D, Nambulli, Sham, Rennick, Linda J, van Run, Peter, Duprex, W Paul, van den Brand, Judith M A, de Swart, Rik L, and de Vries, Rory D

Abstract

Raccoons are naturally susceptible to canine distemper virus (CDV) infection and can be a potential source of spill-over events. CDV is a highly contagious morbillivirus that infects multiple species of carnivores and omnivores, resulting in severe and often fatal disease. Here, we used a recombinant CDV (rCDV) based on a full-genome sequence detected in a naturally infected raccoon to perform pathogenesis studies in raccoons. Five raccoons were inoculated intratracheally with a recombinant virus engineered to express a fluorescentreporter protein, and extensive virological, serological, histological, and immunohistochemical assessments were performed at differenttime points post inoculation. rCDV-infected white blood cells were detected as early as 4 days post inoculation (dpi). Raccoon necropsies at 6 and 8 dpi revealed replication in the lymphoid tissues, preceding spread into peripheral tissues observed during necropsies at 21 dpi. Whereas lymphocytes, and to a lesser extent myeloid cells, were the main target cells of CDV at early time points, CDV additionally targeted epithelia at 21 dpi. At this later time point, CDV-infected cells were observed throughout the host. We observed lymphopenia and lymphocyte depletion from lymphoid tissues after CDV infection, in the absence of detectable CDV neutralizing antibodies and an impaired ability to clear CDV, indicating that the animals were severely immunosuppressed. The use of a wild-type-based recombinant virus in a natural host species infection study allowed systematic and sensitive assessment of antigen detection by immunohistochemistry, enabling further comparative pathology studies of CDV infection in differentspecies.

Published
2023

9. Inoculation of raccoons with a wild-type-based recombinant canine distemper virus results in viremia, lymphopenia, fever, and widespread histological lesions

Author

VPDC pathologie, Pathology, Roelofs, Dagmar, Schmitz, Katharina S, van Amerongen, Geert, Rijsbergen, Laurine C, Laksono, Brigitta M, Comvalius, Anouskha D, Nambulli, Sham, Rennick, Linda J, van Run, Peter, Duprex, W Paul, van den Brand, Judith M A, de Swart, Rik L, de Vries, Rory D, VPDC pathologie, Pathology, Roelofs, Dagmar, Schmitz, Katharina S, van Amerongen, Geert, Rijsbergen, Laurine C, Laksono, Brigitta M, Comvalius, Anouskha D, Nambulli, Sham, Rennick, Linda J, van Run, Peter, Duprex, W Paul, van den Brand, Judith M A, de Swart, Rik L, and de Vries, Rory D

Published
2023

10. Targeting Spike Glycans to Inhibit SARS-CoV2 Viral Entry

Author

Guseman, Alex J., primary, Rennick, Linda J., additional, Nambulli, Sham, additional, Roy, Chandra N., additional, Martinez, David R., additional, Yang, Darian T., additional, Bhinderwhala, Fatema, additional, Vergara, Sandra, additional, Baric, Ralph S., additional, Ambrose, Zandrea, additional, Duprex, W. Paul, additional, and Gronenborn, Angela M., additional

Published
2022
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11. FeMV is a cathepsin-dependent unique morbillivirus infecting the kidneys of domestic cats

Author

Nambulli, Sham, primary, Rennick, Linda J., additional, Acciardo, Andrew S., additional, Tilston-Lunel, Natasha L., additional, Ho, Gregory, additional, Crossland, Nicholas A., additional, Hardcastle, Kathy, additional, Nieto, Betsy, additional, Bainbridge, Graeme, additional, Williams, Tracey, additional, Sharp, Claire R., additional, and Duprex, W. Paul, additional

Published
2022
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12. Measles and Nipah virus assembly: Specific lipid binding drives matrix polymerization

