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3. A molecular barcode and web-based data analysis tool to identify imported Plasmodium vivax malaria

Author

Trimarsanto, Hidayat, Amato, Roberto, Pearson, Richard D., Sutanto, Edwin, Noviyanti, Rintis, Trianty, Leily, Marfurt, Jutta, Pava, Zuleima, Echeverry, Diego F., Lopera-Mesa, Tatiana M., Montenegro, Lidia M., Tobón-Castaño, Alberto, Grigg, Matthew J., Barber, Bridget, William, Timothy, Anstey, Nicholas M., Getachew, Sisay, Petros, Beyene, Aseffa, Abraham, Assefa, Ashenafi, Rahim, Awab G., Chau, Nguyen H., Hien, Tran T., Alam, Mohammad S., Khan, Wasif A., Ley, Benedikt, Thriemer, Kamala, Wangchuck, Sonam, Hamedi, Yaghoob, Adam, Ishag, Liu, Yaobao, Gao, Qi, Sriprawat, Kanlaya, Ferreira, Marcelo U., Laman, Moses, Barry, Alyssa, Mueller, Ivo, Lacerda, Marcus V. G., Llanos-Cuentas, Alejandro, Krudsood, Srivicha, Lon, Chanthap, Mohammed, Rezika, Yilma, Daniel, Pereira, Dhelio B., Espino, Fe E. J., Chu, Cindy S., Vélez, Iván D., Namaik-larp, Chayadol, Villegas, Maria F., Green, Justin A., Koh, Gavin, Rayner, Julian C., Drury, Eleanor, Gonçalves, Sónia, Simpson, Victoria, Miotto, Olivo, Miles, Alistair, White, Nicholas J., Nosten, Francois, Kwiatkowski, Dominic P., Price, Ric N., and Auburn, Sarah

Published
2022
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5. Longitudinal ex vivo and molecular trends of chloroquine and piperaquine activity against Plasmodium falciparum and P. vivax before and after introduction of artemisinin-based combination therapy in Papua, Indonesia

Author

Marfurt, Jutta, Wirjanata, Grennady, Prayoga, Pak, Chalfein, Ferryanto, Leonardo, Leo, Sebayang, Boni F., Apriyanti, Dwi, Sihombing, Maic A.E.M., Trianty, Leily, Suwanarusk, Rossarin, Brockman, Alan, Piera, Kim A., Luo, Irene, Rumaseb, Angela, MacHunter, Barbara, Auburn, Sarah, Anstey, Nicholas M., Kenangalem, Enny, Noviyanti, Rintis, Russell, Bruce, Poespoprodjo, Jeanne R., and Price, Ric N.

Published
2021
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6. Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria

Author

Studniberg, Stephanie I, Ioannidis, Lisa J, Utami, Retno A S, Trianty, Leily, Liao, Yang, Abeysekera, Waruni, Li‐Wai‐Suen, Connie S N, Pietrzak, Halina M, Healer, Julie, Puspitasari, Agatha M, Apriyanti, Dwi, Coutrier, Farah, Poespoprodjo, Jeanne R, Kenangalem, Enny, Andries, Benediktus, Prayoga, Pak, Sariyanti, Novita, Smyth, Gordon K, Cowman, Alan F, Price, Ric N, Noviyanti, Rintis, Shi, Wei, Garnham, Alexandra L, and Hansen, Diana S

Published
2022
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8. Retention of uninfected red blood cells causing congestive splenomegaly is the major mechanism of anemia in malaria

Author

Kho, Steven, primary, Siregar, Nurjati C., additional, Qotrunnada, Labibah, additional, Fricot, Aurélie, additional, Sissoko, Abdoulaye, additional, Shanti, Putu A. I., additional, Candrawati, Freis, additional, Kambuaya, Noy N., additional, Rini, Hasrini, additional, Andries, Benediktus, additional, Hardy, David, additional, Margyaningsih, Nur I., additional, Fadllan, Fauziyah, additional, Rahmayenti, Desandra A., additional, Puspitasari, Agatha M., additional, Aisah, Amelia R., additional, Leonardo, Leo, additional, Yayang, Bagus T. G., additional, Margayani, Dewi S., additional, Prayoga, Pak, additional, Trianty, Leily, additional, Kenangalem, Enny, additional, Price, Ric N., additional, Yeo, Tsin W., additional, Minigo, Gabriela, additional, Noviyanti, Rintis, additional, Poespoprodjo, Jeanne R., additional, Anstey, Nicholas M., additional, and Buffet, Pierre A., additional

Published
2023
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9. Implementing parasite genotyping into national surveillance frameworks: feedback from control programmes and researchers in the Asia–Pacific region

Author

Noviyanti, Rintis, Miotto, Olivo, Barry, Alyssa, Marfurt, Jutta, Siegel, Sasha, Thuy-Nhien, Nguyen, Quang, Huynh Hong, Anggraeni, Nancy Dian, Laihad, Ferdinand, Liu, Yaobao, Sumiwi, Maria Endang, Trimarsanto, Hidayat, Coutrier, Farah, Fadila, Nadia, Ghanchi, Najia, Johora, Fatema Tuj, Puspitasari, Agatha Mia, Tavul, Livingstone, Trianty, Leily, Utami, Retno Ayu Setya, Wang, Duoquan, Wangchuck, Kesang, Price, Ric N., and Auburn, Sarah

Published
2020
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11. Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study

Author

Kho, Steven, Qotrunnada, Labibah, Leonardo, Leo, Andries, Benediktus, Wardani, Putu A. I., Fricot, Aurelie, Henry, Benoit, Hardy, David, Margyaningsih, Nur I., Apriyanti, Dwi, Puspitasari, Agatha M., Prayoga, Pak, Trianty, Leily, Kenangalem, Enny, Chretien, Fabrice, Brousse, Valentine, Safeukui, Innocent, del Portillo, Hernando A., Fernandez-Becerra, Carmen, Meibalan, Elamaran, Marti, Matthias, Price, Ric N., Woodberry, Tonia, Ndour, Papa A., Russell, Bruce M., Yeo, Tsin W., Minigo, Gabriela, Noviyanti, Rintis, Poespoprodjo, Jeanne R., Siregar, Nurjati C., Buffet, Pierre A., and Anstey, Nicholas M.

Subjects
Spleen -- Health aspects -- Physiological aspects, Plasmodium vivax -- Physiological aspects, Erythrocytes -- Health aspects -- Physiological aspects, Malaria -- Physiological aspects -- Complications and side effects, Carrier state (Communicable diseases) -- Physiological aspects -- Complications and side effects, Host-parasite relationships -- Physiological aspects, Biological sciences
Abstract

Background A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival. Methods and findings We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted. Conclusions Immature CD71.sup.+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen., Author(s): Steven Kho 1, Labibah Qotrunnada 2, Leo Leonardo 3, Benediktus Andries 3, Putu A. I. Wardani 4, Aurelie Fricot 5, Benoit Henry 5, David Hardy 6, Nur I. Margyaningsih [...]

