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1. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Author

Aguado, Julio, Amarilla, Alberto A., Taherian Fard, Atefeh, Albornoz, Eduardo A., Tyshkovskiy, Alexander, Schwabenland, Marius, Chaggar, Harman K., Modhiran, Naphak, Gómez-Inclán, Cecilia, Javed, Ibrahim, Baradar, Alireza A., Liang, Benjamin, Peng, Lianli, Dharmaratne, Malindrie, Pietrogrande, Giovanni, Padmanabhan, Pranesh, Freney, Morgan E., Parry, Rhys, Sng, Julian D. J., Isaacs, Ariel, Khromykh, Alexander A., Valenzuela Nieto, Guillermo, Rojas-Fernandez, Alejandro, Davis, Thomas P., Prinz, Marco, Bengsch, Bertram, Gladyshev, Vadim N., Woodruff, Trent M., Mar, Jessica C., Watterson, Daniel, and Wolvetang, Ernst J.

Published
2023
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2. SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein

Author

Albornoz, Eduardo A., Amarilla, Alberto A., Modhiran, Naphak, Parker, Sandra, Li, Xaria X., Wijesundara, Danushka K., Aguado, Julio, Zamora, Adriana Pliego, McMillan, Christopher L. D., Liang, Benjamin, Peng, Nias Y. G., Sng, Julian D. J., Saima, Fatema Tuj, Fung, Jenny N., Lee, John D., Paramitha, Devina, Parry, Rhys, Avumegah, Michael S., Isaacs, Ariel, Lo, Martin W., Miranda-Chacon, Zaray, Bradshaw, Daniella, Salinas-Rebolledo, Constanza, Rajapakse, Niwanthi W., Wolvetang, Ernst J., Munro, Trent P., Rojas-Fernandez, Alejandro, Young, Paul R., Stacey, Katryn J., Khromykh, Alexander A., Chappell, Keith J., Watterson, Daniel, and Woodruff, Trent M.

Published
2023
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3. Long-term safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2 in adults aged 18–55 years or ≥56 years: 12-month results from a randomised, double-blind, placebo-controlled, phase 1 trial

Author

Chappell, Keith J., Mordant, Francesca L., Amarilla, Alberto A., Modhiran, Naphak, Liang, Benjamin, Li, Zheyi, Wijesundara, Danushka K., Lackenby, Julia A., Griffin, Paul, Bennet, Jillian K., Hensen, Luca, Zhang, Wuji, Nguyen, Thi H.O., Tran, Mai H., Tapley, Peter, Barnes, James, Reading, Patrick C., Kedzierska, Katherine, Ranasinghe, Charani, Subbarao, Kanta, Watterson, Daniel, Young, Paul R., and Munro, Trent P.

Published
2023
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4. A nanobody recognizes a unique conserved epitope and potently neutralizes SARS-CoV-2 omicron variants

Author

Modhiran, Naphak, Lauer, Simon Malte, Amarilla, Alberto A., Hewins, Peter, Lopes van den Broek, Sara Irene, Low, Yu Shang, Thakur, Nazia, Liang, Benjamin, Nieto, Guillermo Valenzuela, Jung, James, Paramitha, Devina, Isaacs, Ariel, Sng, Julian D.J., Song, David, Jørgensen, Jesper Tranekjær, Cheuquemilla, Yorka, Bürger, Jörg, Andersen, Ida Vang, Himelreichs, Johanna, Jara, Ronald, MacLoughlin, Ronan, Miranda-Chacon, Zaray, Chana-Cuevas, Pedro, Kramer, Vasko, Spahn, Christian, Mielke, Thorsten, Khromykh, Alexander A., Munro, Trent, Jones, Martina L., Young, Paul R., Chappell, Keith, Bailey, Dalan, Kjaer, Andreas, Herth, Matthias Manfred, Jurado, Kellie Ann, Schwefel, David, Rojas-Fernandez, Alejandro, and Watterson, Daniel

Published
2023
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6. Dynamin independent endocytosis is an alternative cell entry mechanism for multiple animal viruses.

Author

Ojha, Ravi, Jiang, Anmin, Mäntylä, Elina, Quirin, Tania, Modhira, Naphak, Witte, Robert, Gaudin, Arnaud, De Zanetti, Lisa, Gormal, Rachel Sarah, Vihinen-Ranta, Maija, Mercer, Jason, Suomalainen, Maarit, Greber, Urs F., Yamauchi, Yohei, Lozach, Pierre-Yves, Helenius, Ari, Vapalahti, Olli, Young, Paul, Watterson, Daniel, and Meunier, Frédéric A.

