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3. Malaria: Targeting parasite and host cell kinomes

Author

Doerig, Christian, Abdi, Abdirahman, Bland, Nicholas, Eschenlauer, Sylvain, Dorin-Semblat, Dominique, Fennell, Clare, Halbert, Jean, Holland, Zoe, Nivez, Marie-Paule, Semblat, Jean-Philippe, Sicard, Audrey, and Reininger, Luc

Published
2010
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6. Plasmodium-infected erythrocytes induce secretion of IGFBP7 to form type II rosettes and escape phagocytosis

Author

Lee, Wenn-Chyau, primary, Russell, Bruce, additional, Sobota, Radoslaw Mikolaj, additional, Ghaffar, Khairunnisa, additional, Howland, Shanshan W, additional, Wong, Zi Xin, additional, Maier, Alexander G, additional, Dorin-Semblat, Dominique, additional, Biswas, Subhra, additional, Gamain, Benoit, additional, Lau, Yee-Ling, additional, Malleret, Benoit, additional, Chu, Cindy, additional, Nosten, François, additional, and Renia, Laurent, additional

Published
2020
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7. Author response: Plasmodium-infected erythrocytes induce secretion of IGFBP7 to form type II rosettes and escape phagocytosis

Author

Lee, Wenn-Chyau, primary, Russell, Bruce, additional, Sobota, Radoslaw Mikolaj, additional, Ghaffar, Khairunnisa, additional, Howland, Shanshan W, additional, Wong, Zi Xin, additional, Maier, Alexander G, additional, Dorin-Semblat, Dominique, additional, Biswas, Subhra, additional, Gamain, Benoit, additional, Lau, Yee-Ling, additional, Malleret, Benoit, additional, Chu, Cindy, additional, Nosten, François, additional, and Renia, Laurent, additional

Published
2020
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9. Involvement of Plasmodium falciparum protein kinase CK2 in the chromatin assembly pathway

Author

Dastidar Eeshita G, Dayer Guillem, Holland Zoe M, Dorin-Semblat Dominique, Claes Aurélie, Chêne Arnaud, Sharma Amit, Hamelin Romain, Moniatte Marc, Lopez-Rubio Jose-Juan, Scherf Artur, and Doerig Christian

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Background Protein kinase CK2 is a pleiotropic serine/threonine protein kinase with hundreds of reported substrates, and plays an important role in a number of cellular processes. The cellular functions of Plasmodium falciparum CK2 (PfCK2) are unknown. The parasite's genome encodes one catalytic subunit, PfCK2α, which we have previously shown to be essential for completion of the asexual erythrocytic cycle, and two putative regulatory subunits, PfCK2β1 and PfCK2β2. Results We now show that the genes encoding both regulatory PfCK2 subunits (PfCK2β1 and PfCK2β2) cannot be disrupted. Using immunofluorescence and electron microscopy, we examined the intra-erythrocytic stages of transgenic parasite lines expressing hemagglutinin (HA)-tagged catalytic and regulatory subunits (HA-CK2α, HA-PfCK2β1 or HA-PfCK2β2), and localized all three subunits to both cytoplasmic and nuclear compartments of the parasite. The same transgenic parasite lines were used to purify PfCK2β1- and PfCK2β2-containing complexes, which were analyzed by mass spectrometry. The recovered proteins were unevenly distributed between various pathways, with a large proportion of components of the chromatin assembly pathway being present in both PfCK2β1 and PfCK2β2 precipitates, implicating PfCK2 in chromatin dynamics. We also found that chromatin-related substrates such as nucleosome assembly proteins (Naps), histones, and two members of the Alba family are phosphorylated by PfCK2α in vitro. Conclusions Our reverse-genetics data show that each of the two regulatory PfCK2 subunits is required for completion of the asexual erythrocytic cycle. Our interactome study points to an implication of PfCK2 in many cellular pathways, with chromatin dynamics being identified as a major process regulated by PfCK2. This study paves the way for a kinome-wide interactomics-based approach to elucidate protein kinase function in malaria parasites.