Author

Norris, Michael J., primary, Husby, Monica L., additional, Kiosses, William B., additional, Yin, Jieyun, additional, Saxena, Roopashi, additional, Rennick, Linda J., additional, Heiner, Anja, additional, Harkins, Stephanie S., additional, Pokhrel, Rudramani, additional, Schendel, Sharon L., additional, Hastie, Kathryn M., additional, Landeras-Bueno, Sara, additional, Salie, Zhe Li, additional, Lee, Benhur, additional, Chapagain, Prem P., additional, Maisner, Andrea, additional, Duprex, W. Paul, additional, Stahelin, Robert V., additional, and Saphire, Erica Ollmann, additional

Published
2022
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14. Sustained Replication of Synthetic Canine Distemper Virus Defective Genomes In Vitro and In Vivo

Author

Tilston-Lunel, Natasha L., primary, Welch, Stephen R., additional, Nambulli, Sham, additional, de Vries, Rory D., additional, Ho, Gregory W., additional, Wentworth, David E., additional, Shabman, Reed, additional, Nichol, Stuart T., additional, Spiropoulou, Christina F., additional, de Swart, Rik L., additional, Rennick, Linda J., additional, and Duprex, W. Paul, additional

Published
2021
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15. Molecular assembly of measles and Nipah virus: specific lipid binding drives conformational change and matrix polymerization

Author

Norris, Michael J., primary, Husby, Monica L., additional, Kiosses, William B., additional, Yin, Jieyun, additional, Rennick, Linda J., additional, Heiner, Anja, additional, Harkins, Stephanie, additional, Pokhrel, Rudramani, additional, Schendel, Sharon L., additional, Hastie, Kathryn M., additional, Landeras-Bueno, Sara, additional, Salie, Zhe Li, additional, Lee, Benhur, additional, Chapagain, Prem P., additional, Maisner, Andrea, additional, Duprex, W Paul, additional, Stahelin, Robert V., additional, and Saphire, Erica Ollmann, additional

Published
2021
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17. Memory B cell repertoire for recognition of evolving SARS-CoV-2 spike

Author

Tong, Pei, primary, Gautam, Avneesh, additional, Windsor, Ian W., additional, Travers, Meghan, additional, Chen, Yuezhou, additional, Garcia, Nicholas, additional, Whiteman, Noah B., additional, McKay, Lindsay G.A., additional, Storm, Nadia, additional, Malsick, Lauren E., additional, Honko, Anna N., additional, Lelis, Felipe J.N., additional, Habibi, Shaghayegh, additional, Jenni, Simon, additional, Cai, Yongfei, additional, Rennick, Linda J., additional, Duprex, W. Paul, additional, McCarthy, Kevin R., additional, Lavine, Christy L., additional, Zuo, Teng, additional, Lin, Junrui, additional, Zuiani, Adam, additional, Feldman, Jared, additional, MacDonald, Elizabeth A., additional, Hauser, Blake M., additional, Griffths, Anthony, additional, Seaman, Michael S., additional, Schmidt, Aaron G., additional, Chen, Bing, additional, Neuberg, Donna, additional, Bajic, Goran, additional, Harrison, Stephen C., additional, and Wesemann, Duane R., additional

Published
2021
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18. Sustained replication of synthetic canine distemper virus defective genomes in vitro and in vivo

Author

Tilston-Lunel, Natasha L., Welch, Stephen R., Nambulli, Sham, De Vries, Rory D., Ho, Gregory W., Wentworth, David E., Shabman, Reed, Nichol, Stuart T., Spiropoulou, Christina F., De Swart, Rik L., Rennick, Linda J., Paul Duprex, W., Tilston-Lunel, Natasha L., Welch, Stephen R., Nambulli, Sham, De Vries, Rory D., Ho, Gregory W., Wentworth, David E., Shabman, Reed, Nichol, Stuart T., Spiropoulou, Christina F., De Swart, Rik L., Rennick, Linda J., and Paul Duprex, W.

