scholarly journals Plasmodium falciparum Line-Dependent Association ofIn VitroGrowth-Inhibitory Activity and Risk of Malaria

2012 ◽  
Vol 80 (5) ◽  
pp. 1900-1908 ◽  
Author(s):  
Josea Rono ◽  
Anna Färnert ◽  
Daniel Olsson ◽  
Faith Osier ◽  
Ingegerd Rooth ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Content Type ◽  
Phenotypic Differences ◽  
Erythrocyte Invasion ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Control Study

ABSTRACTPlasmodium falciparum's ability to invade erythrocytes is essential for its survival within the human host. Immune mechanisms that impair this ability are therefore expected to contribute to immunity against the parasite. Plasma of humans who are naturally exposed to malaria has been shown to have growth-inhibitory activity (GIA)in vitro. However, the importance of GIA in relation to protection from malaria has been unclear. In a case-control study nested within a longitudinally followed population in Tanzania, plasma samples collected at baseline from 171 individuals (55 cases and 116 age-matched controls) were assayed for GIA using threeP. falciparumlines (3D7, K1, and W2mef) chosen based on their erythrocyte invasion phenotypes. Distribution of GIA differed between the lines, with most samples inhibiting the growth of 3D7 and K1 and enhancing the growth of W2mef. GIA to 3D7 was associated with a reduced risk of malaria within 40 weeks of follow-up (odds ratio, 0.45; 95% confidence interval [CI], 0.21 to 0.96;P= 0.04), whereas GIA to K1 and W2mef was not. These results show that GIA, as well as its association with protection from malaria, is dependent on theP. falciparumline and can be explained by differences in erythrocyte invasion phenotypes between parasite lines. Our study contributes knowledge on the biological importance of growth inhibition and the potential influence ofP. falciparumerythrocyte invasion phenotypic differences on its relationship to protective immunity against malaria.

scholarly journals Antibody Reactivity to Merozoite Antigens in Ghanaian Adults Correlates With Growth Inhibitory Activity Against Plasmodium falciparum in Culture

2019 ◽  
Vol 6 (7) ◽  
Author(s):  
Henrietta E Mensah-Brown ◽  
Harvey Aspeling-Jones ◽  
Rupert K Delimini ◽  
Kwaku Poku Asante ◽  
Emmanuel Amlabu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Antibody Reactivity ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Merozoite Antigens ◽  
Invasion Inhibition

Abstract Background Plasmodium falciparum uses a repertoire of merozoite-stage proteins for invasion of erythrocytes. Antibodies against some of these proteins halt the replication cycle of the parasite by preventing erythrocyte invasion and are implicated as contributors to protective immunity against malaria. Methods We assayed antibody reactivity against a panel of 9 recombinant antigens based on erythrocyte-binding antigen (EBA) and reticulocyte-like homolog (Rh) proteins in plasma from children with malaria and healthy adults residing in 3 endemic areas in Ghana using enzyme-linked immunosorbent assay. Purified immunoglobulin (Ig)G from adult plasma samples was also tested for invasion inhibition against 7 different P falciparum culture lines, including clinical isolates. Results Antibodies against the antigens increased in an age-dependent manner in children. Breadth of reactivity to the different antigens was strongly associated with in vitro parasite growth inhibitory activity of IgG purified from the adults. The strongest predictors of breadth of antibody reactivity were age and transmission intensity, and a combination of reactivities to Rh2, Rh4, and Rh5 correlated strongly with invasion inhibition. Conclusions Growth inhibitory activity was significantly associated with breadth of antibody reactivity to merozoite antigens, encouraging the prospect of a multicomponent blood-stage vaccine.

scholarly journals A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis

2014 ◽  
Vol 59 (1) ◽  
pp. 356-364 ◽  
Author(s):  
Wesley Wu ◽  
Zachary Herrera ◽  
Danny Ebert ◽  
Katie Baska ◽  
Seok H. Cho ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Drug Targets ◽  
Specific Activity ◽  
Drug Candidate ◽  
Content Type ◽  
Chemical Rescue ◽  
Growth Inhibitory ◽  
Parasite Populations

ABSTRACTThe apicoplast is an essential plastid organelle found inPlasmodiumparasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the “Malaria Box” library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stagePlasmodium falciparumgrowth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC50) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations inP. falciparumIspD, an enzyme in the MEP (methyl-d-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activityin vitrowith a 50% inhibitory concentration (IC50) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.

scholarly journals Serologic Markers of Previous Malaria Exposure and Functional Antibodies Inhibiting Parasite Growth Are Associated With Parasite Kinetics Following a Plasmodium falciparum Controlled Human Infection