Published
2021
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13. SARS-CoV-2 Antibody Seroprevalence in Jakarta, Indonesia

Author

Ariawan, Iwan, primary, Jusril, Hafizah, additional, N Farid, Muhammad, additional, Riono, Pandu, additional, Wahyuningsih, Wiji, additional, Widyastuti, Widyastuti, additional, Handayani, Dwi Oktavia T L, additional, Wahyuningsih, Endang Sri, additional, Daulay, Rebekka, additional, Henderiawati, Retno, additional, Malik, Safarina G, additional, Noviyanti, Rintis, additional, Trianty, Leily, additional, Fadila, Nadia, additional, Myint, Khin Saw Aye, additional, Yudhaputri, Frilasita A., additional, Venkateswaran, Neeraja, additional, Venkateswaran, Kodumudi, additional, Udhayakumar, Venkatachalam, additional, Hawley, William A., additional, Morgan, Juliette, additional, and Pronyk, Paul M, additional

Published
2022
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14. Hypnozoite depletion in successive Plasmodium vivax relapses

Author

Noviyanti, Rintis, primary, Carey-Ewend, Kelly, additional, Trianty, Leily, additional, Parobek, Christian, additional, Puspitasari, Agatha Mia, additional, Balasubramanian, Sujata, additional, Park, Zackary, additional, Hathaway, Nicholas, additional, Utami, Retno A. S., additional, Soebianto, Saraswati, additional, Jeny, Jeny, additional, Yudhaputri, Frilasita, additional, Perkasa, Aditya, additional, Coutrier, Farah N., additional, Tirta, Yusrifar K., additional, Ekawati, Lenny, additional, Tjahyono, Bagus, additional, Sutanto, Inge, additional, Nelwan, Erni J., additional, Sudoyo, Herawati, additional, Baird, J. Kevin, additional, and Lin, Jessica T., additional

Published
2022
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15. Identifying Targets of Protective Antibodies against Severe Malaria in Papua, Indonesia, Using Locally Expressed Domains of Plasmodium falciparum Erythrocyte Membrane Protein 1

Author

Rambhatla, Janavi S., primary, Tonkin-Hill, Gerry Q., additional, Takashima, Eizo, additional, Tsuboi, Takafumi, additional, Noviyanti, Rintis, additional, Trianty, Leily, additional, Sebayang, Boni F., additional, Lampah, Daniel A., additional, Marfurt, Jutta, additional, Price, Ric N., additional, Anstey, Nicholas M., additional, Papenfuss, Anthony T., additional, Damelang, Timon, additional, Chung, Amy W., additional, Duffy, Michael F., additional, and Rogerson, Stephen J., additional

Published
2022
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16. High-dimensional mass cytometry identifies T cell and B cell signatures predicting reduced risk of Plasmodium vivax malaria

Author

Ioannidis, Lisa J., primary, Pietrzak, Halina M., additional, Ly, Ann, additional, Utami, Retno A.S., additional, Eriksson, Emily M., additional, Studniberg, Stephanie I., additional, Abeysekera, Waruni, additional, Li-Wai-Suen, Connie S.N., additional, Sheerin, Dylan, additional, Healer, Julie, additional, Puspitasari, Agatha M., additional, Apriyanti, Dwi, additional, Coutrier, Farah N., additional, Poespoprodjo, Jeanne R., additional, Kenangalem, Enny, additional, Andries, Benediktus, additional, Prayoga, Pak, additional, Sariyanti, Novita, additional, Smyth, Gordon K., additional, Trianty, Leily, additional, Cowman, Alan F., additional, Price, Ric N., additional, Noviyanti, Rintis, additional, and Hansen, Diana S., additional

Published
2021
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17. Hidden Biomass of Intact Malaria Parasites in the Human Spleen

Author

Kho, Steven, primary, Qotrunnada, Labibah, additional, Leonardo, Leo, additional, Andries, Benediktus, additional, Wardani, Putu A.I., additional, Fricot, Aurelie, additional, Henry, Benoit, additional, Hardy, David, additional, Margyaningsih, Nur I., additional, Apriyanti, Dwi, additional, Puspitasari, Agatha M., additional, Prayoga, Pak, additional, Trianty, Leily, additional, Kenangalem, Enny, additional, Chretien, Fabrice, additional, Safeukui, Innocent, additional, del Portillo, Hernando A., additional, Fernandez-Becerra, Carmen, additional, Meibalan, Elamaran, additional, Marti, Matthias, additional, Price, Ric N., additional, Woodberry, Tonia, additional, Ndour, Papa A., additional, Russell, Bruce M., additional, Yeo, Tsin W., additional, Minigo, Gabriela, additional, Noviyanti, Rintis, additional, Poespoprodjo, Jeanne R., additional, Siregar, Nurjati C., additional, Buffet, Pierre A., additional, and Anstey, Nicholas M., additional

Published
2021
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18. SARS CoV-2 Antibody Seroprevalence in Jakarta, Indonesia: March 2021

Author

Ariawan, Iwan, primary, Jusril, Hafizah, additional, Farid, Muhammad N., additional, Riono, Pandu, additional, Wahyuningsih, Wiji, additional, Oktavia, Dwi, additional, Wahyuningsih, Endang Sri, additional, Daulay, Rebekka, additional, Henderiawati, Retno, additional, Malik, Safarina G., additional, Noviyanti, Rintis, additional, Trianty, Leily, additional, Fadila, Nadia, additional, Myint, Khin Saw Aye, additional, Yudhaputri, Frilasita Aisyah, additional, Hawley, William A., additional, Udhayakumar, Venkatachalam, additional, Morgan, Juliette, additional, Venkateswaran, Neeraja, additional, Venkateswaran, Kodumudi, additional, and Pronyk, Paul M., additional

Published
2021
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19. Supervised Versus Unsupervised Primaquine Radical Cure for the Treatment of Falciparum and Vivax Malaria in Papua, Indonesia: A Cluster Randomised, Controlled, Open-Label Superiority Trial

Author

Poespoprodjo, Jeanne Rini, primary, Burdam, Faustina Helena, additional, Candrawati, Freis, additional, Ley, Benedikt, additional, Meagher, Niamh, additional, Kenangalem, Enny, additional, Indrawanti, Ratni, additional, Trianty, Leily, additional, Thriemer, Kamala, additional, Price, David J., additional, Simpson, Julie A., additional, and Price, Ric N., additional