Abstract

Defective interfering (DI) genomes restrict viral replication and induce type I interferon. Since DI genomes have been proposed as vaccine adjuvants or therapeutic antiviral agents, it is important to understand their generation, delineate their mechanism of action, develop robust production capacities, assess their safety and in vivo longevity, and determine their long-term effects. To address this, we generated a recombinant canine distemper virus (rCDV) from an entirely synthetic molecular clone designed using the genomic sequence from a clinical isolate obtained from a free-ranging raccoon with distemper. rCDV was serially passaged in vitro to identify DI genomes that naturally arise during rCDV replication. Defective genomes were identified by Sanger and next-generation sequencing techniques, and predominant genomes were synthetically generated and cloned into T7-driven plasmids. Fully encapsidated DI particles (DIPs) were then generated using a rationally attenuated rCDV as a producer virus to drive DI genome replication. We demonstrate that these DIPs interfere with rCDV replication in a dose-dependent manner in vitro. Finally, we show sustained replication of a fluorescent DIP in experimentally infected ferrets over a period of 14 days. Most importantly, DIPs were isolated from the lymphoid tissues, which are a major site of CDV replication. Our established pipeline for detection, generation, and assaying DIPs is transferable to highly pathogenic paramyxoviruses and will allow qualitative and quantitative assessment of the therapeutic effects of DIP administration on disease outcome.

Published
2021

22. Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study

Author

Hensley, Matthew K, primary, Bain, William G, additional, Jacobs, Jana, additional, Nambulli, Sham, additional, Parikh, Urvi, additional, Cillo, Anthony, additional, Staines, Brittany, additional, Heaps, Amy, additional, Sobolewski, Michele D, additional, Rennick, Linda J, additional, Macatangay, Bernard J C, additional, Klamar-Blain, Cynthia, additional, Kitsios, Georgios D, additional, Methé, Barbara, additional, Somasundaram, Ashwin, additional, Bruno, Tullia C, additional, Cardello, Carly, additional, Shan, Feng, additional, Workman, Creg, additional, Ray, Prabir, additional, Ray, Anuradha, additional, Lee, Janet, additional, Sethi, Rahil, additional, Schwarzmann, William E, additional, Ladinsky, Mark S, additional, Bjorkman, Pamela J, additional, Vignali, Dario A, additional, Duprex, W Paul, additional, Agha, Mounzer E, additional, Mellors, John W, additional, McCormick, Kevin D, additional, Morris, Alison, additional, and Haidar, Ghady, additional

Published
2021
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25. SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected hospitalized COVID-19 patients

Author

Klimstra, William B., primary, Tilston-Lunel, Natasha L., additional, Nambulli, Sham, additional, Boslett, James, additional, McMillen, Cynthia M., additional, Gilliland, Theron, additional, Dunn, Matthew D., additional, Sun, Chengun, additional, Wheeler, Sarah E., additional, Wells, Alan, additional, Hartman, Amy L., additional, McElroy, Anita K., additional, Reed, Douglas S., additional, Rennick, Linda J., additional, and Duprex, W. Paul, additional

Published
2020
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28. Comparative Loss-of-Function Screens Reveal ABCE1 as an Essential Cellular Host Factor for Efficient Translation of Paramyxoviridae and Pneumoviridae

Author

Anderson, Danielle E., primary, Pfeffermann, Kristin, additional, Kim, So Young, additional, Sawatsky, Bevan, additional, Pearson, James, additional, Kovtun, Mikhail, additional, Corcoran, David L., additional, Krebs, Yvonne, additional, Sigmundsson, Kristmundur, additional, Jamison, Sharon F., additional, Yeo, Zhen Zhen Joanna, additional, Rennick, Linda J., additional, Wang, Lin-Fa, additional, Talbot, Pierre J., additional, Duprex, W. Paul, additional, Garcia-Blanco, Mariano A., additional, and von Messling, Veronika, additional

Published
2019
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29. Delineating morbillivirus entry, dissemination and airborne transmission by studying in vivo competition of multicolor canine distemper viruses in ferrets

