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3. Employment of a high throughput functional assay to define the critical factors that influence vaccine induced cross-variant neutralizing antibodies for SARS-CoV-2

Author

Gu, Yue, Shunmuganathan, Bhuvaneshwari, Qian, Xinlei, Gupta, Rashi, Tan, Rebecca S. W., Kozma, Mary, Purushotorman, Kiren, Murali, Tanusya M., Tan, Nikki Y. J., Preiser, Peter R., Lescar, Julien, Nasir, Haziq, Somani, Jyoti, Tambyah, Paul A., Smith, Kenneth G. C., Renia, Laurent, Ng, Lisa F. P., Lye, David C., Young, Barnaby E., and MacAry, Paul A.

Published
2023
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6. Targeted Phenotypic Screening in Plasmodium falciparum and Toxoplasma gondii Reveals Novel Modes of Action of Medicines for Malaria Venture Malaria Box Molecules

Author

Subramanian, Gowtham, Belekar, Meenakshi A, Shukla, Anurag, Tong, Jie Xin, Sinha, Ameya, Chu, Trang TT, Kulkarni, Akshay S, Preiser, Peter R, Reddy, D Srinivasa, Tan, Kevin SW, Shanmugam, Dhanasekaran, and Chandramohanadas, Rajesh

Subjects
Biodefense, Vaccine Related, Rare Diseases, Emerging Infectious Diseases, HIV/AIDS, Malaria, Foodborne Illness, Vector-Borne Diseases, Infectious Diseases, Prevention, Orphan Drug, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, MMV Malaria Box, malaria, Plasmodium falciparum, Toxoplasma gondii, apicoplast, chemical phenotyping, egress, flow cytometry, invasion, merozoites, tachyzoites, toxoplasmosis, Immunology, Microbiology
Abstract

The Malaria Box collection includes 400 chemically diverse small molecules with documented potency against malaria parasite growth, but the underlying modes of action are largely unknown. Using complementary phenotypic screens against Plasmodium falciparum and Toxoplasma gondii, we report phenotype-specific hits based on inhibition of overall parasite growth, apicoplast segregation, and egress or host invasion, providing hitherto unavailable insights into the possible mechanisms affected. First, the Malaria Box library was screened against tachyzoite stage T. gondii and the half-maximal effective concentrations (EC50s) of molecules showing ≥80% growth inhibition at 10 µM were determined. Comparison of the EC50s for T. gondii and P. falciparum identified a subset of 24 molecules with nanomolar potency against both parasites. Thirty molecules that failed to induce acute growth inhibition in T. gondii tachyzoites in a 2-day assay caused delayed parasite death upon extended exposure, with at least three molecules interfering with apicoplast segregation during daughter cell formation. Using flow cytometry and microscopy-based examinations, we prioritized 26 molecules with the potential to inhibit host cell egress/invasion during asexual developmental stages of P. falciparum. None of the inhibitors affected digestive vacuole integrity, ruling out a mechanism mediated by broadly specific protease inhibitor activity. Interestingly, five of the plasmodial egress inhibitors inhibited ionophore-induced egress of T. gondii tachyzoites. These findings highlight the advantage of comparative and targeted phenotypic screens in related species as a means to identify lead molecules with a conserved mode of action. Further work on target identification and mechanism analysis will facilitate the development of antiparasitic compounds with cross-species efficacy. IMPORTANCE The phylum Apicomplexa includes many human and animal pathogens, such as Plasmodium falciparum (human malaria) and Toxoplasma gondii (human and animal toxoplasmosis). Widespread resistance to current antimalarials and the lack of a commercial vaccine necessitate novel pharmacological interventions with distinct modes of action against malaria. For toxoplasmosis, new drugs to effectively eliminate tissue-dwelling latent cysts of the parasite are needed. The Malaria Box antimalarial collection, managed and distributed by the Medicines for Malaria Venture, includes molecules of novel chemical classes with proven antimalarial efficacy. Using targeted phenotypic assays of P. falciparum and T. gondii, we have identified a subset of the Malaria Box molecules as potent inhibitors of plastid segregation and parasite invasion and egress, thereby providing early insights into their probable mode of action. Five molecules that inhibit the egress of both parasites have been identified for further mechanistic studies. Thus, the approach we have used to identify novel molecules with defined modes of action in multiple parasites can expedite the development of pan-active antiparasitic agents.