Published
2012
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10. Phosphorylation of the VAR2CSA extracellular region is associated with enhanced adhesive properties to the placental receptor CSA

Author

Dorin-Semblat, Dominique, primary, Tétard, Marilou, additional, Claës, Aurélie, additional, Semblat, Jean-Philippe, additional, Dechavanne, Sébastien, additional, Fourati, Zaineb, additional, Hamelin, Romain, additional, Armand, Florence, additional, Matesic, Graziella, additional, Nunes-Silva, Sofia, additional, Srivastava, Anand, additional, Gangnard, Stéphane, additional, Lopez-Rubio, Jose-Juan, additional, Moniatte, Marc, additional, Doerig, Christian, additional, Scherf, Artur, additional, and Gamain, Benoît, additional

Published
2019
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11. Heterozygous HbAC but not HbAS is associated with higher newborn birthweight among women with pregnancy-associated malaria

Author

Tétard , Marilou, Milet , Jacqueline, Dechavanne , Sébastien, Fievet , Nadine, Dorin-Semblat , Dominique, Elion , Jacques, Fairhurst , Rick, Deloron , Philippe, Tuikue-Ndam , Nicaise, Gamain , Benoît, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Communautés d’universités et établissements Sorbonne Paris Cité (COMUE Sorbonne Paris Cité), Université Sorbonne Paris Cité (USPC)-Chimie ParisTech-Université Paris sciences et lettres (PSL), Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases-National Institutes of Health, Gamain, Benoit, Biologie Intégrée du Globule Rouge ( BIGR ), Institut National de la Transfusion Sanguine [Paris] ( INTS ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université de la Réunion ( UR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles ( UA ), Mère et enfant face aux infections tropicales ( MERIT - UMR_D 216 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut de Recherche pour le Développement ( IRD ), Communautés d’universités et établissements Sorbonne Paris Cité ( COMUE Sorbonne Paris Cité ), and Université Sorbonne Paris Cité ( USPC ) -Chimie ParisTech-Paris Sciences et Lettres ( PSL )

Subjects
Heterozygote, Genotype, Science, Hemoglobins, Abnormal, [SDV]Life Sciences [q-bio], Hemoglobin, Sickle, malaria, Gestational Age, Article, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, parasitic diseases, Birth Weight, Humans, Prospective Studies, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, reproductive and urinary physiology, [ SDV ] Life Sciences [q-bio], Hemoglobin A, [SDV] Life Sciences [q-bio], Africa, Western, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, plasmodium, Pregnancy Complications, Parasitic, Medicine, Female, pregnancy
Abstract

International audience; Pregnancy-associated malaria (PAM) is associated with poor pregnancy outcomes. Hemoglobin S (HbS) and hemoglobin C (HbC) mutations are frequently encountered in malaria-endemic areas of Africa, where they protect children from severe and uncomplicated Plasmodium falciparum malaria. However, scant epidemiological data exist on the impact of these Hb variants on PAM. A prospective cohort of 635 Beninese pregnant women was recruited before 24 weeks of gestational age and followed until the end of pregnancy. HbAA, HbAC, and HbAS genotypes were determined and tested for association with pregnancy outcomes and PAM indicators using linear and logistic multivariate models. Newborns from HbAC mothers had higher birthweights than those from HbAA mothers among women infected at any time during pregnancy (mean difference 182.9 g, p = 0.08), or during the first half of pregnancy (654.3 g, p = 0.0006). No such birthweight differences were observed between newborns from HbAS and HbAA mothers. HbAC and HbAS were not associated with other pregnancy outcomes or PAM indicators. In conclusion, HbAC but not HbAS is associated with an improved birth outcome in pregnant women with documented PAM. Higher-birthweight newborns from HbAC mothers may have a survival advantage that contributes to the natural selection of HbC in malaria-endemic areas.