Author

de Vries, Rory D., primary, Ludlow, Martin, additional, de Jong, Alwin, additional, Rennick, Linda J., additional, Verburgh, R. Joyce, additional, van Amerongen, Geert, additional, van Riel, Debby, additional, van Run, Peter R. W. A., additional, Herfst, Sander, additional, Kuiken, Thijs, additional, Fouchier, Ron A. M., additional, Osterhaus, Albert D. M. E., additional, de Swart, Rik L., additional, and Duprex, W. Paul, additional

Published
2017
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31. Recombinant Subgroup B Human Respiratory Syncytial Virus Expressing Enhanced Green Fluorescent Protein Efficiently Replicates in Primary Human Cells and Is Virulent in Cotton Rats

Author

Lemon, Ken, primary, Nguyen, D. Tien, additional, Ludlow, Martin, additional, Rennick, Linda J., additional, Yüksel, Selma, additional, van Amerongen, Geert, additional, McQuaid, Stephen, additional, Rima, Bert K., additional, de Swart, Rik L., additional, and Duprex, W. Paul, additional

Published
2015
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32. Live-Attenuated Measles Virus Vaccine Targets Dendritic Cells and Macrophages in Muscle of Nonhuman Primates

Author

Rennick, Linda J., primary, de Vries, Rory D., additional, Carsillo, Thomas J., additional, Lemon, Ken, additional, van Amerongen, Geert, additional, Ludlow, Martin, additional, Nguyen, D. Tien, additional, Yüksel, Selma, additional, Verburgh, R. Joyce, additional, Haddock, Paula, additional, McQuaid, Stephen, additional, Duprex, W. Paul, additional, and de Swart, Rik L., additional

Published
2015
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37. Inactivation of RNA Viruses by Gamma Irradiation: A Study on Mitigating Factors.

Author

Hume, Adam J., Ames, Joshua, Rennick, Linda J., Duprex, W. Paul, Marzi, Andrea, Tonkiss, John, and Mühlberger, Elke

Subjects
RNA viruses, BIOSAFETY, PATHOGENIC microorganisms, VIRION, RECOMBINANT viruses, FLUORESCENT proteins
Abstract

Effective inactivation of biosafety level 4 (BSL-4) pathogens is vital in order to study these agents safely. Gamma irradiation is a commonly used method for the inactivation of BSL-4 viruses, which among other advantages, facilitates the study of inactivated yet morphologically intact virions. The reported values for susceptibility of viruses to inactivation by gamma irradiation are sometimes inconsistent, likely due to differences in experimental protocols. We analyzed the effects of common sample attributes on the inactivation of a recombinant vesicular stomatitis virus expressing the Zaire ebolavirus glycoprotein and green fluorescent protein. Using this surrogate virus, we found that sample volume and protein content of the sample modulated viral inactivation by gamma irradiation but that air volume within the sample container and the addition of external disinfectant surrounding the sample did not. These data identify several factors which alter viral susceptibility to inactivation and highlight the usefulness of lower biosafety level surrogate viruses for such studies. Our results underscore the need to validate inactivation protocols of BSL-4 pathogens using “worst-case scenario” procedures to ensure complete sample inactivation. [ABSTRACT FROM AUTHOR]

Published
2016
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38. Early Target Cells of Measles Virus after Aerosol Infection of Non-Human Primates

Author

Lemon, Ken, primary, de Vries, Rory D., additional, Mesman, Annelies W., additional, McQuaid, Stephen, additional, van Amerongen, Geert, additional, Yüksel, Selma, additional, Ludlow, Martin, additional, Rennick, Linda J., additional, Kuiken, Thijs, additional, Rima, Bertus K., additional, Geijtenbeek, Teunis B. H., additional, Osterhaus, Albert D. M. E., additional, Duprex, W. Paul, additional, and de Swart, Rik L., additional

Published
2011
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41. Determination of Spontaneous Mutation Frequencies in Measles Virus under Nonselective Conditions.

Author

Xiaomeng Zhang, Rennick, Linda J., Duprex, W. Paul, and Rima, Bert K.