Published
2018

9. A rapid simple point-of-care assay for the detection of SARS-CoV-2 neutralizing antibodies

Author

Kongsuphol, Patthara, Jia, Huan, Cheng, Hoi Lok, Gu, Yue, Shunmuganathan, Bhuvaneshwari D/O, Chen, Ming Wei, Lim, Sing Mei, Ng, Say Yong, Tambyah, Paul Ananth, Nasir, Haziq, Gao, Xiaohong, Tay, Dousabel, Kim, Seunghyeon, Gupta, Rashi, Qian, Xinlei, Kozma, Mary M., Purushotorman, Kiren, McBee, Megan E., MacAry, Paul A., Sikes, Hadley D., and Preiser, Peter R.

Published
2021
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13. Employment of a high-throughput functional assay to define the critical factors that influence vaccine-induced, cross-variant neutralizing antibodies for SARS-CoV-2.

Author

Gu, Yue, primary, Shunmuganathan, Bhuvaneshwari, additional, Qian, Xinlei, additional, Gupta, Rashi, additional, Tan, Rebecca See Weng, additional, Kozma, Mary, additional, Purushotorman, Kiren, additional, Murali, Tanusya M., additional, Tan, Nikki Y.J., additional, Preiser, Peter R., additional, Lescar, Julien, additional, Nasir, Haziq, additional, Somani, Jyoti, additional, Tambyah, Paul, additional, Smith, Kenneth G.C., additional, Renia, Laurent, additional, Ng, Lisa F.P., additional, Lye, David C., additional, Young, Barnaby E., additional, MacAry, Paul A., additional, and Wai, SCOPE cohort study group Fong Siew, additional

Published
2023
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15. Rapid Evaluation of Vaccine Booster Effectiveness against SARS-CoV-2 Variants

Author

Cheng, Hoi Lok, primary, Lim, Sing Mei, additional, Jia, Huan, additional, Chen, Ming Wei, additional, Ng, Say Yong, additional, Gao, Xiaohong, additional, Somani, Jyoti, additional, Sengupta, Sharmila, additional, Tay, Dousabel M. Y., additional, Chua, Patrina W. L., additional, R., Abirami, additional, Ling, Sharon Y. H., additional, McBee, Megan E., additional, Young, Barnaby E., additional, Sikes, Hadley D., additional, and Preiser, Peter R., additional

Published
2022
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16. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance

Author

Mok, Sachel, Ashley, Elizabeth A., Ferreira, Pedro E., Zhu, Lei, Lin, Zhaoting, Yeo, Tomas, Chotivanich, Kesinee, Imwong, Mallika, Pukrittayakamee, Sasithon, Dhorda, Mehul, Nguon, Chea, Lim, Pharath, Amaratunga, Chanaki, Suon, Seila, Hien, Tran Tinh, Htut, Ye, Faiz, M. Abul, Onyamboko, Marie A., Mayxay, Mayfong, Newton, Paul N., Tripura, Rupam, Woodrow, Charles J., Miotto, Olivo, Kwiatkowski, Dominic P., Nosten, François, Day, Nichoals P. J., Preiser, Peter R., White, Nicholas J., Dondorp, Arjen M., Fairhurst, Rick M., and Bozdech, Zbynek

Published
2015

21. Author response for 'Finger stick blood test to assess postvaccination SARS-CoV-2 neutralizing antibody response against variants'

Author

null Lim, Sing Mei, null Cheng, Hoi Lok, null Jia, Huan, null Kongsuphol, Patthara, null Shunmuganathan, Bhuvaneshwari, null Chen, Ming Wei, null Ng, Say Yong, null Gao, Xiaohong, null Turaga, Shuvan Prashant, null Heussler, Sascha P., null Somani, Jyoti, null Sengupta, Sharmila, null Tay, Dousabel M. Y., null McBee, Megan E., null Young, Barnaby E., null MacAry, Paul A., null Sikes, Hadley D., and null Preiser, Peter R.

