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1. Single cell transcriptomics shows that malaria promotes unique regulatory responses across multiple immune cell subsets

Author

Dooley, Nicholas L., Chabikwa, Tinashe G., Pava, Zuleima, Loughland, Jessica R., Hamelink, Julianne, Berry, Kiana, Andrew, Dean, Soon, Megan S. F., SheelaNair, Arya, Piera, Kim A., William, Timothy, Barber, Bridget E., Grigg, Matthew J., Engwerda, Christian R., Lopez, J. Alejandro, Anstey, Nicholas M., and Boyle, Michelle J.

Published
2023
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7. Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis

Author

Adhikari, Bipin, Anstey, Nicholas M, Assefa, Ashenafi, Boyd, Sarah C, Chau, Nguyen Hoang, Day, Nicholas PJ, Degaga, Tamiru Shibiru, Dondorp, Arjen M, Erhart, Annette, Ferreira, Marcelo Urbano, Ghimire, Prakash, Green, Justin A, Koh, Gavin CKW, Mekuria, Asrat Hailu, Mueller, Ivo, Naadim, Mohammad Nader, Nelwan, Erni J, Nosten, Francois, Price, David J, Sattabongkot, Jetsumon, Stepniewska, Kasia, von Seidlein, Lorenz, William, Timothy, Woodrow, Charles J, Woyessa, Adugna, Commons, Robert J, Rajasekhar, Megha, Edler, Peta, Abreha, Tesfay, Awab, Ghulam R, Baird, J Kevin, Barber, Bridget E, Chu, Cindy S, Cui, Liwang, Daher, André, Gonzalez-Ceron, Lilia, Grigg, Matthew J, Hwang, Jimee, Karunajeewa, Harin, Lacerda, Marcus V G, Ladeia-Andrade, Simone, Lidia, Kartini, Llanos-Cuentas, Alejandro, Longley, Rhea J, Pereira, Dhelio B, Pasaribu, Ayodhia P, Pukrittayakamee, Sasithon, Rijal, Komal R, Sutanto, Inge, Taylor, Walter R J, Thanh, Pham V, Thriemer, Kamala, Vieira, José Luiz F, Watson, James A, Zuluaga-Idarraga, Lina M, White, Nicholas J, Guerin, Philippe J, Simpson, Julie A, and Price, Ric N

Published
2024
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8. Primaquine dose and the risk of haemolysis in patients with uncomplicated Plasmodium vivax malaria: a systematic review and individual patient data meta-analysis

Author

Adhikari, Bipin, Alam, Mohammad Shafiul, Anstey, Nicholas M, Assefa, Ashenafi, Boyd, Sarah C, Chau, Nguyen Hoang, Day, Nicholas PJ, Degaga, Tamiru Shibiru, Dondorp, Arjen M, Ferreira, Marcelo Urbano, Ghimire, Prakash, Green, Justin A, Khan, Wasif Ali, Koh, Gavin CKW, Mekuria, Asrat Hailu, Naadim, Mohammad Nader, Nelwan, Erni J, Nosten, Francois, Pasaribu, Ayodhia Pitaloka, Price, David J, Stepniewska, Kasia, von Seidlein, Lorenz, William, Timothy, Woodrow, Charles J, Woyessa, Adugna, Rajasekhar, Megha, Simpson, Julie A, Ley, Benedikt, Edler, Peta, Chu, Cindy S, Abreha, Tesfay, Awab, Ghulam R, Baird, J Kevin, Bancone, Germana, Barber, Bridget E, Grigg, Matthew J, Hwang, Jimee, Karunajeewa, Harin, Lacerda, Marcus V G, Ladeia-Andrade, Simone, Llanos-Cuentas, Alejandro, Pukrittayakamee, Sasithon, Rijal, Komal R, Saravu, Kavitha, Sutanto, Inge, Taylor, Walter R J, Thriemer, Kamala, Watson, James A, Guerin, Philippe J, White, Nicholas J, Price, Ric N, and Commons, Robert J

Published
2024
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9. Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria.