Published
2017

12. Characterization of Plasmodium falciparum Atypical Kinase PfPK7– Dependent Phosphoproteome

Author

Pease, Brittany N., primary, Huttlin, Edward L., additional, Jedrychowski, Mark P., additional, Dorin-Semblat, Dominique, additional, Sebastiani, Daniela, additional, Segarra, Daniel T., additional, Roberts, Bracken F., additional, Chakrabarti, Ratna, additional, Doerig, Christian, additional, Gygi, Steven P., additional, and Chakrabarti, Debopam, additional

Published
2018
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13. Plasmodium falciparum Adhesins Play an Essential Role in Signalling and Activation of Invasion into Human Erythrocytes

Author

Tham, Wai-Hong, primary, Lim, Nicholas T. Y., additional, Weiss, Greta E., additional, Lopaticki, Sash, additional, Ansell, Brendan R. E., additional, Bird, Megan, additional, Lucet, Isabelle, additional, Dorin-Semblat, Dominique, additional, Doerig, Christian, additional, Gilson, Paul R., additional, Crabb, Brendan S., additional, and Cowman, Alan F., additional

Published
2015
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15. Characterization of Plasmodium falciparumAtypical Kinase PfPK7–Dependent Phosphoproteome

Author

Pease, Brittany N., Huttlin, Edward L., Jedrychowski, Mark P., Dorin-Semblat, Dominique, Sebastiani, Daniela, Segarra, Daniel T., Roberts, Bracken F., Chakrabarti, Ratna, Doerig, Christian, Gygi, Steven P., and Chakrabarti, Debopam

Abstract

PfPK7 is an “orphan” kinase displaying regions of homology to multiple protein kinase families. PfPK7 functions in regulating parasite proliferation/development as evident from the phenotype analysis of knockout parasites. Despite this regulatory role, the functions of PfPK7 in signaling pathways are not known. To better understand PfPK7-regulated phosphorylation events, we performed isobaric tag-based quantitative comparative phosphoproteomics of the schizont and segmenter stages from wild-type and pfpk7-parasite lines. This analysis identified 3,875 phosphorylation sites on 1,047 proteins. Among these phosphorylation events, 146 proteins with 239 phosphorylation sites displayed reduction in phosphorylation in the absence of PfPK7. Further analysis of the phosphopeptides revealed three motifs whose phosphorylation was down regulated in the pfpk7–cell line in both schizonts and segmenters. Decreased phosphorylation following loss of PfPK7 indicates that these proteins may function as direct substrates of PfPK7. We demonstrated that PfPK7 is active toward three of these potential novel substrates; however, PfPK7 did not phosphorylate many of the other proteins, suggesting that decreased phosphorylation in these proteins is an indirect effect. Our phosphoproteomics analysis is the first study to identify direct substrates of PfPK7 and reveals potential downstream or compensatory signaling pathways.

Published
2018
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16. Plasmodium falciparum NIMA-related kinase Pfnek-1: sex specificity and assessment of essentiality for the erythrocytic asexual cycle

Author

Dorin-semblat, Dominique, Schmitt, Sophie, Semblat, Jean-philippe, Sicard, Audrey, Reininger, Luc, Goldring, Dean, Patterson, Shelley, Quashie, Neils, Chakrabarti, Debopam, Meijer, Laurent, Doerig, Christian, Dorin-semblat, Dominique, Schmitt, Sophie, Semblat, Jean-philippe, Sicard, Audrey, Reininger, Luc, Goldring, Dean, Patterson, Shelley, Quashie, Neils, Chakrabarti, Debopam, Meijer, Laurent, and Doerig, Christian