Abstract

Mammalian receptor-mediated endocytosis (RME) often involves at least one of three isoforms of the large GTPase dynamin (Dyn). Dyn pinches-off vesicles at the plasma membrane and mediates uptake of many viruses, although some viruses directly penetrate the plasma membrane. RME is classically interrogated by genetic and pharmacological interference, but this has been hampered by undesired effects. Here we studied virus entry in conditional genetic knock-out (KO) mouse embryonic fibroblasts lacking expression of all three dynamin isoforms (Dyn-KO-MEFs). The small canine parvovirus known to use a single receptor, transferrin receptor, strictly depended on dynamin. Larger viruses or viruses known to use multiple receptors, including alphaviruses, influenza, vesicular stomatitis, bunya, adeno, vaccinia, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and rhinoviruses infected Dyn-KO-MEFs, albeit at higher dosage than wild-type MEFs. In absence of the transmembrane protease serine subtype 2 (TMPRSS2), which normally activates the SARS-CoV-2 spike protein for plasma membrane fusion, SARS-CoV-2 infected angiotensin-converting enzyme 2 (ACE2)-expressing MEFs predominantly through dynamin- and actin-dependent endocytosis. In presence of TMPRSS2 the ancestral Wuhan-strain bypassed both dynamin-dependent and -independent endocytosis, and was less sensitive to endosome maturation inhibitors than the Omicron B1 and XBB variants, supporting the notion that the Omicron variants do not efficiently use TMPRSS2. Collectively, our study suggests that dynamin function at endocytic pits can be essential for infection with single-receptor viruses, while it is not essential but increases uptake and infection efficiency of multi-receptor viruses that otherwise rely on a functional actin network for infection. Author summary: To initiate their infection cycle, most viruses first need to enter their target cells, a process called endocytosis. In mammalian cells, endocytosis often involves a class of proteins called dynamins. While numerous viruses, including SARS-CoV-2, efficiently infect cells by dynamin-mediated endocytosis we found that in the absence of these proteins an alternative cell entry mechanism exists, allowing multiple pathogenic human viruses to enter and infect cells. Unlike the dynamin-mediated infection, the efficient internalization of viral particles via dynamin-independent endocytosis seems to always require functional actin fibers, which are structural components of the cell contractile cytoskeleton. Thus, multiple viruses can infect their target cells using at last two entry mechanisms, inhibiting both may provide effective antiviral therapies. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial

Author

Chappell, Keith J, Mordant, Francesca L, Li, Zheyi, Wijesundara, Danushka K, Ellenberg, Paula, Lackenby, Julia A, Cheung, Stacey T M, Modhiran, Naphak, Avumegah, Michael S, Henderson, Christina L, Hoger, Kym, Griffin, Paul, Bennet, Jillian, Hensen, Luca, Zhang, Wuji, Nguyen, Thi H O, Marrero-Hernandez, Sara, Selva, Kevin J, Chung, Amy W, Tran, Mai H, Tapley, Peter, Barnes, James, Reading, Patrick C, Nicholson, Suellen, Corby, Stavroula, Holgate, Thomas, Wines, Bruce D, Hogarth, P Mark, Kedzierska, Katherine, Purcell, Damian F J, Ranasinghe, Charani, Subbarao, Kanta, Watterson, Daniel, Young, Paul R, and Munro, Trent P

Published
2021
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10. Antiviral Activities of Heparan Sulfate Mimetic RAFT Polymers Against Mosquito-borne Viruses

Author

Nahain, Abdullah Al, Li, Jinlin, Modhiran, Naphak, Watterson, Daniel, Li, Jin-Ping, Ignjatovic, Vera, Monagle, Paul, Tsanaktsidis, John, Vamvounis, George, Ferro, Vito, Nahain, Abdullah Al, Li, Jinlin, Modhiran, Naphak, Watterson, Daniel, Li, Jin-Ping, Ignjatovic, Vera, Monagle, Paul, Tsanaktsidis, John, Vamvounis, George, and Ferro, Vito

Abstract

Mosquito-borne viruses are a major worldwide health problem associated with high morbidity and mortality rates and significant impacts on national healthcare budgets. The development of antiviral drugs for both the treatment and prophylaxis of these diseases is thus of considerable importance. To address the need for therapeutics with antiviral activity, a library of heparan sulfate mimetic polymers was screened against dengue virus (DENV), Yellow fever virus (YFV), Zika virus (ZIKV), and Ross River virus (RRV). The polymers were prepared by RAFT polymerization of various acidic monomers with a target MW of 20 kDa (average Mn ∼ 27 kDa by GPC). Among the polymers, poly(SS), a homopolymer of sodium styrenesulfonate, was identified as a broad spectrum antiviral with activity against all the tested viruses and particularly potent inhibition of YFV (IC50 = 310 pM). Our results further uncovered that poly(SS) exhibited a robust inhibition of ZIKV infection in both mosquito and human cell lines, which points out the potential functions of poly(SS) in preventing mosquito-borne viruses associated diseases by blocking viral transmission in their mosquito vectors and mitigating viral infection in patients.

Published
2024
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11. Amphiphilic Heparinoids as Potent Antiviral Agents against SARS-CoV‑2.