Author

Rubach, Matthew P, Mukemba, Jackson P, Florence, Salvatore M, Lopansri, Bert K, Hyland, Keith, Simmons, Ryan A, Langelier, Charles, Nakielny, Sara, DeRisi, Joseph L, Yeo, Tsin W, Anstey, Nicholas M, Weinberg, J Brice, Mwaikambo, Esther D, and Granger, Donald L

Subjects
Neurosciences, Malaria, Pediatric, Vector-Borne Diseases, Rare Diseases, Brain Disorders, Clinical Research, Good Health and Well Being, Biopterin, Central Nervous System Diseases, Child, Child, Preschool, Female, Homovanillic Acid, Humans, Hydroxyindoleacetic Acid, Infant, Malaria, Cerebral, Male, Neopterin, Neurotransmitter Agents, Prospective Studies, Pterins, Reference Values, Tanzania, Tyrosine, cerebral malaria, neopterin, neurotransmitter, P falciparum, tetrahydrobiopterin, P falciparum, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

BackgroundCerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH4 and BH4-dependent neurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM.MethodsWe prospectively enrolled Tanzanian children with CM and children with nonmalaria central nervous system conditions (NMCs). We measured CSF levels of BH4, neopterin, and BH4-dependent neurotransmitter metabolites, 3-O-methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using published reference ranges.ResultsCerebrospinal fluid BH4 was elevated in CM (n = 49) compared with NMC (n = 51) (z-score 0.75 vs -0.08; P

Published
2021

10. Malaria

Author

Poespoprodjo, Jeanne Rini, Douglas, Nicholas M, Ansong, Daniel, Kho, Steven, and Anstey, Nicholas M

Published
2023
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12. Genomic epidemiology of Plasmodium knowlesi reveals putative genetic drivers of adaptation in Malaysia.

Author

Westaway, Jacob, primary, Diez Benavente, Ernest, additional, Auburn, Sarah, additional, Kucharski, Michal, additional, Aranciaga, Nicolas, additional, Nayak, Sourav, additional, William, Timothy, additional, Rajahram, Giri S, additional, Piera, Kim A, additional, Braima, Kamil, additional, Tan, Angelica F, additional, Alaza, Danshy, additional, Barber, Bridget E, additional, Drakeley, Chris, additional, Amato, Roberto, additional, Sutanto, Edwin, additional, Trimarsanto, Hidayat, additional, Anstey, Nicholas M, additional, Bozdech, Zbynek, additional, Field, Matthew, additional, and Grigg, Matthew J, additional

Published
2024
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16. 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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18. Plasmodium vivax malaria serological exposure markers: Assessing the degree and implications of cross-reactivity with P. knowlesi

Author

Longley, Rhea J., Grigg, Matthew J., Schoffer, Kael, Obadia, Thomas, Hyslop, Stephanie, Piera, Kim A., Nekkab, Narimane, Mazhari, Ramin, Takashima, Eizo, Tsuboi, Takafumi, Harbers, Matthias, Tetteh, Kevin, Drakeley, Chris, Chitnis, Chetan E., Healer, Julie, Tham, Wai-Hong, Sattabongkot, Jetsumon, White, Michael T., Cooper, Daniel J., Rajahram, Giri S., Barber, Bridget E., William, Timothy, Anstey, Nicholas M., and Mueller, Ivo

Published
2022
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19. Neutrophil activation, acute lung injury and disease severity in Plasmodium knowlesi malaria.

Author

Tan, Angelica F., Sakam, Sitti Saimah binti, Piera, Kim, Rajahram, Giri S., William, Timothy, Barber, Bridget E., Anstey, Nicholas M., Grigg, Matthew J., and Kho, Steven

Subjects
LEUCOCYTES, LEUCOCYTE elastase, HOSPITAL admission & discharge, MALARIA, NEUTROPHILS
Abstract