Abstract

The Plasmodium falciparum kinome includes a family of four protein kinases (Pfnek-1 to -4) related to the NIMA (never-in-mitosis) family, members of which play important roles in mitosis and meiosis in eukaryotic cells. Only one of these, Pfnek-1, which we previously characterized at the biochemical level, is expressed in asexual parasites. The other three (Pfnek-2, -3 and -4) are expressed predominantly in gametocytes, and a role for nek-2 and nek-4 in meiosis has been documented. Here we show by reverse genetics that Pfnek-1 is required for completion of the asexual cycle in red blood cells and that its expression in gametocytes in detectable by immunofluorescence in male (but not in female) gametocytes, in contrast with Pfnek-2 and Pfnek-4. This indicates that the function of Pfnek-1 is non-redundant with those of the other members of the Pfnek family and identifies Pfnek-1 as a potential target for antimalarial chemotherapy. A medium-throughput screen of a small-molecule library provides proof of concept that recombinant Pfnek-1 can be used as a target in drug discovery.

Published
2011
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17. Synthesis of 3-(1,2,3-triazol-1-yl)- and 3-(1,2,3-triazol-4-yl)-substituted pyrazolo[3,4-d]pyrimidin-4-amines via click chemistry : potential inhibitors of the Plasmodium falciparum PfPK7 protein kinase

Author

Klein, Michael, Dinér, Peter, Dorin-Semblat, Dominique, Doerig, Christian, Grøtli, Morten, Klein, Michael, Dinér, Peter, Dorin-Semblat, Dominique, Doerig, Christian, and Grøtli, Morten

Abstract

Efficient routes to 3-(1,2,3-triazol-1-yl)- and 3-(1,2,3-triazol-4-yl)pyrazolo[3,4-d]pyrimidin-4-amines using a one-pot two-step reaction are presented. The two routes give easy access to two different isomers of 1,4-disubstituted triazoles and the target compounds are obtained from a variety of readily available aromatic and aliphatic halides without isolation of potentially unstable organic azide intermediates. Two compounds show activity towards the PfPK7 kinase (IC(50) 10-20 microM) of P. falciparum, the organism responsible for the most virulent form of malaria, and can be regarded as hits useful for further development into lead compounds.

Published
2009
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18. An atypical cyclin-dependent kinase controls Plasmodium falciparum proliferation rate

Author

Dorin-Semblat, Dominique, primary, Carvalho, Teresa Gil, additional, Nivez, Marie-Paule, additional, Halbert, Jean, additional, Poullet, Patrick, additional, Semblat, Jean-Philippe, additional, Goldring, Dean, additional, Chakrabarti, Debopam, additional, Mehra, Parul, additional, Dhar, Suman, additional, Paing, May M., additional, Goldberg, Daniel E., additional, McMillan, Paul J., additional, Tilley, Leann, additional, and Doerig, Christian, additional

Published
2013
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19. A NIMA-related protein kinase is essential for completion of the sexual cycle of malaria parasites

Author

Reininger, Luc, Billker, Oliver, Tewari, Rita, Mukhopadhyay, Arunima, Fennell, Clare, Dorin-Semblat, Dominique, Doerig, Caroline, Goldring, Dean, Harmse, Leonie, Ranford-Cartwright, Lisa, Packer, Jeremy, Doerig, Christian, Reininger, Luc, Billker, Oliver, Tewari, Rita, Mukhopadhyay, Arunima, Fennell, Clare, Dorin-Semblat, Dominique, Doerig, Caroline, Goldring, Dean, Harmse, Leonie, Ranford-Cartwright, Lisa, Packer, Jeremy, and Doerig, Christian