2019 ◽  
Vol 70 (12) ◽  
pp. 2544-2552 ◽  
Author(s):  
Jane Achan ◽  
Isaie J Reuling ◽  
Xi Zen Yap ◽  
Edgard Dabira ◽  
Abdullahi Ahmad ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Quantitative Polymerase Chain Reaction ◽  
Parasite Growth ◽  
High Group ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Malaria Exposure ◽  
The Impact ◽  
High Median

Abstract Background We assessed the impact of exposure to Plasmodium falciparum on parasite kinetics, clinical symptoms, and functional immunity after controlled human malaria infection (CHMI) in 2 cohorts with different levels of previous malarial exposure. Methods Nine adult males with high (sero-high) and 10 with low (sero-low) previous exposure received 3200 P. falciparum sporozoites (PfSPZ) of PfSPZ Challenge by direct venous inoculation and were followed for 35 days for parasitemia by thick blood smear (TBS) and quantitative polymerase chain reaction. Endpoints were time to parasitemia, adverse events, and immune responses. Results Ten of 10 (100%) volunteers in the sero-low and 7 of 9 (77.8%) in the sero-high group developed parasitemia detected by TBS in the first 28 days (P = .125). The median time to parasitemia was significantly shorter in the sero-low group than the sero-high group (9 days [interquartile range {IQR} 7.5–11.0] vs 11.0 days [IQR 7.5–18.0], respectively; log-rank test, P = .005). Antibody recognition of sporozoites was significantly higher in the sero-high (median, 17.93 [IQR 12.95–24] arbitrary units [AU]) than the sero-low volunteers (median, 10.54 [IQR, 8.36–12.12] AU) (P = .006). Growth inhibitory activity was significantly higher in the sero-high (median, 21.8% [IQR, 8.15%–29.65%]) than in the sero-low group (median, 8.3% [IQR, 5.6%–10.23%]) (P = .025). Conclusions CHMI was safe and well tolerated in this population. Individuals with serological evidence of higher malaria exposure were able to better control infection and had higher parasite growth inhibitory activity. Clinical Trials Registration NCT03496454.

scholarly journals Anti-Trypanosomal Alkaloids from Xymalos Monospora

2006 ◽  
Vol 1 (8) ◽  
pp. 1934578X0600100
Author(s):  
Dieudonne Ngamga ◽  
Pierre Tane ◽  
Donna Rattendi ◽  
Cyrus Bacchi ◽  
Christopher C. Okunji ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Stem Bark ◽  
Aporphine Alkaloid ◽  
African Trypanosomes ◽  
Benzylisoquinoline Alkaloids ◽  
Benzylisoquinoline Alkaloid ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity

From an extract of the stem bark of Xymalos monospora, a bis-benzylisoquinoline alkaloid (1), three benzylisoquinoline alkaloids (mollinedine, 1-(p-methoxybenzyl)-6,7-methylenedioxyisoquino-line, doryafranine), and an aporphine alkaloid (N-methyllaurotetanine) were isolated. These compounds were tested for growth inhibitory activity against bloodstream forms of three strains of African trypanosomes. In vitro IC50 values starting from 1.8 μg /mL were obtained.

scholarly journals In Vitro Growth-Inhibitory Activity and Malaria Risk in a Cohort Study in Mali

2009 ◽  
Vol 78 (2) ◽  
pp. 737-745 ◽  
Author(s):  
Peter D. Crompton ◽  
Kazutoyo Miura ◽  
Boubacar Traore ◽  
Kassoum Kayentao ◽  
Aissata Ongoiba ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Vaccine Development ◽  
Critical Role ◽  
Malaria Risk ◽  
Activity Level ◽  
Asexual Blood Stage ◽  
Growth Inhibition Assay ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity

ABSTRACT Immunity to the asexual blood stage of Plasmodium falciparum is complex and likely involves several effector mechanisms. Antibodies are thought to play a critical role in malaria immunity, and a corresponding in vitro correlate of antibody-mediated immunity has long been sought to facilitate malaria vaccine development. The growth inhibition assay (GIA) measures the capacity of antibodies to limit red blood cell (RBC) invasion and/or growth of P. falciparum in vitro. In humans, naturally acquired and vaccine-induced P. falciparum-specific antibodies have growth-inhibitory activity, but it is unclear if growth-inhibitory activity correlates with protection from clinical disease. In a longitudinal study in Mali, purified IgGs, obtained from plasmas collected before the malaria season from 220 individuals aged 2 to 10 and 18 to 25 years, were assayed for growth-inhibitory activity. Malaria episodes were recorded by passive surveillance over the subsequent 6-month malaria season. Logistic regression showed that greater age (odds ratio [OR], 0.78; 95% confidence interval [95% CI], 0.63 to 0.95; P = 0.02) and growth-inhibitory activity (OR, 0.50; 95% CI, 0.30 to 0.85; P = 0.01) were significantly associated with decreased malaria risk in children. A growth-inhibitory activity level of 40% was determined to be the optimal cutoff for discriminating malaria-immune and susceptible individuals in this cohort, with a sensitivity of 97.0%, but a low specificity of 24.3%, which limited the assay's ability to accurately predict protective immunity and to serve as an in vitro correlate of antibody-mediated immunity. These data suggest that antibodies which block merozoite invasion of RBC and/or inhibit the intra-RBC growth of the parasite contribute to but are not sufficient for the acquisition of malaria immunity.

scholarly journals Specific growth inhibitory sequences in genomic DNA from quiescent human embryo fibroblasts.