Published
2021
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20. Molecular surveillance over 14 years confirms reduction of Plasmodium vivax and falciparum transmission after implementation of Artemisinin-based combination therapy in Papua, Indonesia

Author

Pava, Zuleima, primary, Puspitasari, Agatha M., additional, Rumaseb, Angela, additional, Handayuni, Irene, additional, Trianty, Leily, additional, Utami, Retno A. S., additional, Tirta, Yusrifar K., additional, Burdam, Faustina, additional, Kenangalem, Enny, additional, Wirjanata, Grennady, additional, Kho, Steven, additional, Trimarsanto, Hidayat, additional, Anstey, Nicholas M., additional, Poespoprodjo, Jeanne Rini, additional, Noviyanti, Rintis, additional, Price, Ric N., additional, Marfurt, Jutta, additional, and Auburn, Sarah, additional

Published
2020
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21. Therapeutic response to Dihydroartemisinin-Piperaquine for P. falciparum and P. vivax nine years after its introduction in Southern Papua, Indonesia

Author

Poespoprodjo, Jeanne Rini, Kenangalem, Enny, Wafom, Johny, Chandrawati, Freis, Puspitasari, Agatha M., Ley, Benedikt, Trianty, Leily, Korten, Zoé, Surya, Asik, Syafruddin, Din, Anstey, Nicholas M., Marfurt, Jutta, Noviyanti, Rintis, and Price, Ric N.

Subjects
Adult, Adolescent, Infant, Articles, Middle Aged, Parasitemia, Artemisinins, Antimalarials, Drug Combinations, Young Adult, Child, Preschool, parasitic diseases, Malaria, Vivax, Quinolines, Humans, Prospective Studies, Treatment Failure, Malaria, Falciparum, Child
Abstract

Dihydroartemisinin–piperaquine (DHP) has been the first-line treatment of uncomplicated malaria due to both Plasmodium falciparum and Plasmodium vivax infections in Papua, Indonesia, since March 2006. The efficacy of DHP was reassessed to determine whether there had been any decline following almost a decade of its extensive use. An open-label drug efficacy study of DHP for uncomplicated P. falciparum and P. vivax malaria was carried out between March 2015 and April 2016 in Timika, Papua, Indonesia. Patients with uncomplicated malaria were administered supervised DHP tablets once daily for 3 days. Clinical and laboratory data were collected daily until parasite clearance and then weekly for 6 weeks. Molecular analysis was undertaken for all patients with recurrent parasitemia. A total of 129 study patients were enrolled in the study. At day 42, the polymerase chain reaction-adjusted efficacy was 97.7% (95% confidence intervals [CI]: 87.4–99.9) in the 61 patients with P. falciparum malaria, and 98.2% [95% CI: 90.3–100] in the 56 patients with P. vivax malaria. By day 2, 98% (56/57) of patients with P. falciparum and 96.9% (63/65) of those with P. vivax had cleared their peripheral parasitemia; none of the patients were still parasitaemic on day 3. Molecular analysis of P. falciparum parasites showed that none (0/61) had K13 mutations associated previously with artemisinin resistance or increased copy number of plasmepsin 2–3 (0/61). In the absence of artemisinin resistance, DHP has retained high efficacy for the treatment of uncomplicated malaria despite extensive drug pressure over a 9-year period.

Published
2018

22. A molecular barcode and online tool to identify and map imported infection with Plasmodium vivax

Author

Trimarsanto, Hidayat, primary, Amato, Roberto, additional, Pearson, Richard D, additional, Sutanto, Edwin, additional, Noviyanti, Rintis, additional, Trianty, Leily, additional, Marfurt, Jutta, additional, Pava, Zuleima, additional, Echeverry, Diego F, additional, Lopera-Mesa, Tatiana M, additional, Montenegro, Lidia Madeline, additional, Tobón-Castaño, Alberto, additional, Grigg, Matthew J, additional, Barber, Bridget, additional, William, Timothy, additional, Anstey, Nicholas M, additional, Getachew, Sisay, additional, Petros, Beyene, additional, Aseffa, Abraham, additional, Assefa, Ashenafi, additional, Rahim, Awab Ghulam, additional, Chau, Nguyen Hoang, additional, Hien, Tran Tinh, additional, Alam, Mohammad Shafiul, additional, Khan, Wasif A, additional, Ley, Benedikt, additional, Thriemer, Kamala, additional, Wangchuck, Sonam, additional, Hamedi, Yaghoob, additional, Adam, Ishag, additional, Liu, Yaobao, additional, Gao, Qi, additional, Sriprawat, Kanlaya, additional, Ferreira, Marcelo U, additional, Barry, Alyssa, additional, Mueller, Ivo, additional, Drury, Eleanor, additional, Goncalves, Sonia, additional, Simpson, Victoria, additional, Miotto, Olivo, additional, Miles, Alistair, additional, White, Nicholas J, additional, Nosten, Francois, additional, Kwiatkowski, Dominic P, additional, Price, Ric N, additional, and Auburn, Sarah, additional

Published
2019
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25. Plasmodium falciparum and Plasmodium vivax Demonstrate Contrasting Chloroquine Resistance Reversal Phenotypes

Author

Wirjanata, Grennady, Handayuni, Irene, Prayoga, Pak, Leonardo, Leo, Apriyanti, Dwi, Trianty, Leily, Wandosa, Ruland, Gobay, Basbak, Kenangalem, Enny, Poespoprodjo, Jeanne Rini, Noviyanti, Rintis, Kyle, Dennis E., Cheng, Qin, Price, Ric N., and Marfurt, Jutta

Subjects
drug resistance, chloroquine resistance reversal, Plasmodium falciparum, malaria, Chloroquine, Antimalarials, Parasitic Sensitivity Tests, Susceptibility, Indonesia, parasitic diseases, Malaria, Vivax, Humans, Malaria, Falciparum, Plasmodium vivax
Abstract

High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.