Published
2022

23. A switch in infected erythrocyte deformability at the maturation and blood circulation of Plasmodium falciparum transmission stages

Author

Tibúrcio, Marta, Niang, Makhtar, Deplaine, Guillaume, Perrot, Sylvie, Bischoff, Emmanuel, Ndour, Papa Alioune, Silvestrini, Francesco, Khattab, Ayman, Milon, Geneviève, David, Peter H., Hardeman, Max, Vernick, Kenneth D., Sauerwein, Robert W., Preiser, Peter R., Mercereau-Puijalon, Odile, Buffet, Pierre, Alano, Pietro, and Lavazec, Catherine

Published
2012
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24. Finger stick blood test to assess postvaccination SARS‐CoV ‐2 neutralizing antibody response against variants

Author

Lim, Sing Mei, primary, Cheng, Hoi Lok, additional, Jia, Huan, additional, Kongsuphol, Patthara, additional, D/O Shunmuganathan, Bhuvaneshwari, additional, Chen, Ming Wei, additional, Ng, Say Yong, additional, Gao, Xiaohong, additional, Turaga, Shuvan Prashant, additional, Heussler, Sascha P., additional, Somani, Jyoti, additional, Sengupta, Sharmila, additional, Tay, Dousabel M. Y., additional, McBee, Megan E., additional, Young, Barnaby E., additional, MacAry, Paul A., additional, Sikes, Hadley D., additional, and Preiser, Peter R., additional

Published
2022
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25. Development and translation of a paper-based top readout vertical flow assay for SARS-CoV-2 surveillance

Author

Jia, Huan, primary, Miller, Eric A., additional, Chan, Chia Ching, additional, Ng, Say Yong, additional, Prabakaran, Mookkan, additional, Tao, Meng, additional, Cheong, Ian Shen-Yi, additional, Lim, Sing Mei, additional, Chen, Ming Wei, additional, Gao, Xiaohong, additional, R., Abirami, additional, McBee, Megan E., additional, Preiser, Peter R., additional, Sikes, Hadley D., additional, and Kongsuphol, Patthara, additional

Published
2022
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27. Finger stick blood test to assess post vaccination SARS-CoV-2 neutralizing antibody response against variants

Author

Lim, Sing Mei, primary, Cheng, Hoi Lok, additional, Jia, Huan, additional, Kongsuphol, Patthara, additional, D/O Shunmuganathan, Bhuvaneshwari, additional, Chen, Ming Wei, additional, Ng, Say Yong, additional, Gao, Xiaohong, additional, Turaga, Shuvan Prashant, additional, Heussler, Sascha P., additional, Somani, Joyti, additional, Sengupta, Sharmila, additional, Tay, Dousabel MY, additional, McBee, Megan E., additional, Young, Barnaby E., additional, MacAry, Paul A., additional, Sikes, Hadley D., additional, and Preiser, Peter R., additional

Published
2021
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29. DRUG RESISTANCE: Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance

Author

Mok, Sachel, Ashley, Elizabeth A., Ferreira, Pedro E., Zhu, Lei, Lin, Zhaoting, Yeo, Tomas, Chotivanich, Kesinee, Imwong, Mallika, Pukrittayakamee, Sasithon, Dhorda, Mehul, Nguon, Chea, Lim, Pharath, Amaratunga, Chanaki, Suon, Seila, Hien, Tran Tinh, Htut, Ye, Faiz, Abul M., Onyamboko, Marie A., Mayxay, Mayfong, Newton, Paul N., Tripura, Rupam, Woodrow, Charles J., Miotto, Olivo, Kwiatkowski, Dominic P., Nosten, François, Day, Nicholas P. J., Preiser, Peter R., White, Nicholas J., Dondorp, Arjen M., Fairhurst, Rick M., and Bozdech, Zbynek

Published
2015
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30. Functional Characterization of the m 6 A-Dependent Translational Modulator PfYTH.2 in the Human Malaria Parasite

Author

Sinha, Ameya, primary, Baumgarten, Sebastian, additional, Distiller, Amy, additional, McHugh, Emma, additional, Chen, Patty, additional, Singh, Meetali, additional, Bryant, Jessica M., additional, Liang, Jiaqi, additional, Cecere, Germano, additional, Dedon, Peter C., additional, Preiser, Peter R., additional, Ralph, Stuart A., additional, and Scherf, Artur, additional