Subjects
*MEASLES, *MONOCLONAL antibodies, *GENETIC mutation, *GREEN fluorescent protein, *TRANSCRIPTION factors
Abstract

There is a paradox between the remarkable genetic stability of measles virus (MV) in the field and the high mutation rates implied by the frequency of the appearance of monoclonal antibody escape mutants generated when the virus is pressured to revert in vitro (S. J. Schrag, P. A. Rota, and W. J. Bellini, J. Virol. 73:51-54, 1999). We established a highly sensitive assay to determine frequencies of various categories of mutations in large populations of wild-type and laboratory-adapted MVs using recombinant viruses containing an additional transcription unit (ATU) encoding enhanced green fluorescent protein (EGFP). Single and double mutations were made in the fluorophore of EGFP to ablate fluorescence. The frequencies of reversion mutants in the population were determined by measuring the appearance of fluorescence indicating a revertant virus. This allows mutation rates to be measured under nonselective conditions, as phenotypic reversion to fluorescence requires only either a single- or a double-nucleotide change and amino acid substitution, which does not affect the length of the nonessential reporter protein expressed from the ATU. Mutation rates in MV are the same for wild-type and laboratory-adapted viruses, and they are an order of magnitude lower than the previous measurement assessed under selective conditions. The actual mutation rate for MV is approximately 1.8 x 10-6 per base per replication event. [ABSTRACT FROM AUTHOR]

Published
2013
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42. Comparative Loss-of-Function Screens Reveal ABCE1 as an Essential Cellular Host Factor for Efficient Translation of Paramyxoviridaeand Pneumoviridae

Author

Anderson, Danielle E., Pfeffermann, Kristin, Kim, So Young, Sawatsky, Bevan, Pearson, James, Kovtun, Mikhail, Corcoran, David L., Krebs, Yvonne, Sigmundsson, Kristmundur, Jamison, Sharon F., Yeo, Zhen Zhen Joanna, Rennick, Linda J., Wang, Lin-Fa, Talbot, Pierre J., Duprex, W. Paul, Garcia-Blanco, Mariano A., and von Messling, Veronika

Abstract

The Paramyxoviridaeand Pneumoviridaefamilies include important human and animal pathogens. To identify common host factors, we performed genome-scale siRNA screens with wild-type-derived measles, mumps, and respiratory syncytial viruses in the same cell line. A comparative bioinformatics analysis yielded different members of the coatomer complex I, translation factors ABCE1 and eIF3A, and several RNA binding proteins as cellular proteins with proviral activity for all three viruses. A more detailed characterization of ABCE1 revealed its essential role for viral protein synthesis. Taken together, these data sets provide new insight into the interactions between paramyxoviruses and pneumoviruses and host cell proteins and constitute a starting point for the development of broadly effective antivirals.

Published
2019
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43. Generation of Defective Interfering Particles of Morbilliviruses Using Reverse Genetics.

Author

Rennick LJ, Duprex WP, and Tilston-Lunel NL

Subjects
Animals, Humans, Virion genetics, Vero Cells, Chlorocebus aethiops, RNA, Viral genetics, Reverse Genetics methods, Defective Viruses genetics, Virus Replication genetics, Genome, Viral, Morbillivirus genetics
Abstract

RNA viruses generate defective genomes naturally during virus replication. Defective genomes that interfere with the infection dynamics either through resource competition or by interferon stimulation are known as defective interfering (DI) genomes. DI genomes can be successfully packaged into virus-like-particles referred to as defective interfering particles (DIPs). Such DIPs can sustainably coexist with the full-length virus particles and have been shown to negatively impact virus replication in vitro and in vivo. Here, we describe a method to generate a clonal DI genome population by reverse genetics. This method is applicable to other RNA viruses and will enable assessment of DIPs for their antiviral properties., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2024
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44. Targeting Spike Glycans to Inhibit SARS-CoV2 Viral Entry.