Abstract

The molecular mechanisms regulating the sexual development of malaria parasites from gametocytes to oocysts in their mosquito vector are still largely unexplored. In other eukaryotes, NIMA-related kinases (Neks) regulate cell cycle progression and have been implicated in the regulation of meiosis. Here, we demonstrate that Nek-4, a new Plasmodium member of the Nek family, is essential for completion of the sexual cycle of the parasite. Recombinant Plasmodium falciparum Nek-4 possesses protein kinase activity and displays substrate preferences similar to those of other Neks. Nek-4 is highly expressed in gametocytes, yet disruption of the nek-4 gene in the rodent malaria parasite P. berghei has no effect on gamete formation and subsequent fertilization. However, further differentiation of zygotes into ookinetes is abolished. Measurements of nuclear DNA content indicate that zygotes lacking Nek-4 fail to undergo the genome replication to the tetraploid level that precedes meiosis. Cell cycle progression in the zygote is identified as a likely precondition for its morphological transition to the ookinete and for the successful establishment of a malaria infection in the mosquito.

Published
2005
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20. Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum

Author

Solyakov, Lev, primary, Halbert, Jean, additional, Alam, Mahmood M., additional, Semblat, Jean-Philippe, additional, Dorin-Semblat, Dominique, additional, Reininger, Luc, additional, Bottrill, Andrew R., additional, Mistry, Sharad, additional, Abdi, Abdirhaman, additional, Fennell, Clare, additional, Holland, Zoe, additional, Demarta, Claudia, additional, Bouza, Yvan, additional, Sicard, Audrey, additional, Nivez, Marie-Paule, additional, Eschenlauer, Sylvain, additional, Lama, Tenzing, additional, Thomas, Divya Catherine, additional, Sharma, Pushkar, additional, Agarwal, Shruti, additional, Kern, Selina, additional, Pradel, Gabriele, additional, Graciotti, Michele, additional, Tobin, Andrew B., additional, and Doerig, Christian, additional

Published
2011
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21. Plasmodium falciparum NIMA-related kinase Pfnek-1: sex specificity and assessment of essentiality for the erythrocytic asexual cycle

Author

Dorin-Semblat, Dominique, primary, Schmitt, Sophie, additional, Semblat, Jean-Philippe, additional, Sicard, Audrey, additional, Reininger, Luc, additional, Goldring, Dean, additional, Patterson, Shelley, additional, Quashie, Neils, additional, Chakrabarti, Debopam, additional, Meijer, Laurent, additional, and Doerig, Christian, additional

Published
2011
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22. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes

Author

Sicard, Audrey, primary, Semblat, Jean-Philippe, additional, Doerig, Caroline, additional, Hamelin, Romain, additional, Moniatte, Marc, additional, Dorin-Semblat, Dominique, additional, Spicer, Julie A., additional, Srivastava, Anubhav, additional, Retzlaff, Silke, additional, Heussler, Volker, additional, Waters, Andrew P., additional, and Doerig, Christian, additional

Published
2011
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28. A NIMA-related Protein Kinase Is Essential for Completion of the Sexual Cycle of Malaria Parasites

Author

Reininger, Luc, primary, Billker, Oliver, additional, Tewari, Rita, additional, Mukhopadhyay, Arunima, additional, Fennell, Clare, additional, Dorin-Semblat, Dominique, additional, Doerig, Caroline, additional, Goldring, Dean, additional, Harmse, Leonie, additional, Ranford-Cartwright, Lisa, additional, Packer, Jeremy, additional, and Doerig, Christian, additional

Published
2005
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29. Disruption of the PfPK7 Gene Impairs Schizogony and Sporogony in the Human Malaria Parasite Plasmodium falciparum

Author

Dorin-Semblat, Dominique, Sicard, Audrey, Doerig, Caroline, Ranford-Cartwright, Lisa, and Doerig, Christian

Abstract

PfPK7 is an orphan protein kinase of Plasmodium falciparum with maximal homology to MEK3/6 and to fungal protein kinase A proteins in its C-terminal and N-terminal regions, respectively. We showed previously that recombinant PfPK7 is active on various substrates but is unable to phosphorylate the Plasmodium falciparum mitogen-activated protein kinase homologues, suggesting that it is not a MEK functional homologue. Using a reverse genetics approach to investigate the function of this enzyme in live parasites, we now show that PfPK7–parasite clones display phenotypes at two stages of their life cycle: first, a decrease in the rate of asexual growth in erythrocytes associated with a lower number of daughter merozoites generated per schizont, and second, a dramatic reduction in the ability to produce oocysts in the mosquito vector. A normal asexual growth rate and the ability to produce oocysts are restored if a functional copy of the PfPK7 gene is reintroduced into the PfPK7–parasites. Hence, PfPK7 is involved in a pathway that regulates parasite proliferation and development.