Published
2017

26. The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen–encoding var genes

Author

Tonkin-Hill, Gerry Q., primary, Trianty, Leily, additional, Noviyanti, Rintis, additional, Nguyen, Hanh H. T., additional, Sebayang, Boni F., additional, Lampah, Daniel A., additional, Marfurt, Jutta, additional, Cobbold, Simon A., additional, Rambhatla, Janavi S., additional, McConville, Malcolm J., additional, Rogerson, Stephen J., additional, Brown, Graham V., additional, Day, Karen P., additional, Price, Ric N., additional, Anstey, Nicholas M., additional, Papenfuss, Anthony T., additional, and Duffy, Michael F., additional

Published
2018
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27. Passively versus Actively Detected Malaria: Similar Genetic Diversity but Different Complexity of Infection

Author

Pava, Zuleima, primary, Handayuni, Irene, additional, Trianty, Leily, additional, Utami, Retno A. S., additional, Tirta, Yusrifar K., additional, Puspitasari, Agatha M., additional, Burdam, Faustina, additional, Kenangalem, Enny, additional, Wirjanata, Grennady, additional, Kho, Steven, additional, Trimarsanto, Hidayat, additional, Anstey, Nicholas, additional, Poespoprodjo, Jeanne Rini, additional, Noviyanti, Rintis, additional, Price, Ric N., additional, Marfurt, Jutta, additional, and Auburn, Sarah, additional

Published
2017
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28. Genetic micro-epidemiology of malaria in Papua Indonesia: Extensive P. vivax diversity and a distinct subpopulation of asymptomatic P. falciparum infections

Author

Pava, Zuleima, primary, Noviyanti, Rintis, additional, Handayuni, Irene, additional, Trimarsanto, Hidayat, additional, Trianty, Leily, additional, Burdam, Faustina H., additional, Kenangalem, Enny, additional, Utami, Retno A. S., additional, Tirta, Yusrifar K., additional, Coutrier, Farah, additional, Poespoprodjo, Jeanne R., additional, Price, Ric N., additional, Marfurt, Jutta, additional, and Auburn, Sarah, additional

Published
2017
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29. VivaxGEN: An open access platform for comparative analysis of short tandem repeat genotyping data in Plasmodium vivax populations

Author

Trimarsanto, Hidayat, primary, Benavente, Ernest D., additional, Noviyanti, Rintis, additional, Utami, Retno Ayu Setya, additional, Trianty, Leily, additional, Pava, Zuleima, additional, Getachew, Sisay, additional, Kim, Jung-Yeon, additional, Goo, Youn-Kyoung, additional, Wangchuck, Sonam, additional, Liu, Yaobao, additional, Gao, Qi, additional, Dowd, Simone, additional, Cheng, Qin, additional, Clark, Taane G., additional, Price, Ric N., additional, and Auburn, Sarah, additional

Published
2017
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30. Differences in PfEMP1s recognized by antibodies from patients with uncomplicated or severe malaria

Author

Duffy, Michael F, Noviyanti, Rintis, Tsuboi, Takafumi, Feng, Zhi-Ping, Trianty, Leily, Sebayang, Boni F, Takashima, Eizo, Sumardy, Fransisca, Lampah, Daniel A, Turner, Louise, Lavstsen, Thomas, Fowkes, Freya J I, Siba, Peter, Rogerson, Stephen J, Theander, Thor G, Marfurt, Jutta, Price, Ric N, Anstey, Nicholas M, Brown, Graham V, Papenfuss, Anthony T, Duffy, Michael F, Noviyanti, Rintis, Tsuboi, Takafumi, Feng, Zhi-Ping, Trianty, Leily, Sebayang, Boni F, Takashima, Eizo, Sumardy, Fransisca, Lampah, Daniel A, Turner, Louise, Lavstsen, Thomas, Fowkes, Freya J I, Siba, Peter, Rogerson, Stephen J, Theander, Thor G, Marfurt, Jutta, Price, Ric N, Anstey, Nicholas M, Brown, Graham V, and Papenfuss, Anthony T

Abstract

BACKGROUND: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants are encoded by var genes and mediate pathogenic cytoadhesion and antigenic variation in malaria. PfEMP1s can be broadly divided into three principal groups (A, B and C) and they contain conserved arrangements of functional domains called domain cassettes. Despite their tremendous diversity there is compelling evidence that a restricted subset of PfEMP1s is expressed in severe disease. In this study antibodies from patients with severe and uncomplicated malaria were compared for differences in reactivity with a range of PfEMP1s to determine whether antibodies to particular PfEMP1 domains were associated with severe or uncomplicated malaria.METHODS: Parts of expressed var genes in a severe malaria patient were identified by RNAseq and several of these partial PfEMP1 domains were expressed together with others from laboratory isolates. Antibodies from Papuan patients to these parts of multiple PfEMP1 proteins were measured.RESULTS: Patients with uncomplicated malaria were more likely to have antibodies that recognized PfEMP1 of Group C type and recognized a broader repertoire of group A and B PfEMP1s than patients with severe malaria.CONCLUSION: These data suggest that exposure to a broad range of group A and B PfEMP1s is associated with protection from severe disease in Papua, Indonesia.

Published
2016

31. Submicroscopic and Asymptomatic Plasmodium Parasitaemia Associated with Significant Risk of Anaemia in Papua, Indonesia

Author

Pava, Zuleima, primary, Burdam, Faustina H., additional, Handayuni, Irene, additional, Trianty, Leily, additional, Utami, Retno A. S., additional, Tirta, Yusrifar Kharisma, additional, Kenangalem, Enny, additional, Lampah, Daniel, additional, Kusuma, Andreas, additional, Wirjanata, Grennady, additional, Kho, Steven, additional, Simpson, Julie A., additional, Auburn, Sarah, additional, Douglas, Nicholas M., additional, Noviyanti, Rintis, additional, Anstey, Nicholas M., additional, Poespoprodjo, Jeanne R., additional, Marfurt, Jutta, additional, and Price, Ric N., additional

Published
2016
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32. Asymptomatic Vivax and Falciparum Parasitaemia with Helminth Co-Infection: Major Risk Factors for Anaemia in Early Life

Author

Burdam, Faustina Helena, primary, Hakimi, Mohammad, additional, Thio, Franciscus, additional, Kenangalem, Enny, additional, Indrawanti, Ratni, additional, Noviyanti, Rintis, additional, Trianty, Leily, additional, Marfurt, Jutta, additional, Handayuni, Irene, additional, Soenarto, Yati, additional, Douglas, Nicholas M., additional, Anstey, Nicholas M., additional, Price, Ric N., additional, and Poespoprodjo, Jeanne Rini, additional

Published
2016
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33. Differences in PfEMP1s recognized by antibodies from patients with uncomplicated or severe malaria

Author

Duffy, Michael F., primary, Noviyanti, Rintis, additional, Tsuboi, Takafumi, additional, Feng, Zhi-Ping, additional, Trianty, Leily, additional, Sebayang, Boni F., additional, Takashima, Eizo, additional, Sumardy, Fransisca, additional, Lampah, Daniel A., additional, Turner, Louise, additional, Lavstsen, Thomas, additional, Fowkes, Freya J. I., additional, Siba, Peter, additional, Rogerson, Stephen J., additional, Theander, Thor G., additional, Marfurt, Jutta, additional, Price, Ric N., additional, Anstey, Nicholas M., additional, Brown, Graham V., additional, and Papenfuss, Anthony T., additional