Author

Chhabra, Mohit, Shanthamurthy, Chethan D., Kumar, Nanjudaswamy Vijendra, Mardhekar, Sandhya, Vishweshwara, Sharath S., Wimmer, Norbert, Modhiran, Naphak, Watterson, Daniel, Amarilla, Alberto A., Cha, Jonathan S., Beckett, James R., De Voss, James J., Kayal, Yasmin, Vlodavsky, Israel, Dorsett, Lauren R., Smith, Raymond A. A., Gandhi, Neha S., Kikkeri, Raghavendra, and Ferro, Vito

Published
2024
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16. Systems serology detects functionally distinct coronavirus antibody features in children and elderly

Author

Selva, Kevin J., van de Sandt, Carolien E., Lemke, Melissa M., Lee, Christina Y., Shoffner, Suzanne K., Chua, Brendon Y., Davis, Samantha K., Nguyen, Thi H. O., Rowntree, Louise C., Hensen, Luca, Koutsakos, Marios, Wong, Chinn Yi, Mordant, Francesca, Jackson, David C., Flanagan, Katie L., Crowe, Jane, Tosif, Shidan, Neeland, Melanie R., Sutton, Philip, Licciardi, Paul V., Crawford, Nigel W., Cheng, Allen C., Doolan, Denise L., Amanat, Fatima, Krammer, Florian, Chappell, Keith, Modhiran, Naphak, Watterson, Daniel, Young, Paul, Lee, Wen Shi, Wines, Bruce D., Mark Hogarth, P., Esterbauer, Robyn, Kelly, Hannah G., Tan, Hyon-Xhi, Juno, Jennifer A., Wheatley, Adam K., Kent, Stephen J., Arnold, Kelly B., Kedzierska, Katherine, and Chung, Amy W.

Published
2021
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17. A versatile reverse genetics platform for SARS-CoV-2 and other positive-strand RNA viruses

Author

Amarilla, Alberto A., Sng, Julian D. J., Parry, Rhys, Deerain, Joshua M., Potter, James R., Setoh, Yin Xiang, Rawle, Daniel J., Le, Thuy T., Modhiran, Naphak, Wang, Xiaohui, Peng, Nias Y. G., Torres, Francisco J., Pyke, Alyssa, Harrison, Jessica J., Freney, Morgan E., Liang, Benjamin, McMillan, Christopher L. D., Cheung, Stacey T. M., Guevara, Darwin J. Da Costa, Hardy, Joshua M., Bettington, Mark, Muller, David A., Coulibaly, Fasséli, Moore, Frederick, Hall, Roy A., Young, Paul R., Mackenzie, Jason M., Hobson-Peters, Jody, Suhrbier, Andreas, Watterson, Daniel, and Khromykh, Alexander A.

Published
2021
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18. Potent neutralization of clinical isolates of SARS-CoV-2 D614 and G614 variants by a monomeric, sub-nanomolar affinity nanobody

Author

Valenzuela Nieto, Guillermo, Jara, Ronald, Watterson, Daniel, Modhiran, Naphak, Amarilla, Alberto A., Himelreichs, Johanna, Khromykh, Alexander A., Salinas-Rebolledo, Constanza, Pinto, Teresa, Cheuquemilla, Yorka, Margolles, Yago, López González del Rey, Natalia, Miranda-Chacon, Zaray, Cuevas, Alexei, Berking, Anne, Deride, Camila, González-Moraga, Sebastián, Mancilla, Héctor, Maturana, Daniel, Langer, Andreas, Toledo, Juan Pablo, Müller, Ananda, Uberti, Benjamín, Krall, Paola, Ehrenfeld, Pamela, Blesa, Javier, Chana-Cuevas, Pedro, Rehren, German, Schwefel, David, Fernandez, Luis Ángel, and Rojas-Fernandez, Alejandro

Published
2021
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19. Plugging the Leak in Dengue Shock

Author

Watterson, Daniel, Modhiran, Naphak, Muller, David A., Stacey, Katryn J., Young, Paul R., COHEN, IRUN R., Series Editor, LAJTHA, ABEL, Series Editor, LAMBRIS, JOHN D., Series Editor, PAOLETTI, RODOLFO, Series Editor, REZAEI, NIMA, Series Editor, Hilgenfeld, Rolf, editor, and Vasudevan, Subhash G., editor

Published
2018
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22. Determinants of Zika virus host tropism uncovered by deep mutational scanning

Author

Setoh, Yin Xiang, Amarilla, Alberto A., Peng, Nias Y. G., Griffiths, Rebecca E., Carrera, Julio, Freney, Morgan E., Nakayama, Eri, Ogawa, Shinya, Watterson, Daniel, Modhiran, Naphak, Nanyonga, Faith Elizabeth, Torres, Francisco J., Slonchak, Andrii, Periasamy, Parthiban, Prow, Natalie A., Tang, Bing, Harrison, Jessica, Hobson-Peters, Jody, Cuddihy, Thom, Cooper-White, Justin, Hall, Roy A., Young, Paul R., Mackenzie, Jason M., Wolvetang, Ernst, Bloom, Jesse D., Suhrbier, Andreas, and Khromykh, Alexander A.