Author

Guseman AJ, Rennick LJ, Nambulli S, Roy CN, Martinez DR, Yang DT, Bhinderwhala F, Vergara S, Baric RS, Ambrose Z, Duprex WP, and Gronenborn AM

Abstract

SARS-CoV-2 Spike harbors glycans which function as ligands for lectins. Therefore, it should be possible to exploit lectins to target SARS-CoV-2 and inhibit cellular entry by binding glycans on the Spike protein. Burkholderia oklahomensis agglutinin (BOA) is an antiviral lectin that interacts with viral glycoproteins via N-linked high mannose glycans. Here, we show that BOA binds to the Spike protein and is a potent inhibitor of SARS-CoV-2 viral entry at nanomolar concentrations. Using a variety of biophysical tools, we demonstrate that the interaction is avidity driven and that BOA crosslinks the Spike protein into soluble aggregates. Furthermore, using virus neutralization assays, we demonstrate that BOA effectively inhibits all tested variants of concern as well as SARS-CoV 2003, establishing that glycan-targeting molecules have the potential to be pan-coronavirus inhibitors.

Published
2022
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45. Memory B cell repertoire for recognition of evolving SARS-CoV-2 spike.

Author

Tong P, Gautam A, Windsor I, Travers M, Chen Y, Garcia N, Whiteman NB, McKay LGA, Lelis FJN, Habibi S, Cai Y, Rennick LJ, Duprex WP, McCarthy KR, Lavine CL, Zuo T, Lin J, Zuiani A, Feldman J, MacDonald EA, Hauser BM, Griffths A, Seaman MS, Schmidt AG, Chen B, Neuberg D, Bajic G, Harrison SC, and Wesemann DR

Abstract

Memory B cell reserves can generate protective antibodies against repeated SARS-CoV-2 infections, but with an unknown reach from original infection to antigenically drifted variants. We charted memory B cell receptor-encoded monoclonal antibodies (mAbs) from 19 COVID-19 convalescent subjects against SARS-CoV-2 spike (S) and found 7 major mAb competition groups against epitopes recurrently targeted across individuals. Inclusion of published and newly determined structures of mAb-S complexes identified corresponding epitopic regions. Group assignment correlated with cross-CoV-reactivity breadth, neutralization potency, and convergent antibody signatures. mAbs that competed for binding the original S isolate bound differentially to S variants, suggesting the protective importance of otherwise-redundant recognition. The results furnish a global atlas of the S-specific memory B cell repertoire and illustrate properties conferring robustness against emerging SARS-CoV-2 variants., Competing Interests: Competing interests The authors declare no competing interests.

Published
2021
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46. Inhalable Nanobody (PiN-21) prevents and treats SARS-CoV-2 infections in Syrian hamsters at ultra-low doses.

Author

Nambulli S, Xiang Y, Tilston-Lunel NL, Rennick LJ, Sang Z, Klimstra WB, Reed DS, Crossland NA, Shi Y, and Duprex WP

Abstract

Globally there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 (COVID-19). We previously generated the stable and ultrapotent homotrimeric Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate to severe COVID-19 disease, we demonstrate the high efficacy of PiN-21 to prevent and treat SARS-CoV-2 infection. Intranasal delivery of PiN-21 at 0.6 mg/kg protects infected animals from weight loss and substantially reduces viral burdens in both lower and upper airways compared to control. Aerosol delivery of PiN-21 facilitates deposition throughout the respiratory tract and dose minimization to 0.2 mg/kg. Inhalation treatment quickly reverses animals' weight loss post-infection and decreases lung viral titers by 6 logs leading to drastically mitigated lung pathology and prevents viral pneumonia. Combined with the marked stability and low production cost, this novel therapy may provide a convenient and cost-effective option to mitigate the ongoing pandemic.

Published
2021
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47. SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 patients.