Published
2016
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35. Potent Ex Vivo Activity of Naphthoquine and Methylene Blue against Drug-Resistant Clinical Isolates of Plasmodium falciparum and Plasmodium vivax

Author

Wirjanata, Grennady, Sebayang, Boni F., Chalfein, Ferryanto, Prayoga, Pak, Handayuni, Irene, Trianty, Leily, Kenangalem, Enny, Noviyanti, Rintis, Campo, Brice, Poespoprodjo, Jeanne R., Mohrle, Jorg J., Price, Ric N., Marfurt, Jutta, Wirjanata, Grennady, Sebayang, Boni F., Chalfein, Ferryanto, Prayoga, Pak, Handayuni, Irene, Trianty, Leily, Kenangalem, Enny, Noviyanti, Rintis, Campo, Brice, Poespoprodjo, Jeanne R., Mohrle, Jorg J., Price, Ric N., and Marfurt, Jutta

Abstract

The 4-aminoquinoline naphthoquine (NQ) and the thiazine dye methylene blue (MB) have potent in vitro efficacies against Plasmodium falciparum, but susceptibility data for P. vivax are limited. The species- and stage-specific ex vivo activities of NQ and MB were assessed using a modified schizont maturation assay on clinical field isolates from Papua, Indonesia, where multidrug-resistant P. falciparum and P. vivax are prevalent. Both compounds were highly active against P. falciparum (median [range] 50% inhibitory concentration [IC50]: NQ, 8.0 nM [2.6 to 71.8 nM]; and MB, 1.6 nM [0.2 to 7.0 nM]) and P. vivax (NQ, 7.8 nM [1.5 to 34.2 nM]; and MB, 1.2 nM [0.4 to 4.3 nM]). Stage-specific drug susceptibility assays revealed significantly greater IC50s in parasites exposed at the trophozoite stage than at the ring stage for NQ in P. falciparum (26.5 versus 5.1 nM, P = 0.021) and P. vivax (341.6 versus 6.5 nM, P = 0.021) and for MB in P. vivax (10.1 versus 1.6 nM, P = 0.010). The excellent ex vivo activities of NQ and MB against both P. falciparum and P. vivax highlight their potential utility for the treatment of multidrug-resistant malaria in areas where both species are endemic.

Published
2015

36. Contrasting Transmission Dynamics of Co-endemic Plasmodium vivax and P. falciparum: Implications for Malaria Control and Elimination

Author

Noviyanti, Rintis, Farah, Coutrier, Utami, Retno A.S., Trimarsanto, Hidayat, Tirta, Yusrifar K., Trianty, Leily, Kusuma, Andreas, Sutanto, Inge, Kosasih, Ayleen, Kusriastuti, Rita, Hawley, William A., Laihad, Ferdinand, Lobo, Neil, Marfurt, Jutta, Clark, Taane, Price, Ric N., Auburn, Sarah, Noviyanti, Rintis, Farah, Coutrier, Utami, Retno A.S., Trimarsanto, Hidayat, Tirta, Yusrifar K., Trianty, Leily, Kusuma, Andreas, Sutanto, Inge, Kosasih, Ayleen, Kusriastuti, Rita, Hawley, William A., Laihad, Ferdinand, Lobo, Neil, Marfurt, Jutta, Clark, Taane, Price, Ric N., and Auburn, Sarah

Abstract

BackgroundOutside of Africa, P. falciparum and P. vivax usually coexist. In such co-endemic regions, successful malaria control programs have a greater impact on reducing falciparum malaria, resulting in P. vivax becoming the predominant species of infection. Adding to the challenges of elimination, the dormant liver stage complicates efforts to monitor the impact of ongoing interventions against P. vivax. We investigated molecular approaches to inform the respective transmission dynamics of P. falciparum and P. vivax and how these could help to prioritize public health interventions.Methodology/ Principal FindingsGenotype data generated at 8 and 9 microsatellite loci were analysed in 168 P. falciparum and 166 P. vivax isolates, respectively, from four co-endemic sites in Indonesia (Bangka, Kalimantan, Sumba and West Timor). Measures of diversity, linkage disequilibrium (LD) and population structure were used to gauge the transmission dynamics of each species in each setting. Marked differences were observed in the diversity and population structure of P. vivax versus P. falciparum. In Bangka, Kalimantan and Timor, P. falciparum diversity was low, and LD patterns were consistent with unstable, epidemic transmission, amenable to targeted intervention. In contrast, P. vivax diversity was higher and transmission appeared more stable. Population differentiation was lower in P. vivax versus P. falciparum, suggesting that the hypnozoite reservoir might play an important role in sustaining local transmission and facilitating the spread of P. vivax infections in different endemic settings. P. vivax polyclonality varied with local endemicity, demonstrating potential utility in informing on transmission intensity in this species.Conclusions/ SignificanceMolecular approaches can provide important information on malaria transmission that is not readily available from traditional epidemiological measures. Elucidation of the transmission dynamics circulating in a given setting wi

Published
2015

37. Contrasting Transmission Dynamics of Co-endemic Plasmodium vivax and P. falciparum: Implications for Malaria Control and Elimination

Author

Noviyanti, Rintis, primary, Coutrier, Farah, additional, Utami, Retno A. S., additional, Trimarsanto, Hidayat, additional, Tirta, Yusrifar K., additional, Trianty, Leily, additional, Kusuma, Andreas, additional, Sutanto, Inge, additional, Kosasih, Ayleen, additional, Kusriastuti, Rita, additional, Hawley, William A., additional, Laihad, Ferdinand, additional, Lobo, Neil, additional, Marfurt, Jutta, additional, Clark, Taane G., additional, Price, Ric N., additional, and Auburn, Sarah, additional

Published
2015
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38. Placental weight ratio affects placental mRNA expression of insulin-like growth factor-I and long isoform of the leptin receptor in Plasmodium falciparuminfected pregnant women.

Author

Oktavianthi, Sukma, Trianty, Leily, Noviyanti, Rintis, Trimarsanto, Hidayat, Sudoyo, Herawati, and Malik, Safarina G.