The risk of severe malaria from the zoonotic parasite Plasmodium knowlesi approximates that from P. falciparum. In severe falciparum malaria, neutrophil activation contributes to inflammatory pathogenesis, including acute lung injury. The role of neutrophil activation in the pathogenesis of severe knowlesi malaria has not been examined. We evaluated 213 patients with P. knowlesi mono-infection (138 non-severe, 75 severe) and 49 Plasmodium-negative controls from Malaysia. Markers of neutrophil activation (soluble neutrophil elastase [NE], citrullinated histone [CitH3] and circulating neutrophil extracellular traps [NETs]) were quantified in peripheral blood by microscopy and immunoassays. Findings were correlated with malaria severity, ALI clinical criteria, biomarkers of parasite biomass, haemolysis, and endothelial activation. Neutrophil activation increased with disease severity, with median levels higher in severe than non-severe malaria and controls for NE (380[IQR:210–930]ng/mL, 236[139–448]ng/mL, 218[134–307]ng/mL, respectively) and CitH3 (8.72[IQR:3.0–23.1]ng/mL, 4.29[1.46–9.49]ng/mL, 1.53[0.6–2.59]ng/mL, respectively)[all p<0.01]. NETs were higher in severe malaria compared to controls (126/μL[IQR:49–323] vs 51[20–75]/μL, p<0.001). In non-severe malaria, neutrophil activation fell significantly upon discharge from hospital (p<0.03). In severe disease, NETs, NE, and CitH3 were correlated with parasitaemia, cell-free haemoglobin and angiopoietin-2 (all Pearson's r>0.24, p<0.05). Plasma NE and angiopoietin-2 were higher in knowlesi patients with ALI than those without (p<0.008); neutrophilia was associated with an increased risk of ALI (aOR 3.27, p<0.01). In conclusion, neutrophil activation is increased in ALI and in proportion to disease severity in knowlesi malaria, is associated with endothelial activation, and may contribute to disease pathogenesis. Trials of adjunctive therapies to regulate neutrophil activation are warranted in severe knowlesi malaria. Author summary: The most common malaria in Malaysia is caused by animal-to-human transmission of Plasmodium knowlesi from its natural monkey hosts to humans via mosquito bites. As the human immune system responds to such infection, white blood cells such as neutrophils are recruited, activated and release products with pathogen-killing activity. There is increasing evidence that neutrophil products cause damage to the host and contribute to severe disease. While this has been studied in human-only malaria, the role of neutrophils in zoonotic P. knowlesi malaria is poorly understood. In this study, we examined three markers of neutrophil activation (neutrophil elastase, citrullinated histone H3 and neutrophil extracellular traps) in hospital patients with severe and non-severe knowlesi malaria from Sabah, East Malaysia. Compared to healthy controls, neutrophil activation was increased in patients with knowlesi malaria in proportion to disease severity. The increase in neutrophil activation was also linked to different types of severe malaria manifestations, especially acute lung injury. These findings have implications for development of new strategies to prevent host organ damage for better treatment of severe knowlesi malaria. [ABSTRACT FROM AUTHOR]

Published
2024
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20. 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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22. Updating estimates of Plasmodium knowlesi malaria risk in response to changing land use patterns across Southeast Asia

Author

Tobin, Ruarai J., primary, Harrison, Lucinda E., additional, Tully, Meg K., additional, Lubis, Inke N. D., additional, Noviyanti, Rintis, additional, Anstey, Nicholas M., additional, Rajahram, Giri S., additional, Grigg, Matthew J., additional, Flegg, Jennifer A., additional, Price, David J., additional, and Shearer, Freya M., additional

Published
2024
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23. Longitudinal changes in iron homeostasis in human experimental and clinical malaria

Author

Woolley, Stephen D, primary, Grigg, Matthew J, additional, Marquart, Louise, additional, Gower, Jeremy, additional, Piera, Kim, additional, Sheela Nair, Arya, additional, Amante, Fiona M, additional, Rajahram, Giri S, additional, William, Timothy, additional, Frazer, David M, additional, Chalon, Stephan, additional, McCarthy, James S, additional, Anstey, Nicholas M, additional, and Barber, Bridget E, additional

Published
2023
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26. Monocyte polarization in children with falciparum malaria: relationship to nitric oxide insufficiency and disease severity

Author

Weinberg, J Brice, Volkheimer, Alicia D, Rubach, Matthew P, Florence, Salvatore M, Mukemba, Jackson P, Kalingonji, Ayam R, Langelier, Charles, Chen, Youwei, Bush, Margaret, Yeo, Tsin W, Granger, Donald L, Anstey, Nicholas M, and Mwaikambo, Esther D

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Malaria, Rare Diseases, Infectious Diseases, Vector-Borne Diseases, Pediatric, Infection, Good Health and Well Being, Antigens, CD, Arginase, Arginine, Biomarkers, Cell Polarity, Chemokines, Child, Child, Preschool, Female, Humans, Malaria, Falciparum, Male, Models, Biological, Monocytes, Nitric Oxide, Phagocytes, Severity of Illness Index
Abstract