Published
2019
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24. Alternative cell entry mechanisms for SARS-CoV-2 and multiple animal viruses

Author

Ojha, Ravi, primary, Jiang, Anmin, additional, Mäntylä, Elina, additional, Modhira, Naphak, additional, Witte, Robert, additional, Gaudin, Arnaud, additional, De Zanetti, Lisa, additional, Gormal, Rachel, additional, Vihinen-Ranta, Maija, additional, Mercer, Jason, additional, Suomalainen, Maarit, additional, Greber, Urs F., additional, Yamauchi, Yohei, additional, Yves-Lozach, Pierre, additional, Helenius, Ari, additional, Vapalahti, Olli, additional, Young, Paul, additional, Watterson, Daniel, additional, Meunier, Frédéric A., additional, Joensuu, Merja, additional, and Balistreri, Giuseppe, additional

Published
2023
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25. The role of N-glycosylation in spike antigenicity for the SARS-CoV-2 gamma variant.

Author

Pegg, Cassandra L, Modhiran, Naphak, Parry, Rhys H, Liang, Benjamin, Amarilla, Alberto A, Khromykh, Alexander A, Burr, Lucy, Young, Paul R, Chappell, Keith, Schulz, Benjamin L, and Watterson, Daniel

Subjects
SARS-CoV-2, VIRAL proteins, CONVALESCENT plasma, GLYCANS, AMINO acids, ASPARAGINE
Abstract

The emergence of SARS-CoV-2 variants alters the efficacy of existing immunity towards the viral spike protein, whether acquired from infection or vaccination. Mutations that impact N -glycosylation of spike may be particularly important in influencing antigenicity, but their consequences are difficult to predict. Here, we compare the glycosylation profiles and antigenicity of recombinant viral spike of ancestral Wu-1 and the Gamma strain, which has two additional N -glycosylation sites due to amino acid substitutions in the N-terminal domain (NTD). We found that a mutation at residue 20 from threonine to asparagine within the NTD caused the loss of NTD-specific antibody COVA2-17 binding. Glycan site-occupancy analyses revealed that the mutation resulted in N -glycosylation switching to the new sequon at N20 from the native N17 site. Site-specific glycosylation profiles demonstrated distinct glycoform differences between Wu-1, Gamma, and selected NTD variant spike proteins, but these did not affect antibody binding. Finally, we evaluated the specificity of spike proteins against convalescent COVID-19 sera and found reduced cross-reactivity against some mutants, but not Gamma spike compared to Wuhan spike. Our results illustrate the impact of viral divergence on spike glycosylation and SARS-CoV-2 antibody binding profiles. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Author

Aguado, Julio, primary, Amarilla, Alberto A., additional, Taherian Fard, Atefeh, additional, Albornoz, Eduardo A., additional, Tyshkovskiy, Alexander, additional, Schwabenland, Marius, additional, Chaggar, Harman K., additional, Modhiran, Naphak, additional, Gómez-Inclán, Cecilia, additional, Javed, Ibrahim, additional, Baradar, Alireza A., additional, Liang, Benjamin, additional, Dharmaratne, Malindrie, additional, Pietrogrande, Giovanni, additional, Padmanabhan, Pranesh, additional, Freney, Morgan E., additional, Parry, Rhys, additional, Sng, Julian D.J., additional, Isaacs, Ariel, additional, Khromykh, Alexander A., additional, Rojas-Fernandez, Alejandro, additional, Davis, Thomas P., additional, Prinz, Marco, additional, Bengsch, Bertram, additional, Gladyshev, Vadim N., additional, Woodruff, Trent M., additional, Mar, Jessica C., additional, Watterson, Daniel, additional, and Wolvetang, Ernst J., additional

Published
2023
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28. Inactivation of SARS‐CoV ‐2 infectivity in platelet concentrates or plasma following treatment with ultraviolet C light or with methylene blue combined with visible light

Author

Hobson‐Peters, Jody, primary, Amarilla, Alberto A., additional, Rustanti, Lina, additional, Marks, Denese C., additional, Roulis, Eileen, additional, Khromykh, Alexander A., additional, Modhiran, Naphak, additional, Watterson, Daniel, additional, Reichenberg, Stefan, additional, Tolksdorf, Frank, additional, Sumian, Chryslain, additional, Seltsam, Axel, additional, Gravemann, Ute, additional, and Faddy, Helen M., additional

Published
2023
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29. Monoclonal Antibodies Specific for SARS-CoV-2 Spike Protein Suitable for Multiple Applications for Current Variants of Concern

Author

Morgan, Mahali S., primary, Yan, Kexin, additional, Le, Thuy T., additional, Johnston, Ryan A., additional, Amarilla, Alberto A., additional, Muller, David A., additional, McMillan, Christopher L. D., additional, Modhiran, Naphak, additional, Watterson, Daniel, additional, Potter, James R., additional, Sng, Julian D.J., additional, Lor, Mary, additional, Paramitha, Devina, additional, Isaacs, Ariel, additional, Khromykh, Alexander A., additional, Hall, Roy A., additional, Suhrbier, Andreas, additional, Rawle, Daniel J., additional, and Hobson-Peters, Jody, additional

Published
2022
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30. An alpaca-derived nanobody recognizes a unique conserved epitope and retains potent activity against the SARS-CoV-2 omicron variant