Subjects
*MESSENGER RNA, *SOMATOMEDIN C, *LEPTIN, *LEPTIN receptors, *PLASMODIUM falciparum, *PREGNANCY complications, *PLACENTA physiology, *RNA metabolism, *ANTHROPOMETRY, *CELL receptors, *GENES, *MALARIA, *PARASITIC diseases in pregnancy, *PROTOZOA, *SOMATOMEDIN, *DISEASE complications
Abstract

Background and Objectives: Plasmodium falciparum infection during pregnancy is characterised by placental inefficiency caused by infected erythrocyte sequestration. Reduced placental efficiency leads to placental intrauterine adaptation for sustaining fetal growth, which is reflected by changes in the expression of placental genes involved in intrauterine growth regulation. Therefore, we aimed to determine whether the placental weight ratio, an indicator of placental efficiency, affects the placental expression of the components of the insulin-like growth factor axis and leptin signalling pathway in P. falciparum-infected pregnant women.Methods and Study Design: A malaria case-only analysis of 50 P. falciparum-infected pregnant women in Timika, Papua, Indonesia, was conducted. The placental mRNA expression of insulin-like growth factor-I, insulin-like growth factor binding protein-1, leptin, and the long and short isoforms of the leptin receptor was measured through quantitative realtime PCR.Results: The placental weight ratio exerted a positive effect on the placental mRNA expression of insulin- like growth factor-I (coefficient=6.10, p=0.002) and the long isoform of the leptin receptor (coefficient= 4.73, p=0.015) in malaria-infected pregnant women without fever or chill symptoms.Conclusion: Our results indicate that placental adaptive responses caused by adverse intrauterine conditions in P. falciparuminfected pregnant women vary depending on the presence or absence of fever and chill symptoms. [ABSTRACT FROM AUTHOR]

Published
2016
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39. Effective Preparation of Plasmodium vivax Field Isolates for High-Throughput Whole Genome Sequencing

Author

Auburn, Sarah, Marfurt, Jutta, Maslen, Gareth, Campino, Susana, Ruano-Rubio, Valentin, Manske, Magnus, MacHunter, Barbara, Kenangalem, Enny, Noviyanti, Rintis, Trianty, Leily, Sebayang, Boni, Wirjanata, Grennady, Sriprakash, Kanlaya, Alcock, Daniel, MacInnis, Bronwyn, Miotto, Olivo, Clark, Taane G., Russell, Bruce, Anstey, Nicholas M., Price, Ric N., et al., Auburn, Sarah, Marfurt, Jutta, Maslen, Gareth, Campino, Susana, Ruano-Rubio, Valentin, Manske, Magnus, MacHunter, Barbara, Kenangalem, Enny, Noviyanti, Rintis, Trianty, Leily, Sebayang, Boni, Wirjanata, Grennady, Sriprakash, Kanlaya, Alcock, Daniel, MacInnis, Bronwyn, Miotto, Olivo, Clark, Taane G., Russell, Bruce, Anstey, Nicholas M., Price, Ric N., and et al.

Abstract

Whole genome sequencing (WGS) of Plasmodium vivax is problematic due to the reliance on clinical isolates which are generally low in parasitaemia and sample volume. Furthermore, clinical isolates contain a significant contaminating background of host DNA which confounds efforts to map short read sequence of the target P. vivax DNA. Here, we discuss a methodology to significantly improve the success of P. vivax WGS on natural (non-adapted) patient isolates. Using 37 patient isolates from Indonesia, Thailand, and travellers, we assessed the application of CF11-based white blood cell filtration alone and in combination with short term ex vivo schizont maturation. Although CF11 filtration reduced human DNA contamination in 8 Indonesian isolates tested, additional short-term culture increased the P. vivax DNA yield from a median of 0.15 to 6.2 ng µl−1 packed red blood cells (pRBCs) (p = 0.001) and reduced the human DNA percentage from a median of 33.9% to 6.22% (p = 0.008). Furthermore, post-CF11 and culture samples from Thailand gave a median P. vivax DNA yield of 2.34 ng µl−1 pRBCs, and 2.65% human DNA. In 22 P. vivax patient isolates prepared with the 2-step method, we demonstrate high depth (median 654X coverage) and breadth (≥89%) of coverage on the Illumina GAII and HiSeq platforms. In contrast to the A+T-rich P. falciparum genome, negligible bias was observed in coverage depth between coding and non-coding regions of the P. vivax genome. This uniform coverage will greatly facilitate the detection of SNPs and copy number variants across the genome, enabling unbiased exploration of the natural diversity in P. vivax populations.

Published
2013

41. Effective Preparation of Plasmodium vivax Field Isolates for High-Throughput Whole Genome Sequencing

Author

Auburn, Sarah, primary, Marfurt, Jutta, additional, Maslen, Gareth, additional, Campino, Susana, additional, Ruano Rubio, Valentin, additional, Manske, Magnus, additional, MacHunter, Barbara, additional, Kenangalem, Enny, additional, Noviyanti, Rintis, additional, Trianty, Leily, additional, Sebayang, Boni, additional, Wirjanata, Grennady, additional, Sriprawat, Kanlaya, additional, Alcock, Daniel, additional, MacInnis, Bronwyn, additional, Miotto, Olivo, additional, Clark, Taane G., additional, Russell, Bruce, additional, Anstey, Nicholas M., additional, Nosten, François, additional, Kwiatkowski, Dominic P., additional, and Price, Ric N., additional

Published
2013
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43. Expression of Plasmodium vivaxcrt-oIs Related to Parasite Stage but Not Ex VivoChloroquine Susceptibility

Author

Pava, Zuleima, Handayuni, Irene, Wirjanata, Grennady, To, Sheren, Trianty, Leily, Noviyanti, Rintis, Poespoprodjo, Jeanne Rini, Auburn, Sarah, Price, Ric N., and Marfurt, Jutta

Abstract

ABSTRACTChloroquine (CQ)-resistant Plasmodium vivaxis present in most countries where P. vivaxinfection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivaxcrt-o(pvcrt-o) has been correlated with in vivoCQ resistance in an area with low-grade resistance. We assessed pvcrt-oexpression in isolates from Papua (Indonesia), where P. vivaxis highly CQ resistant. Ex vivodrug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-owere measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-oexpression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivaxβ-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivaxaldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P< 0.001). Twenty-nine isolates fulfilled the criteria for ex vivodrug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-oexpression levels did not correlate with the ex vivoresponse to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-oexpression and suggest that pvcrt-otranscription is not a primary determinant of ex vivodrug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivaxdrug resistance.

