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.

scholarly journals Rhoptry-Associated Protein 1-Binding Monoclonal Antibody Raised against a Heterologous Peptide Sequence InhibitsPlasmodium falciparum Growth In Vitro

2001 ◽  
Vol 69 (4) ◽  
pp. 2558-2568 ◽  
Author(s):  
Rafael Moreno ◽  
Friederike Pöltl-Frank ◽  
Dietrich Stüber ◽  
Hugues Matile ◽  
Michael Mutz ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Sequence Similarity ◽  
Cross Reactivity ◽  
Parasite Growth ◽  
Peptide Sequence ◽  
Peptide Epitope ◽  
Fine Specificity ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity

ABSTRACT Monoclonal antibodies (MAbs) specific for Plasmodium falciparum rhoptry-associated protein 1 (RAP-1) were generated and tested for inhibition of parasite growth in vitro. The majority of indirect immunofluorescence assay (IFA)-positive MAbs raised against recombinant RAP-1 positions 23 to 711 (rRAP-123–711) recognized epitopes located in the immunodominant N-terminal third of RAP-1. MAbs specific for the building block 35.1 of the synthetic peptide malaria vaccine SPf66 also yielded an IFA staining pattern characteristic for rhoptry-associated proteins and reacted specifically with rRAP-1 and parasite-derived RAP-1 molecules p67 and p82. Cross-reactivity with RAP-1 was blocked by the 35.1 peptide. Epitope mapping with truncated rRAP-1 molecules and overlapping peptides identified the linear RAP-1 sequence Y218KYSL222 as a target of the anti-35.1 MAbs. This sequence lacks primary sequence similarity with the 35.1 peptide (YGGPANKKNAG). Cross-reactivity of the anti-35.1 MAbs thus appears to be associated with conformational rather than sequence homology. While the anti-35.1 MAb SP8.18 exhibited parasite growth-inhibitory activity, none of the tested anti-rRAP-123–711 MAbs inhibited parasite growth, independently of their fine specificity for the RAP-1 sequences at positions 33 to 42, 213 to 222, 243 to 247, 280 to 287, or 405 to 446. The growth-inhibitory activity of MAb SP8.18 was, however, accelerated by noninhibitory anti-RAP-1 MAbs. Results demonstrate that in addition to fine specificity, other binding parameters are also crucial for the inhibitory potential of an antibody.

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 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
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