Author

Klimstra WB, Tilston-Lunel NL, Nambulli S, Boslett J, McMillen CM, Gilliland T, Dunn MD, Sun C, Wheeler SE, Wells A, Hartman AL, McElroy AK, Reed DS, Rennick LJ, and Duprex WP

Abstract

SARS-CoV-2, the causative agent of COVID-19, emerged at the end of 2019 and by mid-June 2020, the virus has spread to at least 215 countries, caused more than 8,000,000 confirmed infections and over 450,000 deaths, and overwhelmed healthcare systems worldwide. Like SARS-CoV, which emerged in 2002 and caused a similar disease, SARS-CoV-2 is a betacoronavirus. Both viruses use human angiotensin-converting enzyme 2 (hACE2) as a receptor to enter cells. However, the SARS-CoV-2 spike (S) glycoprotein has a novel insertion that generates a putative furin cleavage signal and this has been postulated to expand the host range. Two low passage (P) strains of SARS-CoV-2 (Wash1: P4 and Munich: P1) were cultured twice in Vero-E6 cells and characterized virologically. Sanger and MinION sequencing demonstrated significant deletions in the furin cleavage signal of Wash1: P6 and minor variants in the Munich: P3 strain. Cleavage of the S glycoprotein in SARS-CoV-2-infected Vero-E6 cell lysates was inefficient even when an intact furin cleavage signal was present. Indirect immunofluorescence demonstrated the S glycoprotein reached the cell surface. Since the S protein is a major antigenic target for the development of neutralizing antibodies we investigated the development of neutralizing antibody titers in serial serum samples obtained from COVID-19 human patients. These were comparable regardless of the presence of an intact or deleted furin cleavage signal. These studies illustrate the need to characterize virus stocks meticulously prior to performing either in vitro or in vivo pathogenesis studies.

Published
2020
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48. Paramyxovirus Infections in Ex Vivo Lung Slice Cultures of Different Host Species.

Author

De Vries RD, Rennick LJ, Duprex WP, and De Swart RL

Abstract

In vivo experiments in animal models of disease are of crucial importance for viral tropism and pathogenesis studies. However, these experiments must be complemented with in vitro and ex vivo experiments. Here, we describe a protocol for the preparation and ex vivo infection of lung slices from different mammalian host species with various respiratory paramyxoviruses expressing fluorescent reporter proteins, and suggest follow-up experiments including immunohistochemistry, flow cytometry and confocal microscopy., Competing Interests: The authors declare no conflict of interest.

Published
2018
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49. Wild-type measles virus infection of primary epithelial cells occurs via the basolateral surface without syncytium formation or release of infectious virus.

Author

Ludlow M, Rennick LJ, Sarlang S, Skibinski G, McQuaid S, Moore T, de Swart RL, and Duprex WP

Subjects
Animals, Bronchi virology, Cells, Cultured, Chlorocebus aethiops, Epithelial Cells virology, Green Fluorescent Proteins, Humans, Macaca, Membrane Cofactor Protein physiology, Vero Cells, Virus Internalization, Giant Cells physiology, Measles virus physiology, Virus Release
Abstract

The lymphotropic and myelotropic nature of wild-type measles virus (wt-MV) is well recognized, with dendritic cells and lymphocytes expressing the MV receptor CD150 mediating systemic spread of the virus. Infection of respiratory epithelial cells has long been considered crucial for entry of MV into the body. However, the lack of detectable CD150 on these cells raises the issue of their importance in the pathogenesis of measles. This study utilized a combination of in vitro, ex vivo and in vivo model systems to characterize the susceptibility of epithelial cells to wt-MV of proven pathogenicity. Low numbers of MV-infected epithelial cells in close proximity to underlying infected lymphocytes or myeloid cells suggested infection via the basolateral side of the epithelium in the macaque model. In primary cultures of human bronchial epithelial cells, foci of MV-infected cells were only observed following infection via the basolateral cell surface. The extent of infection in primary cells was enhanced both in vitro and in ex vivo cornea rim tissue by disrupting the integrity of the cells prior to the application of virus. This demonstrated that, whilst epithelial cells may not be the primary target cells for wt-MV, areas of epithelium in which tight junctions are disrupted can become infected using high m.o.i. The low numbers of MV-infected epithelial cells observed in vivo in conjunction with the absence of infectious virus release from infected primary cell cultures suggest that epithelial cells have a peripheral role in MV transmission.

Published
2010
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