1987 ◽  
Vol 7 (5) ◽  
pp. 1894-1899 ◽  
Author(s):  
R Padmanabhan ◽  
T H Howard ◽  
B H Howard
Keyword(s):  
Dna Sequences ◽  
Hela Cells ◽  
Human Embryo ◽  
Inhibitory Activity ◽  
Genomic Dna ◽  
Molecular Mechanisms ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Embryo Fibroblasts

We used HeLa cells as recipients in a gene transfer assay to characterize DNA sequences that negatively regulate mammalian cell growth. In this assay, genomic DNA from quiescent human embryo fibroblasts was more inhibitory for HeLa replication than was DNA from either Escherichia coli or HeLa cells. Surprisingly, growth inhibitory activity depended on the growth state of the cells from which genomic DNA was prepared; it was strongest in DNA prepared from serum-deprived, quiescent embryo fibroblasts. This latter observation implies a role for DNA modification(s) in regulating the activity of the inhibitory sequences detected in our assay. The level of the observed growth inhibitory activity was sometimes high, suggesting that the relevant sequences may be abundantly represented in the mammalian genome. We speculate that these findings may provide new insights into the molecular mechanisms involved in cellular quiescence and in vitro senescence.

Synthesis of new oxathiazinane dioxides and their in vitro cancer cell growth inhibitory activity

2010 ◽  
Vol 20 (17) ◽  
pp. 5353-5356 ◽  
Author(s):  
Françoise Borcard ◽  
Matthias Baud ◽  
Claudia Bello ◽  
Giovanna Dal Bello ◽  
Francesco Grossi ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cancer Cell ◽  
Inhibitory Activity ◽  
Cancer Cell Growth ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity

scholarly journals Growth-Inhibitory Antibodies Are Not Necessary for Protective Immunity to Malaria Infection

2009 ◽  
Vol 78 (2) ◽  
pp. 680-687 ◽  
Author(s):  
E. Elsa Herdiana Murhandarwati ◽  
Lina Wang ◽  
Harini D. de Silva ◽  
Charles Ma ◽  
Magdalena Plebanski ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Transgenic Line ◽  
Plasmodium Yoelii ◽  
Parasite Growth ◽  
Blood Stage ◽  
Immune State ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Inhibitory Antibodies

ABSTRACT The absence of a validated surrogate marker for the immune state has complicated the design of a subunit vaccine against asexual stages of Plasmodium falciparum. In particular, it is not known whether the capacity to induce antibodies that inhibit parasite growth in vitro is an important criterion for selection of P. falciparum proteins to be assessed in human vaccine trials. We examined this issue in the Plasmodium yoelii rodent malaria model using the 19-kDa C-terminal fragment of merozoite surface protein 1 (MSP119). To examine the relationship between inhibitory antibodies in immunized mice and the immune state, as indicated by resistance to a blood-stage challenge, we used an allelic replacement strategy to generate a transgenic P. falciparum line that expresses MSP119 from P. yoelii. We show that MSP119 is functionally conserved across these two divergent Plasmodium species, and replacing PfMSP119 with PyMSP119 has no detectable effect on parasite growth in vitro. By comparing growth rates of this transgenic line with a matched transgenic line that expresses the endogenous PfMSP119, we developed an assay to measure the specific growth-inhibitory activity directed exclusively to the PyMSP119 protein in the sera from vaccinated animals. To validate this assay, sera from rabbits immunized with recombinant PyMSP119 were tested and showed specific inhibitory activity in a concentration-dependent manner. In mice that were immunized with recombinant PyMSP119, the levels of PyMSP119-specific inhibitory activity did not correlate with the total antibody levels measured by enzyme-linked immunosorbent assay. Furthermore, they did not correlate with resistance to subsequent blood-stage infection, and some mice with complete protection showed no detectable inhibitory activity in their prechallenge sera. These data indicated that growth-inhibitory activity measured in vitro was not a reliable predictor of immune status in vivo, and the reliance on this criterion to select vaccine candidates for human clinical trials may be misplaced. The transgenic lines further offer useful tools for comparing the efficacy of MSP119-based vaccines that utilize different immunization regimens and antigen formulations.

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