Published
2008

30. Disruption of the PfPK7Gene Impairs Schizogony and Sporogony in the Human Malaria Parasite Plasmodium falciparum

Author

Dorin-Semblat, Dominique, Sicard, Audrey, Doerig, Caroline, Ranford-Cartwright, Lisa, and Doerig, Christian

Abstract

ABSTRACTPfPK7 is an orphan protein kinase of Plasmodium falciparumwith maximal homology to MEK3/6 and to fungal protein kinase A proteins in its C-terminal and N-terminal regions, respectively. We showed previously that recombinant PfPK7 is active on various substrates but is unable to phosphorylate the Plasmodium falciparummitogen-activated protein kinase homologues, suggesting that it is not a MEK functional homologue. Using a reverse genetics approach to investigate the function of this enzyme in live parasites, we now show that PfPK7-parasite clones display phenotypes at two stages of their life cycle: first, a decrease in the rate of asexual growth in erythrocytes associated with a lower number of daughter merozoites generated per schizont, and second, a dramatic reduction in the ability to produce oocysts in the mosquito vector. A normal asexual growth rate and the ability to produce oocysts are restored if a functional copy of the PfPK7gene is reintroduced into the PfPK7-parasites. Hence, PfPK7 is involved in a pathway that regulates parasite proliferation and development.

Published
2008
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31. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes

Author

Sicard, Audrey, Semblat, Jean-Philippe, Doerig, Caroline, Hamelin, Romain, Moniatte, Marc, Dorin-Semblat, Dominique, Spicer, Julie A., Srivastava, Anubhav, Retzlaff, Silke, Heussler, Volker, Waters, Andrew P., and Doerig, Christian

Subjects
Plasmodium-Falciparum, In-Vitro, Map Kinases, parasitic diseases, Cell, Mechanism, Involvement, Protein-Kinase, Phosphorylation, Inhibition, Cancer
Abstract

P>Merozoites of malaria parasites invade red blood cells (RBCs), where they multiply by schizogony, undergoing development through ring, trophozoite and schizont stages that are responsible for malaria pathogenesis. Here, we report that a protein kinase-mediated signalling pathway involving host RBC PAK1 and MEK1, which do not have orthologues in the Plasmodium kinome, is selectively stimulated in Plasmodium falciparum-infected (versus uninfected) RBCs, as determined by the use of phospho-specific antibodies directed against the activated forms of these enzymes. Pharmacological interference with host MEK and PAK function using highly specific allosteric inhibitors in their known cellular IC50 ranges results in parasite death. Furthermore, MEK inhibitors have parasiticidal effects in vitro on hepatocyte and erythrocyte stages of the rodent malaria parasite Plasmodium berghei, indicating conservation of this subversive strategy in malaria parasites. These findings have profound implications for the development of novel strategies for antimalarial chemotherapy.

32. A comprehensive model of purine uptake by the malaria parasite Plasmodium falciparum: identification of four purine transport activities in intraerythrocytic parasites

Author

Quashie, Neils B., Dorin-Semblat, Dominique, Bray, Patrick G., Biagini, Giancarlo A., Doerig, Christian, Ranford-Cartwright, Lisa C., Koning, De, and Harry, P.