Published
2021
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34. Discovery of a new predominant cytosine DNA modification that is linked to gene expression in malaria parasites

Author

Hammam, Elie, Ananda, Guruprasad, Sinha, Ameya, Scheidig-Benatar, Christine, Bohec, Mylene, Preiser, Peter R, Dedon, Peter C, Scherf, Artur, Vembar, Shruthi S, Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ED 515 - Complexité du vivant, Sorbonne Université (SU), The Jackson Laboratory [Bar Harbor] (JAX), Nanyang Technological University [Singapour], Singapore-MIT Alliance for Research and Technology (SMART), Massachusetts Institute of Technology (MIT), Institut Curie [Paris], European Research Council Advanced Grant [PlasmoSilencing 670301 to A.S.], French Parasitology consortium ParaFrap [ANR-11-LABX0024 to A.S.], Institut Carnot-Pasteur Maladies Infectieuses Fellowship (to S.S.V.), National Research Foundation, Singapore, under its Singapore‐MIT Alliance for Research and Technology (SMART) Centre, Anti-Microbial Resistance IRG (to P.R.P.), Singapore-MIT Alliance (SMA) Graduate Fellowship Program (to Am.S), Funding for open access charge: PlasmoSilencing 670301., We would like to thank Cameron Macpherson for troubleshooting assistance during bioinformatic analysis and the Plasmodium Genome Database (PlasmoDB) consortium for their continued efforts in maintaining https://plasmodb.org., ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), European Project: 670301,H2020,ERC-2014-ADG,PlasmoSilencing(2015), Scherf, Artur, Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID, Exoribonuclease-mediated degradation of nascent RNA in Malaria Parasites: A Novel Mechanism in Virulence Gene Silencing - PlasmoSilencing - - H20202015-11-01 - 2020-10-31 - 670301 - VALID, School of Biological Sciences, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Erythrocytes, [SDV]Life Sciences [q-bio], Plasmodium falciparum, Gene regulation, Chromatin and Epigenetics, Biological sciences [Science], High-Throughput Nucleotide Sequencing, DNA, DNA Methylation, DNA, Protozoan, Hydroxylation, Epigenesis, Genetic, [SDV] Life Sciences [q-bio], Cytosine, parasitic diseases, 5-Methylcytosine, Humans, RNA, Messenger, Genome, Protozoan
Abstract

DNA cytosine modifications are key epigenetic regulators of cellular processes in mammalian cells, with their misregulation leading to varied disease states. In the human malaria parasite Plasmodium falciparum, a unicellular eukaryotic pathogen, little is known about the predominant cytosine modifications, cytosine methylation (5mC) and hydroxymethylation (5hmC). Here, we report the first identification of a hydroxymethylcytosine-like (5hmC-like) modification in P. falciparum asexual blood stages using a suite of biochemical methods. In contrast to mammalian cells, we report 5hmC-like levels in the P. falciparum genome of 0.2–0.4%, which are significantly higher than the methylated cytosine (mC) levels of 0.01–0.05%. Immunoprecipitation of hydroxymethylated DNA followed by next generation sequencing (hmeDIP-seq) revealed that 5hmC-like modifications are enriched in gene bodies with minimal dynamic changes during asexual development. Moreover, levels of the 5hmC-like base in gene bodies positively correlated to transcript levels, with more than 2000 genes stably marked with this modification throughout asexual development. Our work highlights the existence of a new predominant cytosine DNA modification pathway in P. falciparum and opens up exciting avenues for gene regulation research and the development of antimalarials. National Research Foundation (NRF) Singapore-MIT Alliance for Research and Technology (SMART) Published version European Research Council Advanced Grant [PlasmoSilencing 670301 to A.S.]; French Parasitology consortium ParaFrap [ANR-11-LABX0024 to A.S.]; Institut CarnotPasteur Maladies Infectieuses Fellowship (to S.S.V.); National Research Foundation, Singapore, under its Singapore-MIT Alliance for Research and Technology (SMART) Centre, Anti-Microbial Resistance IRG (to P.R.P.); Singapore-MIT Alliance (SMA) Graduate Fellowship Program (to Am.S); Funding for open access charge: PlasmoSilencing 670301.