Author

Modhiran, Naphak, primary, Lauer, Simon Malte, additional, Amarilla, Alberto A, additional, Hewins, Peter, additional, van den Broek, Sara Irene Lopes, additional, Low, Yu Shang, additional, Thakur, Nazia, additional, Liang, Benjamin, additional, Nieto, Guillermo Valenzuela, additional, Jung, James, additional, Paramitha, Devina, additional, Isaacs, Ariel, additional, de Sng, Julian, additional, Song, David, additional, Jørgensen, Jesper Tranekjær, additional, Cheuquemilla, Yorka, additional, Bürger, Jörg, additional, Andersen, Ida Vang, additional, Himelreichs, Johanna, additional, Jara, Ronald, additional, MacLoughlin, Ronan, additional, Miranda-Chacon, Zaray, additional, Chana-Cuevas, Pedro, additional, Kramer, Vasko, additional, Spahn, Christian M.T., additional, Mielke, Thorsten, additional, Khromykh, Alexander A, additional, Munro, Trent, additional, Jones, Martina, additional, Young, Paul R, additional, Chappell, Keith, additional, Bailey, Dalan, additional, Kjaer, Andreas, additional, Herth, Matthias Manfred, additional, Jurado, Kellie Ann, additional, Schwefel, David, additional, Rojas-Fernandez, Alejandro, additional, and Watterson, Daniel, additional

Published
2022
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31. Zika virus noncoding RNA cooperates with the viral protein NS5 to inhibit STAT1 phosphorylation and facilitate viral pathogenesis

Author

Slonchak, Andrii, primary, Wang, Xiaohui, additional, Aguado, Julio, additional, Sng, Julian D. J., additional, Chaggar, Harman, additional, Freney, Morgan E., additional, Yan, Kexin, additional, Torres, Francisco J., additional, Amarilla, Alberto A., additional, Balea, Rickyle, additional, Setoh, Yin Xiang, additional, Peng, Nias, additional, Watterson, Daniel, additional, Wolvetang, Ernst, additional, Suhrbier, Andreas, additional, and Khromykh, Alexander A., additional

Published
2022
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32. Study Design and Operation for Evaluating Nipah Virus Vaccine Candidates Among Backyard Pigs of Indigenous Communities in Bangladesh

Author

Rahman, Mustafizur, Shanta, Ireen Sultana, McLean, Rebecca, Siddika, Ayesha, Begum, Mst. Noorjahan, Rahman, Md Sezanur, Bhuyan, Abdulla, Thakur, Nazia, Bailey, Dalan, Chappell, Keith, Isaacs, Ariel, Watterson, Daniel, Alam, Muntasir, Hassan, Mahdi, Rahman, Mohammed Ziaur, Lambe, T, Gilbert, Sarah C, Young, Paul, and Graham, Simon

Abstract

Background: Nipah virus (NiV) causes a severe and often fatal neurological disease in humans. Although only bats were identified to cause NiV outbreaks in Bangladesh, direct pig-to-human transmission of NiV was responsible for outbreaks in Malaysia and Singapore during 1998-99. Despite the threat, both in animals and humans, no licensed vaccines are currently available. To address this gap, we aim to evaluate the immunogenicity of three NiV vaccine candidates in pigs under field conditions in Bangladesh. Methods: From January-August 2021, we enrolled 7 indigenous communities/villages and carried out community mobilization and engagement activities through interactive discussions . Subsequently, we blood sampled 60 randomly selected pigs and examined the presence of NiV G and F specific antibodies by ELISA. The NiV antibody-negative 45 pigs were immunized with three NiV vaccine candidates: (1) an adjuvanted NiV sG protein; (2) NiV G protein delivered by a replication-deficient simian adenoviral vector (ChAdOx1 NiV G); and (3) an adjuvanted, molecular clamp stabilized NiV F (mcsF) protein. We followed up the pigs for any adverse effects and collected blood samples on day 14, day 28 and day 42 to test both humoral and cellular immunogenicity. Results: We identified that 63% (143/238) households raised pigs as free scavenging livestock in the selected villages. Among the 60 pigs that selected for NiV antibody testing, the mean and median age was 6 months; 16 were female. To analyze the ELISA test positivity for NiV antibodies, we used a standard arbitrary threshold of 4 x the OD of the negative sera. We did not detect any NiV G or F reactive responses in the enrolled pigs. No adverse effects were observed among immunized pigs. Collected blood samples in different time points were stored at icddr,b biorepository for future laboratory investigation to determine T cell IFN-γ responses, NiV-neutralizing antibody (nAb) titers, and NiV antigen-specific Ab ELISA titers. Conclusion: The absence of antibodies against NiV G/F in pigs should be interpreted cautiously due to the relatively small sample size and single-location investigation. The impending findings of this study will provide a platform and strategy for developing NiV vaccine(s) not only for animals but also for humans.

Published
2023
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33. Development and evaluation of an 18F-labeled nanobody to target SARS-CoV-2's spike protein

Author

Lopes van den Broek, Sara, García-Vázquez, Rocío, Andersen, Ida Vang, Valenzuela-Nieto, Guillermo, Shalgunov, Vladimir, Battisti, Umberto M., Schwefel, David, Modhiran, Naphak, Kramer, Vasko, Cheuquemilla, Yorka, Jara, Ronald, Salinas-Varas, Constanza, Amarilla, Alberto A., Watterson, Daniel, Rojas-Fernandez, Alejandro, and Herth, Matthias M.

