Person: ALY, AHMED SAYED IBRAHıM
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Publication Open Access Synthetic DNA Vaccines Adjuvanted with pIL-33 Drive Liver-Localized T Cells and Provide Protection from <i>Plasmodium</i> Challenge in a Mouse Model.(2020-01-10T00:00:00Z) Reeder, SM; Reuschel, EL; Bah, MA; Yun, K; Tursi, NJ; Kim, KY; Chu, J; Zaidi, FI; Yilmaz, I; Hart, RJ; Perrin, B; Xu, Z; Humeau, L; Weiner, DB; Aly, Ahmed Sayed Ibrahım; ALY, AHMED SAYED IBRAHıMThe need for a malaria vaccine is indisputable. A single vaccine for Plasmodium pre-erythrocytic stages targeting the major sporozoite antigen circumsporozoite protein (CSP) has had partial success. Additionally, CD8+ T cells targeting liver-stage (LS) antigens induced by live attenuated sporozoite vaccines were associated with protection in human challenge experiments. To further evaluate protection mediated by LS antigens, we focused on exported pre-erythrocytic proteins (exported protein 1 (EXP1), profilin (PFN), exported protein 2 (EXP2), inhibitor of cysteine proteases (ICP), transmembrane protein 21 (TMP21), and upregulated in infective sporozoites-3 (UIS3)) expressed in all Plasmodium species and designed optimized, synthetic DNA (synDNA) immunogens. SynDNA antigen cocktails were tested with and without the molecular adjuvant plasmid IL-33. Immunized animals developed robust T cell responses including induction of antigen-specific liver-localized CD8+ T cells, which were enhanced by the co-delivery of plasmid IL-33. In total, 100% of mice in adjuvanted groups and 71%–88% in non-adjuvanted groups were protected from blood-stage disease following Plasmodium yoelii sporozoite challenge. This study supports the potential of synDNA LS antigens as vaccine components for malaria parasite infection.Publication Open Access An Attenuated HSV-1-Derived Malaria Vaccine Expressing Liver-Stage Exported Proteins Induces Sterilizing Protection against Infectious Sporozoite Challenge(2022-02-01T00:00:00Z) Rider, Paul J. F.; KAMIL, MOHD; Yilmaz, Ilknur; Atmaca, Habibe N.; Kalkan-Yazici, Merve; Ziya Doymaz, Mehmet; Kousoulas, Konstantin G.; ALY, Ahmed Sayed Ibrahım; KAMIL, MOHD; YAZICI, MERVE; ALY, AHMED SAYED IBRAHıMHere, we present the construction of an attenuated herpes simplex virus type-1 (HSV-1)-vectored vaccine, expressing three liver-stage (LS) malaria parasite exported proteins (EXP1, UIS3 and TMP21) as fusion proteins with the VP26 viral capsid protein. Intramuscular and subcutaneous immunizations of mice with a pooled vaccine, composed of the three attenuated virus strains expressing each LS antigen, induced sterile protection against the intravenous challenge of Plasmodium yoelii 17X-NL salivary gland sporozoites. Our data suggest that this malaria vaccine may be effective in preventing malaria parasite infection using practical routes of immunization in humans.Publication Metadata only A systematic analysis of the early transcribed membrane protein family throughout the life cycle of Plasmodium yoelii(2011-11-01T00:00:00Z) MacKellar, Drew C.; Vaughan, Ashley M.; Aly, Ahmed Sayed Ibrahım; DeLeon, Sasha; Kappe, Stefan H. I.; ALY, AHMED SAYED IBRAHıMThe early transcribed membrane proteins (ETRAMPs) are a family of small, highly charged transmembrane proteins unique to malaria parasites. Some members of the ETRAMP family have been localized to the parasitophorous vacuole membrane that separates the intracellular parasite from the host cell and thus presumably have a role in hostparasite interactions. Although it was previously shown that two ETRAMPs are critical for rodent malaria parasite liver-stage development, the importance of most ETRAMPs during the parasite life cycle remains unknown. Here, we comprehensively identify nine new etramps in the genome of the rodent malaria parasite Plasmodium yoelii, and elucidate their conservation in other malaria parasites. etramp expression profiles are diverse throughout the parasite life cycle as measured by RT-PCR. Epitope tagging of two ETRAMPs demonstrates protein expression in blood and liver stages, and reveals differences in both their timing of expression and their subcellular localization. Gene targeting studies of each of the nine uncharacterized etramps show that two are refractory to deletion and thus likely essential for blood-stage replication. Seven etramps are not essential for any life cycle stage. Systematic characterization of the members of the ETRAMP family reveals the diversity in importance of each family member at the interface between host and parasite throughout the developmental cycle of the malaria parasite.Publication Open Access Highly Sensitive and Rapid Characterization of the Development of Synchronized Blood Stage Malaria Parasites Via Magneto-Optical Hemozoin Quantification(2019-10-01T00:00:00Z) Pukancsik, Maria; Molnar, Petra; Orban, Agnes; Butykai, Adam; Marton, Livia; Kezsmarki, Istvan; Vertessy, Beata G.; KAMIL, MOHD; Abraham, Amanah; ALY, AHMED SAYED IBRAHIM; KAMIL, MOHD; ALY, AHMED SAYED IBRAHıMThe rotating-crystal magneto-optical diagnostic (RMOD) technique was developed as a sensitive and rapid platform for malaria diagnosis. Herein, we report a detailed in vivo assessment of the synchronized Plasmodium vinckei lentum strain blood-stage infections by the RMOD method and comparing the results to the unsynchronized Plasmodium yoelii 17X-NL (non-lethal) infections. Furthermore, we assess the hemozoin production and clearance dynamics in chloroquine-treated compared to untreated self-resolving infections by RMOD. The findings of the study suggest that the RMOD signal is directly proportional to the hemozoin content and closely follows the actual parasitemia level. The lack of long-term accumulation of hemozoin in peripheral blood implies a dynamic equilibrium between the hemozoin production rate of the parasites and the immune system-s clearing mechanism. Using parasites with synchronous blood stage cycle, which resemble human malaria parasite infections with Plasmodium falciparum and Plasmodium vivax, we are demonstrating that the RMOD detects both hemozoin production and clearance rates with high sensitivity and temporal resolution. Thus, RMOD technique offers a quantitative tool to follow the maturation of the malaria parasites even on sub-cycle timescales.Publication Metadata only Genetic Characterization of Coenzyme A Biosynthesis Reveals Essential Distinctive Functions during Malaria Parasite Development in Blood and Mosquito(2017-06-20T00:00:00Z) Hart, Robert J.; Abraham, Amanah; Aly, Ahmed Sayed Ibrahım; ALY, AHMED SAYED IBRAHıMCoenzyme A (CoA) is an essential universal cofactor for all prokaryotic and eukaryotic cells. In nearly all non-photosynthetic cells, CoA biosynthesis depends on the uptake and phosphorylation of vitamin B5 (pantothenic acid or pantothenate). Recently, putative pantothenate transporter (PAT) and pantothenate kinases (PanKs) were functionally characterized in P yoelii. PAT and PanKs were shown to be dispensable for blood stage development, but they were essential for mosquito stages development. Yet, little is known about the cellular functions of the other enzymes of the CoA biosynthesis pathway in malaria parasite life cycle stages. All enzymes of this pathway were targeted for deletion or deletion/complementation analyses by knockout/knock-in plasmid constructs to reveal their essential roles in P yoelii life cycle stages. The intermediate enzymes PPCS (Phosphopantothenylcysteine Synthase), PPCDC (Phosphopantothenylcysteine Decarboxylase) were shown to be dispensable for asexual and sexual blood stage development, but they were essential for oocyst development and the production of sporozoites. However, the last two enzymes of this pathway, PPAT (Phosphopantetheine Adenylyltransferase) and DPCK (Dephospho-CoA Kinase), were essential for blood stage development. These results indicate alternative first substrate requirement for the malaria parasite, other than the canonical pantothenate, for the synthesis of CoA in the blood but not inside the mosquito midgut. Collectively, our data shows that CoA de novo biosynthesis is essential for both blood and mosquito stages, and thus validates the enzymes of this pathway as potential antimalarial targets.Publication Metadata only A Plasmodium /-hydrolase modulates the development of invasive stages(2015-12-01T00:00:00Z) Groat-Carmona, Anna M.; Kain, Heather; Brownell, Jessica; Douglass, Alyse N.; Aly, Ahmed Sayed Ibrahım; Kappe, Stefan H. I.; ALY, AHMED SAYED IBRAHıMThe bud emergence (BEM)46 proteins are evolutionarily conserved members of the /-hydrolase superfamily, which includes enzymes with diverse functions and a wide range of substrates. Here, we identified a PlasmodiumBEM46-like protein (PBLP) and characterized it throughout the life cycle of the rodent malaria parasite Plasmodium yoelii. The PlasmodiumBEM46-like protein is shown to be closely associated with the parasite plasma membrane of asexual erythrocytic stage schizonts and exo-erythrocytic schizonts; however, PBLP localizes to unique intracellular structures in sporozoites. Generation and analysis of P.yoelii knockout (pblp) parasite lines showed that PBLP has an important role in erythrocytic stage merozoite development with pblp parasites forming fewer merozoites during schizogony, which results in decreased parasitemia when compared with wild-type (WT) parasites. pblp parasites showed no defects in gametogenesis or transmission to mosquitoes; however, because they formed fewer oocysts there was a reduction in the number of developed sporozoites in infected mosquitoes when compared with WT. Although pblp sporozoites showed no apparent defect in mosquito salivary gland infection, they showed decreased infectivity in hepatocytes in vitro. Similarly, mice infected with pblp sporozoites exhibited a delay in the onset of blood-stage patency, which is likely caused by reduced sporozoite infectivity and a discernible delay in exo-erythrocytic merozoite formation. These data are consistent with the model that PBLP has an important role in parasite invasive-stage morphogenesis throughout the parasite life cycle.