We earlier established that nitric oxide (NO) is protective against severe malaria and that arginine and NO levels are reduced in malaria patients. We now show that an M2-like blood monocyte phenotype is significantly associated with hypoargininemia, NO insufficiency, and disease severity in Tanzanian children with falciparum malaria. Compared to control children (n = 106), children with moderately severe (n = 77) and severe falciparum malaria (n = 129) had significantly higher mononuclear cell arginase 1 mRNA, protein, and enzyme activity; lower NOS2 mRNA; lower plasma arginine; and higher plasma IL-10, IL-13, and IL-4. In addition, monocyte CD206 and CD163 and plasma soluble CD163 were elevated. Multivariate logistic regression analysis revealed a significant correlation of risk of severe malaria with both plasma IL-10 and soluble CD163 levels. Monocyte M2 skewing likely contributes to NO bioinsufficiency in falciparum malaria in children. Treatments that reverse the M2 polarization may have potential as adjunctive treatment for malaria.

Published
2016

27. 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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29. Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria : A Randomized, Controlled, Open-Label Trial

Author

Plewes, Katherine, Kingston, Hugh W. F., Ghose, Aniruddha, Wattanakul, Thanaporn, Hassan, Md. Mahtab Uddin, Haider, Md. Shafiul, Dutta, Prodip K., Islam, Md. Akhterul, Alam, Shamsul, Jahangir, Selim Md., Zahed, A. S. M., Sattar, Md. Abdus, Chowdhury, M. A. Hassan, Herdman, M. Trent, Leopold, Stije J., Ishioka, Haruhiko, Piera, Kim A., Charunwatthana, Prakaykaew, Silamut, Kamolrat, Yeo, Tsin W., Lee, Sue J., Mukaka, Mavuto, Maude, Richard J., Turner, Gareth D. H., Faiz, Md. Abul, Tarning, Joel, Oates, John A., Anstey, Nicholas M., White, Nicholas J., Day, Nicholas P. J., Hossain, Md. Amir, Roberts, L. Jackson, and Dondorp, Arjen M.

Published
2018

30. Rickettsioses as Major Etiologies of Unrecognized Acute Febrile Illness, Sabah, East Malaysia

Author

Grigg, Matthew J., William, Timothy, Clemens, Emily G., Patel, Kaajal, Chandna, Arjun, Wilkes, Christopher S., Barber, Bridget E., Anstey, Nicholas M., Dumler, J. Stephen, Yeo, Tsin W., and Reller, Megan E.

Subjects
EDTA, Immunoglobulin G, Health
Abstract

Rickettsioses and related infections, including scrub typhus, caused by Orientia tsutsugamushi; spotted fever group rickettsioses (SFGR), often called tick typhus; and typhus group rickettsioses (TGR), also called murine typhus, are [...]

Published
2020
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33. Plasmodium knowlesi detection methods for human infections—Diagnosis and surveillance

Author

Grigg, Matthew J., primary, Lubis, Inke N., additional, Tetteh, Kevin K.A., additional, Barber, Bridget E., additional, William, Timothy, additional, Rajahram, Giri S., additional, Tan, Angelica F., additional, Sutherland, Colin J., additional, Noviyanti, Rintis, additional, Drakeley, Chris J., additional, Britton, Sumudu, additional, and Anstey, Nicholas M., additional

Published
2021
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36. The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis

Author

Commons, Robert J, Simpson, Julie A, Thriemer, Kamala, Humphreys, Georgina S, Abreha, Tesfay, Alemu, Sisay G, Añez, Arletta, Anstey, Nicholas M, Awab, Ghulam R, Baird, J Kevin, Barber, Bridget E, Borghini-Fuhrer, Isabelle, Chu, Cindy S, D'Alessandro, Umberto, Dahal, Prabin, Daher, André, de Vries, Peter J, Erhart, Annette, Gomes, Margarete S M, Gonzalez-Ceron, Lilia, Grigg, Matthew J, Heidari, Aliehsan, Hwang, Jimee, Kager, Piet A, Ketema, Tsige, Khan, Wasif A, Lacerda, Marcus V G, Leslie, Toby, Ley, Benedikt, Lidia, Kartini, Monteiro, Wuelton M, Nosten, Francois, Pereira, Dhelio B, Phan, Giao T, Phyo, Aung P, Rowland, Mark, Saravu, Kavitha, Sibley, Carol H, Siqueira, André M, Stepniewska, Kasia, Sutanto, Inge, Taylor, Walter R J, Thwaites, Guy, Tran, Binh Q, Tran, Hien T, Valecha, Neena, Vieira, José Luiz F, Wangchuk, Sonam, William, Timothy, Woodrow, Charles J, Zuluaga-Idarraga, Lina, Guerin, Philippe J, White, Nicholas J, and Price, Ric N