Abstract

COVID-19, caused by the SARS-CoV-2 virus, has become a global pandemic that is still present after more than two years. COVID-19 is mainly known as a respiratory disease that can cause long-term consequences referred to as long COVID. Molecular imaging of SARS-CoV-2 in COVID-19 patients would be a powerful tool for studying the pathological mechanisms and viral load in different organs, providing insights into the disease and the origin of long-term consequences and assessing the effectiveness of potential COVID-19 treatments. Current diagnostic methods used in the clinic do not allow direct imaging of SARS-CoV-2. In this work, a nanobody (NB) – a small, engineered protein derived from alpacas – and an Fc-fused NB which selectively target the SARS-CoV-2 Spike protein were developed as imaging agents for positron emission tomography (PET). We used the tetrazine ligation to 18F-label the NB under mild conditions once the NBs were successfully modified with trans-cyclooctenes (TCOs). We confirmed binding to the Spike protein by SDS-PAGE. Dynamic PET scans in rats showed excretion through the liver for both constructs. Future work will evaluate in vivo binding to the Spike protein with our radioligands.

Published
2022

34. Democratising large scale instrument-based science through e-Infrastructure

Author

Abramson, David, Barkauskas, Deborah, Carroll, Jake, Condon, Nicholas, Modhiran, Naphak, Nguyen, Hoang, Springfield, James, Watterson, Daniel, and Jin, Chao

Subjects
scientific instruments, microscopy, e-infrastructure
Abstract

Modern scientific instruments are becoming essential for discoveries because they provide unprecedented insight into physical or biological events – often in real time. However, these instruments may generate large amounts of data, and increasingly they require sophisticated e-infrastructure for analysis, storage and archive. The increasing complexity and scale of the data, processing steps and systems has made it difficult for domain scientists to perform their research, narrowing the user base to a select few. In this paper, we present a framework that democratises large-scale instrument-based science, increasing the number of researchers who can engage. We discuss a prototype at the University of Queensland. The system is illustrated through two case studies, one involving light microscopy imaging of the innate immune system, and the other electron microscopy imaging of the SARS-CoV-2 viral proteins.&nbsp

Published
2022
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35. SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein

Author

Albornoz, Eduardo A., primary, Amarilla, Alberto A., additional, Modhiran, Naphak, additional, Parker, Sandra, additional, Li, Xaria X., additional, Wijesundara, Danushka K., additional, Aguado, Julio, additional, Zamora, Adriana Pliego, additional, McMillan, Christopher L. D., additional, Liang, Benjamin, additional, Peng, Nias Y. G., additional, Sng, Julian D. J., additional, Saima, Fatema Tuj, additional, Fung, Jenny N., additional, Lee, John D., additional, Paramitha, Devina, additional, Parry, Rhys, additional, Avumegah, Michael S., additional, Isaacs, Ariel, additional, Lo, Martin W., additional, Miranda-Chacon, Zaray, additional, Bradshaw, Daniella, additional, Salinas-Rebolledo, Constanza, additional, Rajapakse, Niwanthi W., additional, Wolvetang, Ernst J., additional, Munro, Trent P., additional, Rojas-Fernandez, Alejandro, additional, Young, Paul R., additional, Stacey, Katryn J., additional, Khromykh, Alexander A., additional, Chappell, Keith J., additional, Watterson, Daniel, additional, and Woodruff, Trent M., additional

Published
2022
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38. Structure and antigenicity of divergent Henipavirus fusion glycoproteins.

Author

Isaacs, Ariel, Low, Yu Shang, Macauslane, Kyle L., Seitanidou, Joy, Pegg, Cassandra L., Cheung, Stacey T. M., Liang, Benjamin, Scott, Connor A. P., Landsberg, Michael J., Schulz, Benjamin L., Chappell, Keith J., Modhiran, Naphak, and Watterson, Daniel

Subjects
HENIPAVIRUSES, GLYCOPROTEINS, ZOONOSES, ELECTRON microscopy, NONINVASIVE ventilation, GLYCANS
Abstract

In August 2022, a novel henipavirus (HNV) named Langya virus (LayV) was isolated from patients with severe pneumonic disease in China. This virus is closely related to Mòjiāng virus (MojV), and both are divergent from the bat-borne HNV members, Nipah (NiV) and Hendra (HeV) viruses. The spillover of LayV is the first instance of a HNV zoonosis to humans outside of NiV and HeV, highlighting the continuing threat this genus poses to human health. In this work, we determine the prefusion structures of MojV and LayV F proteins via cryogenic electron microscopy to 2.66 and 3.37 Å, respectively. We show that despite sequence divergence from NiV, the F proteins adopt an overall similar structure but are antigenically distinct as they do not react to known antibodies or sera. Glycoproteomic analysis revealed that while LayV F is less glycosylated than NiV F, it contains a glycan that shields a site of vulnerability previously identified for NiV. These findings explain the distinct antigenic profile of LayV and MojV F, despite the extent to which they are otherwise structurally similar to NiV. Our results carry implications for broad-spectrum HNV vaccines and therapeutics, and indicate an antigenic, yet not structural, divergence from prototypical HNVs. In 2022, the zoonotic Langya virus caused cases of severe pneumonia in humans. Here, the authors determine the structure of the fusion glycoprotein of Langya virus and demonstrate antigenic but not structural divergence from bat-borne henipaviruses, yielding insights for future vaccine designs. [ABSTRACT FROM AUTHOR]