Published
2015
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44. Potent Ex VivoActivity of Naphthoquine and Methylene Blue against Drug-Resistant Clinical Isolates of Plasmodium falciparumand Plasmodium vivax

Author

Wirjanata, Grennady, Sebayang, Boni F., Chalfein, Ferryanto, Prayoga, Handayuni, Irene, Trianty, Leily, Kenangalem, Enny, Noviyanti, Rintis, Campo, Brice, Poespoprodjo, Jeanne Rini, Möhrle, Jörg J., Price, Ric N., and Marfurt, Jutta

Abstract

ABSTRACTThe 4-aminoquinoline naphthoquine (NQ) and the thiazine dye methylene blue (MB) have potent in vitroefficacies against Plasmodium falciparum, but susceptibility data for P. vivaxare limited. The species- and stage-specific ex vivoactivities of NQ and MB were assessed using a modified schizont maturation assay on clinical field isolates from Papua, Indonesia, where multidrug-resistant P. falciparumand P. vivaxare prevalent. Both compounds were highly active against P. falciparum(median [range] 50% inhibitory concentration [IC50]: NQ, 8.0 nM [2.6 to 71.8 nM]; and MB, 1.6 nM [0.2 to 7.0 nM]) and P. vivax(NQ, 7.8 nM [1.5 to 34.2 nM]; and MB, 1.2 nM [0.4 to 4.3 nM]). Stage-specific drug susceptibility assays revealed significantly greater IC50s in parasites exposed at the trophozoite stage than at the ring stage for NQ in P. falciparum(26.5 versus 5.1 nM, P= 0.021) and P. vivax(341.6 versus 6.5 nM, P= 0.021) and for MB in P. vivax(10.1 versus 1.6 nM, P= 0.010). The excellent ex vivoactivities of NQ and MB against both P. falciparumand P. vivaxhighlight their potential utility for the treatment of multidrug-resistant malaria in areas where both species are endemic.

Published
2015
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45. Effective Preparation of Plasmodium vivaxField Isolates for High-Throughput Whole Genome Sequencing.

Author

Auburn, Sarah, Marfurt, Jutta, Maslen, Gareth, Campino, Susana, Rubio, Valentin Ruano, Manske, Magnus, MacHunter, Barbara, Kenangalem, Enny, Noviyanti, Rintis, Trianty, Leily, Sebayang, Boni, Wirjanata, Grennady, Sriprawat, Kanlaya, Alcock, Daniel, MacInnis, Bronwyn, Miotto, Olivo, Clark, Taane G., Russell, Bruce, Anstey, Nicholas M., and Nosten, François

Subjects
PLASMODIUM vivax, GENOMES, PARASITEMIA, NUCLEOTIDE sequence, LEUCOCYTES, DNA
Abstract

Whole genome sequencing (WGS) of Plasmodium vivax is problematic due to the reliance on clinical isolates which are generally low in parasitaemia and sample volume. Furthermore, clinical isolates contain a significant contaminating background of host DNA which confounds efforts to map short read sequence of the target P. vivax DNA. Here, we discuss a methodology to significantly improve the success of P. vivax WGS on natural (non-adapted) patient isolates. Using 37 patient isolates from Indonesia, Thailand, and travellers, we assessed the application of CF11-based white blood cell filtration alone and in combination with short term ex vivo schizont maturation. Although CF11 filtration reduced human DNA contamination in 8 Indonesian isolates tested, additional short-term culture increased the P. vivax DNA yield from a median of 0.15 to 6.2 ng µl-1 packed red blood cells (pRBCs) (p = 0.001) and reduced the human DNA percentage from a median of 33.9% to 6.22% (p = 0.008). Furthermore, post-CF11 and culture samples from Thailand gave a median P. vivax DNA yield of 2.34 ng µl-1 pRBCs, and 2.65% human DNA. In 22 P. vivax patient isolates prepared with the 2-step method, we demonstrate high depth (median 654X coverage) and breadth ($89%) of coverage on the Illumina GAII and HiSeq platforms. In contrast to the A+T-rich P. falciparum genome, negligible bias was observed in coverage depth between coding and non-coding regions of the P. vivax genome. This uniform coverage will greatly facilitate the detection of SNPs and copy number variants across the genome, enabling unbiased exploration of the natural diversity in P. vivax populations. [ABSTRACT FROM AUTHOR]

Published
2013
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46. Plasmodium falciparumand Plasmodium vivaxDemonstrate Contrasting Chloroquine Resistance Reversal Phenotypes

Author

Wirjanata, Grennady, Handayuni, Irene, Prayoga, Pak, Leonardo, Leo, Apriyanti, Dwi, Trianty, Leily, Wandosa, Ruland, Gobay, Basbak, Kenangalem, Enny, Poespoprodjo, Jeanne Rini, Noviyanti, Rintis, Kyle, Dennis E., Cheng, Qin, Price, Ric N., and Marfurt, Jutta

Abstract

ABSTRACTHigh-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparumand P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparumand 34 P. vivaxclinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparumwas highly correlated with CQ susceptibility for all CQRRAs (R2= 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparumlaboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparumand P. vivaxsuggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.

Published
2017
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47. Improved limit of detection for zoonotic Plasmodium knowlesi and P. cynomolgi surveillance using reverse transcription for total nucleic acid preserved samples or dried blood spots.

Author

Braima KA, Piera KA, Lubis IN, Noviyanti R, Rajahram GS, Kariodimedjo P, Nainggolan IR, Permatasari R, Trianty L, Amalia R, Sakam SSB, Tan AF, William T, Westaway JA, Lee P, Daim S, Surendra H, Christy N, Letizia AG, Peatey CL, Moideen MA, Barber BE, Sutherland CJ, Anstey NM, and Grigg MJ

Abstract

Background: Zoonotic P. knowlesi and P. cynomolgi symptomatic and asymptomatic infections occur across endemic areas of Southeast Asia. Most infections are low-parasitemia, with an unknown proportion below routine microscopy detection thresholds. Molecular surveillance tools optimizing the limit of detection (LOD) would allow more accurate estimates of zoonotic malaria prevalence., Methods: An established ultra-sensitive Plasmodium genus quantitative-PCR (qPCR) assay targeting the 18S rRNA gene underwent LOD evaluation with and without reverse transcription (RT) for P. knowlesi , P. cynomolgi and P. vivax using total nucleic acid preserved (DNA/RNA Shield ™ ) isolates and archived dried blood spots (DBS). LODs for selected P. knowlesi- specific assays, and reference P. vivax- and P. cynomolgi -specific assays were determined with RT. Assay specificities were assessed using clinical malaria samples and malaria-negative controls., Results: The use of reverse transcription improved Plasmodium species detection by up to 10,000-fold ( Plasmodium genus), 2759-fold ( P. knowlesi ), 1000-fold ( P. vivax ) and 10-fold ( P. cynomolgi ). The median LOD with RT for the Kamau et al. Plasmodium genus RT-qPCR assay was ≤0.0002 parasites/μL for P. knowlesi and 0.002 parasites/μL for both P. cynomolgi and P. vivax . The LODs with RT for P. knowlesi -specific PCRs were: Imwong et al. 18S rRNA (0.0007 parasites/μL); Divis et al. real-time 18S rRNA (0.0002 parasites/μL); Lubis et al. hemi-nested SICAvar (1.1 parasites/μL) and Lee et al. nested 18S rRNA (11 parasites/μL). The LOD for P. vivax- and P. cynomolgi- specific assays with RT were 0.02 and 0.20 parasites/μL respectively. For DBS P. knowlesi samples the median LOD for the Plasmodium genus qPCR with RT was 0.08, and without RT was 19.89 parasites/uL (249-fold change); no LOD improvement was demonstrated in DBS archived beyond 6 years. The Plasmodium genus and P. knowlesi -assays were 100% specific for Plasmodium species and P. knowlesi detection, respectively, from 190 clinical infections and 48 healthy controls. Reference P. vivax- specific primers demonstrated known cross-reactivity with P. cynomolgi ., Conclusion: Our findings support the use of an 18S rRNA Plasmodium genus qPCR and species-specific nested PCR protocol with RT for highly-sensitive surveillance of zoonotic and human Plasmodium species infections.