Published
2018
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49. 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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50. Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study

Author

Woodford, John, Gillman, Ashley, Jenvey, Peter, Roberts, Jennie, Woolley, Stephen, Barber, Bridget E., Fernandez, Melissa, Rose, Stephen, Thomas, Paul, Anstey, Nicholas M., and McCarthy, James S.

Subjects
Spleen -- Health aspects -- Physiological aspects, Plasmodium vivax -- Physiological aspects, PET imaging -- Usage, Magnetic resonance imaging -- Usage, Malaria -- Development and progression -- Complications and side effects -- Physiological aspects, Glucose metabolism -- Health aspects, Host-parasite relationships -- Physiological aspects, Biological sciences
Abstract

Background Plasmodium vivax has been proposed to infect and replicate in the human spleen and bone marrow. Compared to Plasmodium falciparum, which is known to undergo microvascular tissue sequestration, little is known about the behavior of P. vivax outside of the circulating compartment. This may be due in part to difficulties in studying parasite location and activity in life. Methods and findings To identify organ-specific changes during the early stages of P. vivax infection, we performed 18-F fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) at baseline and just prior to onset of clinical illness in P. vivax experimentally induced blood-stage malaria (IBSM) and compared findings to P. falciparum IBSM. Seven healthy, malaria-naive participants were enrolled from 3 IBSM trials: NCT02867059, ACTRN12616000174482, and ACTRN12619001085167. Imaging took place between 2016 and 2019 at the Herston Imaging Research Facility, Australia. Postinoculation imaging was performed after a median of 9 days in both species (n = 3 P. vivax; n = 4 P. falciparum). All participants were aged between 19 and 23 years, and 6/7 were male. Splenic volume (P. vivax: +28.8% [confidence interval (CI) +10.3% to +57.3%], P. falciparum: +22.9 [CI -15.3% to +61.1%]) and radiotracer uptake (P. vivax: +15.5% [CI -0.7% to +31.7%], P. falciparum: +5.5% [CI +1.4% to +9.6%]) increased following infection with each species, but more so in P. vivax infection (volume: p = 0.72, radiotracer uptake: p = 0.036). There was no change in FDG uptake in the bone marrow (P. vivax: +4.6% [CI -15.9% to +25.0%], P. falciparum: +3.2% [CI -3.2% to +9.6%]) or liver (P. vivax: +6.2% [CI -8.7% to +21.1%], P. falciparum: -1.4% [CI -4.6% to +1.8%]) following infection with either species. In participants with P. vivax, hemoglobin, hematocrit, and platelet count decreased from baseline at the time of postinoculation imaging. Decrements in hemoglobin and hematocrit were significantly greater in participants with P. vivax infection compared to P. falciparum. The main limitations of this study are the small sample size and the inability of this tracer to differentiate between host and parasite metabolic activity. Conclusions PET/MRI indicated greater splenic tropism and metabolic activity in early P. vivax infection compared to P. falciparum, supporting the hypothesis of splenic accumulation of P. vivax very early in infection. The absence of uptake in the bone marrow and liver suggests that, at least in early infection, these tissues do not harbor a large parasite biomass or do not provoke a prominent metabolic response. PET/MRI is a safe and noninvasive method to evaluate infection-associated organ changes in morphology and glucose metabolism., Author(s): John Woodford 1,2,*, Ashley Gillman 3, Peter Jenvey 4, Jennie Roberts 4, Stephen Woolley 1,5, Bridget E. Barber 1,6, Melissa Fernandez 1, Stephen Rose 3, Paul Thomas 7, Nicholas [...]

Published
2021
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