Published
2023
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39. Genetic characterization of archived bunyaviruses and their potential for emergence in Australia

Author

Huang, Bixing, Firth, Cadhla, Watterson, Daniel, Allcock, Richard, Colmant, Agathe M.G., Hobson-Peters, Jody, Kirkland, Peter, Hewitson, Glen, McMahon, Jamie, Hall-Mendelin, Sonja, van den Hurk, Andrew F., and Warrilow, David

Subjects
B cells -- Chemical properties -- Health aspects, Infection -- Chemical properties -- Health aspects, Health
Abstract

The family Bunyaviridae contains a diverse group of viruses; 100 species have been approved, and many others have yet to be classified (1). The family comprises 5 genera: Orthobunyavirus, Phlebovirus, [...]

Published
2016
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40. A platform technology for generating subunit vaccines against diverse viral pathogens

Author

Young, Andrew, primary, Isaacs, Ariel, additional, Scott, Connor A. P., additional, Modhiran, Naphak, additional, McMillan, Christopher L. D., additional, Cheung, Stacey T. M., additional, Barr, Jennifer, additional, Marsh, Glenn, additional, Thakur, Nazia, additional, Bailey, Dalan, additional, Li, Kenneth S. M., additional, Luk, Hayes K. H., additional, Kok, Kin-Hang, additional, Lau, Susanna K. P., additional, Woo, Patrick C. Y., additional, Furuyama, Wakako, additional, Marzi, Andrea, additional, Young, Paul R., additional, Chappell, Keith J., additional, and Watterson, Daniel, additional

Published
2022
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42. Nucleocapsid Specific Diagnostics for the Detection of Divergent SARS-CoV-2 Variants

Author

Isaacs, Ariel, primary, Amarilla, Alberto A., additional, Aguado, Julio, additional, Modhiran, Naphak, additional, Albornoz, Eduardo A., additional, Baradar, Alireza A., additional, McMillan, Christopher L. D., additional, Choo, Jovin J. Y., additional, Idris, Adi, additional, Supramaniam, Aroon, additional, McMillan, Nigel A. J., additional, Muller, David A., additional, Young, Paul R., additional, Woodruff, Trent M., additional, Wolvetang, Ernst J., additional, Chappell, Keith J., additional, and Watterson, Daniel, additional

Published
2022
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43. Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction

Author

Guimond, Scott E., Mycroft-West, Courtney J., Gandhi, Neha S., Tree, Julia A., Le, Thuy T., Spalluto, C. Mirella, Humbert, Maria V., Buttigieg, Karen R., Coombes, Naomi, Elmore, Michael J., Wand, Matthew, Nyström, Kristina, Said, Joanna, Setoh, Yin Xiang, Amarilla, Alberto A., Modhiran, Naphak, Sng, Julian D.J., Chhabra, Mohit, Young, Paul R., Rawle, Daniel J., Lima, Marcelo A., Yates, Edwin A., Karlsson, Richard, Miller, Rebecca L., Chen, Yen Hsi, Bagdonaite, Ieva, Yang, Zhang, Stewart, James, Nguyen, Dung, Laidlaw, Stephen, Hammond, Edward, Dredge, Keith, Wilkinson, Tom M.A., Watterson, Daniel, Khromykh, Alexander A., Suhrbier, Andreas, Carroll, Miles W., Trybala, Edward, Bergström, Tomas, Ferro, Vito, Skidmore, Mark A., Turnbull, Jeremy E., Guimond, Scott E., Mycroft-West, Courtney J., Gandhi, Neha S., Tree, Julia A., Le, Thuy T., Spalluto, C. Mirella, Humbert, Maria V., Buttigieg, Karen R., Coombes, Naomi, Elmore, Michael J., Wand, Matthew, Nyström, Kristina, Said, Joanna, Setoh, Yin Xiang, Amarilla, Alberto A., Modhiran, Naphak, Sng, Julian D.J., Chhabra, Mohit, Young, Paul R., Rawle, Daniel J., Lima, Marcelo A., Yates, Edwin A., Karlsson, Richard, Miller, Rebecca L., Chen, Yen Hsi, Bagdonaite, Ieva, Yang, Zhang, Stewart, James, Nguyen, Dung, Laidlaw, Stephen, Hammond, Edward, Dredge, Keith, Wilkinson, Tom M.A., Watterson, Daniel, Khromykh, Alexander A., Suhrbier, Andreas, Carroll, Miles W., Trybala, Edward, Bergström, Tomas, Ferro, Vito, Skidmore, Mark A., and Turnbull, Jeremy E.

Abstract

Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.

