Person: ALY, AHMED SAYED IBRAHıM
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Publication Metadata only SAP1 is a critical post-transcriptional regulator of infectivity in malaria parasite sporozoite stages(2011-02-01T00:00:00Z) Aly, Ahmed Sayed Ibrahım; Lindner, Scott E.; MacKellar, Drew C.; Peng, Xinxia; Kappe, Stefan H. I.; ALY, AHMED SAYED IBRAHıMPlasmodium salivary gland sporozoites upregulate expression of a unique subset of genes, collectively called the UIS (upregulated in infectious sporozoites). Many UIS were shown to be essential for early liver stage development, although little is known about their regulation. We previously identified a conserved sporozoite-specific protein, SAP1, which has an essential role in Plasmodium liver infection. Targeted deletion of SAP1 in Plasmodium yoelii caused the depletion of a number of selectively tested UIS transcripts in sporozoites, resulting in a complete early liver stage arrest. Here, we use a global gene expression survey to more comprehensively identify transcripts that are affected by SAP1 deletion. We find an effect upon both the transcript abundance of UIS genes, as well as of select genes previously not grouped as UIS. Importantly, we show that the lack of SAP1 causes the specific degradation of these transcripts. Collectively, our data suggest that SAP1 is involved in a selective post-transcriptional mechanism to regulate the abundance of transcripts critical to the infectivity of sporozoites. Although Pysap1(-) sporozoites are depleted of many of these important transcripts, they confer long-lasting sterile protection against wild-type sporozoite challenge in mice. SAP1 is therefore an appealing candidate locus for attenuation of Plasmodium falciparum.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 Metadata only Superior Antimalarial Immunity after Vaccination with Late Liver Stage-Arresting Genetically Attenuated Parasites(2011-06-16T00:00:00Z) Butler, Noah S.; Schmidt, Nathan W.; Vaughan, Ashley M.; Aly, Ahmed Sayed Ibrahım; Kappe, Stefan H. I.; Harty, John T.; ALY, AHMED SAYED IBRAHıMWhile subunit vaccines have shown partial efficacy in clinical trials, radiation-attenuated sporozoites (RAS) remain the -gold standard- for sterilizing protection against Plasmodium infection in human vaccinees. The variability in immunogenicity and replication introduced by the extensive, random DNA damage necessary to generate RAS could be overcome by genetically attenuated parasites (GAP) designed via gene deletion to arrest at defined points during liver-stage development. Here, we demonstrate the principle that late liver stage-arresting GAP induce larger and broader CD8 T cell responses that provide superior protection in inbred and outbred mice compared to RAS or early-arresting GAP immunizations. Late liver stage-arresting GAP also engender high levels of cross-stage and cross-species protection and complete protection when administered by translationally relevant intradermal or subcutaneous routes. Collectively, our results underscore the potential utility of late liver stage-arresting GAP as broadly protective next-generation live-attenuated malaria vaccines and support their potential as a powerful model for identifying antigens to generate cross-stage protection.Publication Metadata only Subpatent infection with nucleoside transporter 1-deficient Plasmodium blood stage parasites confers sterile protection against lethal malaria in mice(2010-07-01T00:00:00Z) Aly, Ahmed Sayed Ibrahım; Downie, Megan J.; Ben Mamoun, Choukri; Kappe, Stefan H. I.; ALY, AHMED SAYED IBRAHıMP>Repeated immunizations with whole Plasmodium blood stage parasites and concomitant drug cure of infection confer protective immunity against parasite challenge in mice, monkeys and humans. Moreover, it was recently shown that infections with genetically modified rodent malaria blood stage parasites conferred sterile protection against lethal blood stage challenge. However, in these models vaccination resulted in high parasitemias and, in consequence, carries risk of vaccine-induced pathology and death. Herein, we generated a novel, completely blood stage-attenuated P. yoelii rodent malaria strain by targeted deletion of parasite nucleoside transporter 1 (NT1). Immunization of inbred and outbred mouse strains with a single low dose of Pynt1- blood stages did not induce any patent infections and conferred complete sterile protection against lethal heterologous blood stage and sporozoite challenges. Partial protection was observed against lethal challenges with another parasite species, P. berghei. Importantly, subcutaneous immunization with Pynt1- conferred sterile protection against lethal blood stage challenges. We show that cellular and humoral immune responses are both essential for sterile protection. The study demonstrates that genetic manipulation provides a platform for the designed, complete attenuation of malaria parasite blood stages and suggests testing the safety and efficacy of P. falciparum NT1 knockout strains in humans.Publication Metadata only Plasmodium falciparum PF10_0164 (ETRAMP10.3) Is an Essential Parasitophorous Vacuole and Exported Protein in Blood Stages(2010-05-01T00:00:00Z) MacKellar, Drew C.; O'Neill, Matthew T.; Aly, Ahmed Sayed Ibrahım; Sacci, John B.; Cowman, Alan F.; Kappe, Stefan H. I.; ALY, AHMED SAYED IBRAHıMUpregulated in infectious sporozoites gene 4 (UIS4) encodes a parasitophorous vacuole membrane protein expressed in the sporozoite and liver stages of rodent malaria parasites. Parasites that lack UIS4 arrest in early liver-stage development, and vaccination of mice with uis4-sporozoites confers sterile protection against challenge with infectious sporozoites. Currently, it remains unclear whether an ortholog of UIS4 is carried in the human malaria parasite Plasmodium falciparum, although the gene PF10_0164 has been identified as a candidate ortholog for UIS4 on the basis of synteny and structural similarity of the encoded protein. We show that PF10_0164 is expressed in sporozoites and blood stages of P. falciparum, where it localizes to the parasitophorous vacuole, and is also exported to the host erythrocyte. PF10_0164 is refractory to disruption in asexual blood stages. Functional complementation was tested in Plasmodium yoelii by replacing the endogenous copy of UIS4 with PF10_0164. PF10_0164 localized to the parasitophorous vacuole membrane of liver stages, but transgenic parasites did not complete liver-stage development in mice. We conclude that PF10_0164 is a parasitophorous vacuole protein that is essential in asexual blood stages and that does not complement P. yoelii UIS4, and it is thus likely not a functional ortholog of UIS4.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.