Published
2019

35. Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii

Author

Carlton, Jane M., Angiuoli, Samuel V., Suh, Bernard B., Kooij, Taco W., Pertea, Mihaela, Silva, Joana C., Ermolaeva, Maria D., Allen, Jonathan E., Selengut, Jeremy D., Koo, Hean L., Peterson, Jeremy D., Pop, Mihai, Kosack, Daniel S., Shumway, Martin F., Bidwell, Shelby L., Shallom, Shamira J., van Aken, Susan E., Riedmuller, Steven B., Feldblyum, Tamara V., Cho, Jennifer K., Quackenbush, John, Sedegah, Martha, Shoaibi, Azadeh, Cummings, Leda M., Florens, Laurence, Yates, John R., Raine, J. Dale, Sinden, Robert E., Harris, Michael A., Cunningham, Deirdre A., Preiser, Peter R., Bergman, Lawrence W., Vaidya, Akhil B., van Lin, Leo H., Janse, Chris J., Waters, Andrew P., Smith, Hamilton O., White, Owen R., Salzberg, Steven L., Venter, J. Craig, Fraser, Claire M., Hoffman, Stephen L., Gardner, Malcolm J., and Carucci, Daniel J.

Published
2002
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41. Transcriptome profiling reveals functional variation in Plasmodium falciparum parasites from controlled human malaria infection studies

Author

Hoo, Regina, primary, Bruske, Ellen, additional, Dimonte, Sandra, additional, Zhu, Lei, additional, Mordmüller, Benjamin, additional, Sim, B. Kim Lee, additional, Kremsner, Peter G., additional, Hoffman, Stephen L., additional, Bozdech, Zbynek, additional, Frank, Matthias, additional, and Preiser, Peter R., additional

Published
2019
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47. Erratum for Subramanian et al., “Targeted Phenotypic Screening in Plasmodium falciparum and Toxoplasma gondii Reveals Novel Modes of Action of Medicines for Malaria Venture Malaria Box Molecules”

Author

Subramanian, Gowtham, primary, Belekar, Meenakshi A., additional, Shukla, Anurag, additional, Tong, Jie Xin, additional, Sinha, Ameya, additional, Chu, Trang T. T., additional, Kulkarni, Akshay S., additional, Preiser, Peter R., additional, Reddy, D. Srinivasa, additional, Tan, Kevin S. W., additional, Shanmugam, Dhanasekaran, additional, and Chandramohanadas, Rajesh, additional

Published
2019
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49. Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription

Author

Newton Paul N, Socheat Duong, Russell Bruce, Liong Kek-Yee, Chotivanich Kesinee, Mayxay Mayfong, Yi Poravuth, Ramadoss Ramya, Sim Joan, Mackinnon Margaret J, Imwong Mallika, Mok Sachel, Day Nicholas PJ, White Nicholas J, Preiser Peter R, Nosten François, Dondorp Arjen M, and Bozdech Zbynek

Subjects
Plasmodium falciparum, in vivo artemisinin-resistance, field isolates, comparative genomics, comparative transcriptomics, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Artemisinin resistance in Plasmodium falciparum malaria has emerged in Western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. To identify key features associated with the delayed parasite clearance phenotype, we employed DNA microarrays to profile the physiological gene expression pattern of the resistant isolates. Results In the ring and trophozoite stages, we observed reduced expression of many basic metabolic and cellular pathways which suggests a slower growth and maturation of these parasites during the first half of the asexual intraerythrocytic developmental cycle (IDC). In the schizont stage, there is an increased expression of essentially all functionalities associated with protein metabolism which indicates the prolonged and thus increased capacity of protein synthesis during the second half of the resistant parasite IDC. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of regulatory proteins such as transcription factors or chromatin remodeling associated proteins. In addition, there is a unique and uniform copy number variation pattern in the Cambodian parasites which may represent an underlying genetic background that contributes to the resistance phenotype. Conclusions The decreased metabolic activities in the ring stages are consistent with previous suggestions of higher resilience of the early developmental stages to artemisinin. Moreover, the increased capacity of protein synthesis and protein turnover in the schizont stage may contribute to artemisinin resistance by counteracting the protein damage caused by the oxidative stress and/or protein alkylation effect of this drug. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides insight to the complexities of the molecular basis of pathogens with drug resistance phenotypes in vivo.

Published
2011
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