Published
2022

46. Absence of Anti-RBD Antibodies in SARS-CoV-2 Infected or Naive Individuals Prior to Vaccination with CoronaVac Leads to Short Protection of Only Four Months Duration

Author

Oliveira, Camille F. de, primary, Neto, Walter F. F., additional, Silva, Carla P. da, additional, Ribeiro, Ana Claudia S., additional, Martins, Lívia C., additional, Sousa, Alana W. de, additional, Freitas, Maria N. O., additional, Chiang, Jannifer O., additional, Silva, Franko A., additional, Santos, Eder B. dos, additional, Medeiros, Daniele B. A., additional, Pinheiro, Gleiciane S., additional, Brandão, Gleiciane F., additional, Carvalho, Valéria L., additional, Azevedo, Raimunda S. S., additional, Vasconcelos, Pedro F. C., additional, Costa, Igor B., additional, Costa, Iran B., additional, Santos, Mirleide C. dos, additional, Soares, Luana S., additional, Bedran, Rayssa L. S., additional, Ferreira, James L., additional, Amarilla, Alberto A., additional, Modhiran, Naphak, additional, McMillan, Christopher L. D., additional, Freney, Morgan E., additional, Muller, David A., additional, Watterson, Daniel, additional, Casseb, Lívia M. N., additional, and Henriques, Daniele F., additional

Published
2022
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47. Peptide-Based Vaccine against SARS-CoV-2: Peptide Antigen Discovery and Screening of Adjuvant Systems

Author

Shalash, Ahmed O., primary, Azuar, Armira, additional, Madge, Harrison Y. R., additional, Modhiran, Naphak, additional, Amarilla, Alberto A., additional, Liang, Benjamin, additional, Khromykh, Alexander A., additional, Hussein, Waleed M., additional, Chappell, Keith J., additional, Watterson, Daniel, additional, Young, Paul R., additional, Skwarczynski, Mariusz, additional, and Toth, Istvan, additional

Published
2022
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48. Dermal Delivery of a SARS-CoV-2 Subunit Vaccine Induces Immunogenicity against Variants of Concern

Author

McMillan, Christopher L. D., primary, Azuar, Armira, additional, Choo, Jovin J. Y., additional, Modhiran, Naphak, additional, Amarilla, Alberto A., additional, Isaacs, Ariel, additional, Honeyman, Kate E., additional, Cheung, Stacey T. M., additional, Liang, Benjamin, additional, Wurm, Maria J., additional, Pino, Paco, additional, Kint, Joeri, additional, Fernando, Germain J. P., additional, Landsberg, Michael J., additional, Khromykh, Alexander A., additional, Hobson-Peters, Jody, additional, Watterson, Daniel, additional, Young, Paul R., additional, and Muller, David A., additional

Published
2022
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49. Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike–ACE2 Interaction

Author

Guimond, Scott E., primary, Mycroft-West, Courtney J., additional, Gandhi, Neha S., additional, Tree, Julia A., additional, Le, Thuy T., additional, Spalluto, C. Mirella, additional, Humbert, Maria V., additional, Buttigieg, Karen R., additional, Coombes, Naomi, additional, Elmore, Michael J., additional, Wand, Matthew, additional, Nyström, Kristina, additional, Said, Joanna, additional, Setoh, Yin Xiang, additional, Amarilla, Alberto A., additional, Modhiran, Naphak, additional, Sng, Julian D. J., additional, Chhabra, Mohit, additional, Young, Paul R., additional, Rawle, Daniel J., additional, Lima, Marcelo A., additional, Yates, Edwin A., additional, Karlsson, Richard, additional, Miller, Rebecca L., additional, Chen, Yen-Hsi, additional, Bagdonaite, Ieva, additional, Yang, Zhang, additional, Stewart, James, additional, Nguyen, Dung, additional, Laidlaw, Stephen, additional, Hammond, Edward, additional, Dredge, Keith, additional, Wilkinson, Tom M. A., additional, Watterson, Daniel, additional, Khromykh, Alexander A., additional, Suhrbier, Andreas, additional, Carroll, Miles W., additional, Trybala, Edward, additional, Bergström, Tomas, additional, Ferro, Vito, additional, Skidmore, Mark A., additional, and Turnbull, Jeremy E., additional

Published
2022
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50. SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike-ACE2 receptor interaction

Author

Albornoz, Eduardo A, primary, Amarilla, Alberto A, additional, Modhiran, Naphak, additional, Parker, Sandra, additional, Li, Xaria X, additional, Wijesundara, Danushka K, additional, Pliego Zamora, Adriana, additional, McMillan, Christopher LD, additional, Liang, Benjamin, additional, Peng, Nias Y.G, additional, Sng, Julian D.J, additional, Tuj Saima, Fatema, additional, Paramitha, Devina, additional, Parry, Rhys, additional, Avumegah, Michael S, additional, Isaacs, Ariel, additional, Lo, Martin, additional, Miranda-Chacon, Zaray, additional, Bradshaw, Daniella, additional, Salinas-Rebolledo, Constanza, additional, Rajapakse, Niwanthi W, additional, Munro, Trent, additional, Rojas-Fernandez, Alejandro, additional, Young, Paul R, additional, Stacey, Katryn J, additional, Khromykh, Alexander A, additional, Chappell, Keith J, additional, Watterson, Daniel, additional, and Woodruff, Trent M, additional

Published
2022
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