Published
2024
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48. Retention of uninfected red blood cells causing congestive splenomegaly is the major mechanism of anemia in malaria.

Author

Kho S, Siregar NC, Qotrunnada L, Fricot A, Sissoko A, Shanti PAI, Candrawati F, Kambuaya NN, Rini H, Andries B, Hardy D, Margyaningsih NI, Fadllan F, Rahmayenti DA, Puspitasari AM, Aisah AR, Leonardo L, Yayang BTG, Margayani DS, Prayoga P, Trianty L, Kenangalem E, Price RN, Yeo TW, Minigo G, Noviyanti R, Poespoprodjo JR, Anstey NM, and Buffet PA

Subjects
Humans, Splenomegaly etiology, Erythrocytes, Plasmodium falciparum, Anemia complications, Malaria complications, Malaria, Falciparum complications, Malaria, Vivax complications
Abstract

Splenomegaly frequently occurs in patients with Plasmodium falciparum (Pf) or P. vivax (Pv) malarial anemia, but mechanisms underlying this co-occurrence are unclear. In malaria-endemic Papua, Indonesia, we prospectively analyzed red blood cell (RBC) concentrations in the spleen and spleen-mimetic retention in 37 subjects splenectomized for trauma or hyperreactive splenomegaly, most of whom were infected with Plasmodium. Splenomegaly (median 357 g [range: 80-1918 g]) was correlated positively with the proportion of red-pulp on histological sections (median 88.1% [range: 74%-99.4%]; r = .59, p = .0003) and correlated negatively with the proportion of white-pulp (median 8.3% [range: 0.4%-22.9%]; r = -.50, p = .002). The number of RBC per microscopic field (>95% uninfected) was correlated positively with spleen weight in both Pf-infected (r = .73; p = .017) and Pv-infected spleens (r = .94; p = .006). The median estimated proportion of total-body RBCs retained in Pf-infected spleens was 8.2% (range: 1.0%-33.6%), significantly higher than in Pv-infected (2.6% [range: 0.6%-23.8%]; p = .015) and PCR-negative subjects (2.5% [range: 1.0%-3.3%]; p = .006). Retained RBCs accounted for over half of circulating RBC loss seen in Pf infections. The proportion of total-body RBC retained in Pf- and Pv-infected spleens correlated negatively with hemoglobin concentrations (r = -.56, p = .0003), hematocrit (r = -.58, p = .0002), and circulating RBC counts (r = -.56, p = .0003). Splenic CD71-positive reticulocyte concentrations correlated with spleen weight in Pf (r = 1.0; p = .003). Retention rates of peripheral and splenic RBCs were correlated negatively with circulating RBC counts (r = -.69, p = .07 and r = -.83, p = .008, respectively). In conclusion, retention of mostly uninfected RBC in the spleen, leading to marked congestion of the red-pulp, was associated with splenomegaly and is the major mechanism of anemia in subjects infected with Plasmodium, particularly Pf., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Published
2024
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49. Seroprevalence of SARS-CoV-2 antibodies in Bali Province: Indonesia shows underdetection of COVID-19 cases by routine surveillance.

Author

Sawitri AAS, Yuliyatni PCD, Astuti PAS, Ajis E, Prasetyowati EB, Husni, Morgan J, Mika J, Praptiningsih CY, Mangiri A, Mulyadi E, Noviyanti R, Trianty L, and Hawley WA

Abstract

The international tourist destination of Bali reported its first case of Coronavirus Disease 2019 or COVID-19 in March 2020. To better understand the extent of exposure of Bali's 4.3 million inhabitants to the COVID-19 virus, we performed two repeated cross-sectional serosurveys stratified by urban and rural areas. We used a highly specific multiplex assay that detects antibodies to three different viral antigens. We also assessed demographic and social risk factors and history of symptoms. Our results show that the virus was widespread in Bali by late 2020, with 16.73% (95% CI 12.22-21.12) of the population having been infected by that time. We saw no differences in seroprevalence between urban and rural areas, possibly due to extensive population mixing, and similar levels of seroprevalence by gender and among age groups, except for lower seroprevalence in the very young. We observed no difference in seroprevalence between our two closely spaced surveys. Individuals reporting symptoms in the past six months were about twice as likely to be seropositive as those not reporting symptoms. Based upon official statistics for laboratory diagnosed cases for the six months prior to the survey, we estimate that for every reported case an additional 52 cases, at least, were undetected. Our results support the hypothesis that by late 2020 the virus was widespread in Bali, but largely undetected by surveillance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Published
2022
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50. Expression of Plasmodium vivax crt-o Is Related to Parasite Stage but Not Ex Vivo Chloroquine Susceptibility.

Author

Pava Z, Handayuni I, Wirjanata G, To S, Trianty L, Noviyanti R, Poespoprodjo JR, Auburn S, Price RN, and Marfurt J

Subjects
Amodiaquine pharmacology, Artemisinins pharmacology, Artesunate, Erythrocytes drug effects, Erythrocytes parasitology, Fructose-Bisphosphate Aldolase genetics, Fructose-Bisphosphate Aldolase metabolism, Gene Expression Regulation, Humans, Inhibitory Concentration 50, Life Cycle Stages genetics, Malaria, Vivax drug therapy, Malaria, Vivax parasitology, Mefloquine pharmacology, Membrane Transport Proteins metabolism, Plasmodium vivax genetics, Plasmodium vivax growth & development, Plasmodium vivax metabolism, Protozoan Proteins metabolism, Quinolines pharmacology, Transcription, Genetic, Tubulin genetics, Tubulin metabolism, Antimalarials pharmacology, Chloroquine pharmacology, Drug Resistance, Multiple genetics, Life Cycle Stages drug effects, Membrane Transport Proteins genetics, Plasmodium vivax drug effects, Protozoan Proteins genetics
Abstract

Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P < 0.001). Twenty-nine isolates fulfilled the criteria for ex vivo drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-o expression levels did not correlate with the ex vivo response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance., (Copyright © 2015 Pava et al.)

Published
2015
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