Subjects
Models, Biological
Abstract

Plasmodium falciparum is incapable of de novo purine biosynthesis, and is absolutely dependent on transporters to salvage purines from the environment. Only one low-affinity adenosine transporter has been characterized to date. In the present study we report a comprehensive study of purine nucleobase and nucleoside transport by intraerythrocytic P. falciparum parasites. Isolated trophozoites expressed (i) a high-affinity hypoxanthine transporter with a secondary capacity for purine nucleosides, (ii) a separate high-affinity transporter for adenine, (iii) a low-affinity adenosine transporter, and (iv) a low-affinity/high-capacity adenine carrier. Hypoxanthine was taken up with 12-fold higher efficiency than adenosine. Using a parasite clone with a disrupted PfNT1 (P. falciparum nucleoside transporter 1) gene we found that the high-affinity hypoxanthine/nucleoside transport activity was completely abolished, whereas the low-affinity adenosine transport activity was unchanged. Adenine transport was increased, presumably to partly compensate for the loss of the high-affinity hypoxanthine transporter. We thus propose a model for purine salvage in P. falciparum, based on the highly efficient uptake of hypoxanthine by PfNT1 and a high capacity for purine nucleoside uptake by a lower affinity carrier.

34. Heterozygous HbAC but not HbAS is associated with higher newborn birthweight among women with pregnancy-associated malaria.

Author

Tétard M, Milet J, Dechavanne S, Fievet N, Dorin-Semblat D, Elion J, Fairhurst RM, Deloron P, Tuikue-Ndam N, and Gamain B

Subjects
Africa, Western, Female, Genotype, Gestational Age, Hemoglobin A genetics, Heterozygote, Humans, Pregnancy, Prospective Studies, Birth Weight, Hemoglobin, Sickle genetics, Hemoglobins, Abnormal genetics, Malaria epidemiology, Malaria genetics, Pregnancy Complications, Parasitic epidemiology, Pregnancy Complications, Parasitic genetics
Abstract

Pregnancy-associated malaria (PAM) is associated with poor pregnancy outcomes. Hemoglobin S (HbS) and hemoglobin C (HbC) mutations are frequently encountered in malaria-endemic areas of Africa, where they protect children from severe and uncomplicated Plasmodium falciparum malaria. However, scant epidemiological data exist on the impact of these Hb variants on PAM. A prospective cohort of 635 Beninese pregnant women was recruited before 24 weeks of gestational age and followed until the end of pregnancy. HbAA, HbAC, and HbAS genotypes were determined and tested for association with pregnancy outcomes and PAM indicators using linear and logistic multivariate models. Newborns from HbAC mothers had higher birthweights than those from HbAA mothers among women infected at any time during pregnancy (mean difference 182.9 g, p = 0.08), or during the first half of pregnancy (654.3 g, p = 0.0006). No such birthweight differences were observed between newborns from HbAS and HbAA mothers. HbAC and HbAS were not associated with other pregnancy outcomes or PAM indicators. In conclusion, HbAC but not HbAS is associated with an improved birth outcome in pregnant women with documented PAM. Higher-birthweight newborns from HbAC mothers may have a survival advantage that contributes to the natural selection of HbC in malaria-endemic areas.

Published
2017
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35. Experimental tools for the study of protein phosphorylation in Plasmodium.

Author

Dorin-Semblat D, Bottrill AR, Solyakov L, Tobin A, and Doerig C

Subjects
Computational Biology, Humans, Immunoprecipitation methods, Mass Spectrometry, Phosphorylation, Protein Kinases metabolism, Protozoan Proteins isolation & purification, Recombinant Proteins metabolism, Plasmodium metabolism, Proteome, Proteomics methods, Protozoan Proteins metabolism
Abstract

The central role played by protein phosphorylation in the regulation of eukaryotic cellular processes calls for detailed investigations of this phenomenon in malaria parasites. Here, we describe protocols to measure the activity of protein kinases (using either recombinant proteins or native enzymes purified from parasite extracts), and outline procedures to identify phosphorylation sites on parasite proteins following a mass spectrometry approach.

Published
2013
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