Relationship between the Pfcrt T76 and the Pfmdr-1 Y86 mutations in Plasmodium falciparum and in vitro/in vivo chloroquine resistance in Burkina Faso, West Africa

2003 ◽  
Vol 3 (4) ◽  
pp. 287-292 ◽  
Author(s):  
Halidou Tinto ◽  
Jean Bosco Ouédraogo ◽  
Annette Erhart ◽  
Chantal Van Overmeir ◽  
Jean-Claude Dujardin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
West Africa ◽  
Burkina Faso ◽  
Chloroquine Resistance

Association of cg2 and pfmdr1 genotype with chloroquine resistance in field samples of Plasmodium falciparum from Nigeria

Parasitology ◽  
1999 ◽  
Vol 119 (4) ◽  
pp. 343-348 ◽  
Author(s):  
I. S. ADAGU ◽  
D. C. WARHURST
Keyword(s):  
Plasmodium Falciparum ◽  
Negative Predictive Value ◽  
Predictive Value ◽  
Chloroquine Resistance ◽  
Northern Nigeria ◽  
Field Samples ◽  
Epidemiological Tool ◽  
Resistant Strains

This study examines polymorphisms in 2 genes (pfmdr1 and cg2), which have been associated with resistance to chloroquine in Plasmodium falciparum, to determine their value as predictors of resistance status. Among field samples from children in Zaria, northern Nigeria, the Tyr-86 polymorphism in pfmdr1 and Ala-281 and the Dd2κ repeat of cg2, were significantly associated. In 8 samples classified resistant by the micro-in vitro test, or, where this failed, by in vivo trial, 7 showed the cg2 Dd2 type κ repeat, and 6 of these had both the Ala-281 allele and the pfmdr1 Tyr-86 allele. In 26 chloroquine-sensitive samples, none had this combination of 3 polymorphisms (P = 0·00002). This indicates 75% sensitivity and 100% specificity in detection of resistance and shows a positive predictive value for resistant infections of 100%. The negative predictive value, because of sensitivity less than 100%, would depend on the prevalence of resistance. Where prevalence of resistance is approx. 21% as in Zaria, the negative predictive value would be 94%, while in Gabon, with a prevalence of ca 73% it would be 60%. The use of (cg2: Ala-281, Dd2κ. pfmdr1: Tyr-86) genotype detection as a predictive epidemiological tool to examine the distribution of chloroquine-resistance in parts of Africa is therefore possible. The sensitivity of detection of resistant strains still requires improvement.

scholarly journals In vivo and in vitro analysis of chloroquine resistance in Plasmodium falciparum isolates from Senegal

2005 ◽  
Vol 97 (2) ◽  
pp. 136-140 ◽  
Author(s):  
Ousmane Sarr ◽  
Alissa Myrick ◽  
Johanna Daily ◽  
Bernard M. Diop ◽  
Therese Dieng ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Chloroquine Resistance ◽  
Vitro Analysis ◽  
In Vitro Analysis

scholarly journals Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

2012 ◽  
Vol 56 (10) ◽  
pp. 5356-5364 ◽  
Author(s):  
Carol E. Griffin ◽  
Jonathan M. Hoke ◽  
Upeka Samarakoon ◽  
Junhui Duan ◽  
Jianbing Mu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Cinchona Alkaloids ◽  
Chloroquine Resistance ◽  
Digestive Vacuole ◽  
Content Type ◽  
Chloroquine Resistance Transporter ◽  
Clonal Lines

ABSTRACTTheCinchonaalkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (−)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (−)-isomersin vitroandin vivoagainstPlasmodium falciparummalaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparumchloroquine resistance transporter), reversed the normal potency order of quinine and quinidine towardP. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured thein vitrosusceptibility of eight clonal lines ofP. falciparumderived from the 106/1 strain, each containing a uniquepfcrtallele, to fourCinchonastereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of theCinchonaalkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC50ratio of (−)/(+) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (−) and (+) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and otherCinchonaalkaloids.

In vitro and in vivo reversal of chloroquine resistance in Plasmodium falciparum with promethazine.

1998 ◽  
Vol 58 (5) ◽  
pp. 625-629 ◽  
Author(s):  
A M Oduola ◽  
A Sowunmi ◽  
B G Schuster ◽  
W K Milhous ◽  
D E Kyle ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Chloroquine Resistance

scholarly journals Functional antibodies against Plasmodium falciparum sporozoites are associated with a longer time to qPCR-detected infection among schoolchildren in Burkina Faso

2019 ◽  
Vol 3 ◽  
pp. 159 ◽  
Author(s):  
Aissata Barry ◽  
Marije C. Behet ◽  
Issa Nébié ◽  
Kjerstin Lanke ◽  
Lynn Grignard ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Burkina Faso ◽  
Positive Association ◽  
Epidemiological Studies ◽  
Gliding Motility ◽  
Blood Stage ◽  
Functional Antibodies ◽  
Invasion Inhibition

Background:Individuals living in malaria-endemic regions develop immunity against severe malaria, but it is unclear whether immunity against pre-erythrocytic stages that blocks initiation of blood-stage infection after parasite inoculation develops following continuous natural exposure.Methods:We cleared schoolchildren living in an area (health district of Saponé, Burkina Faso) with highly endemic seasonal malaria of possible sub-patent infections and examined them weekly for incident infections by nested PCR. Plasma samples collected at enrolment were used to quantify antibodies to the pre-eryhrocytic-stage antigens circumsporozoite protein (CSP) and Liver stage antigen 1 (LSA-1).In vitrosporozoite gliding inhibition and hepatocyte invasion inhibition by naturally acquired antibodies were assessed usingPlasmodium falciparumNF54 sporozoites. Associations between antibody responses, functional pre-erythrocytic immunity phenotypes and time to infection detected by18Squantitative PCR were studied.Results:A total of 51 children were monitored. Anti-CSP antibody titres showed a positive association with sporozoite gliding motility inhibition (P<0.0001, Spearman’s ρ=0.76).In vitrohepatocyte invasion was inhibited by naturally acquired antibodies (median inhibition, 19.4% [IQR 15.2-40.9%]), and there were positive correlations between invasion inhibition and gliding inhibition (P=0.005, Spearman’s ρ=0.67) and between invasion inhibition and CSP-specific antibodies (P=0.002, Spearman’s ρ=0.76). Survival analysis indicated longer time to infection in individuals displaying higher-than-median sporozoite gliding inhibition activity (P=0.01), although this association became non-significant after adjustment for blood-stage immunity (P = 0.06).Conclusions:In summary, functional antibodies against the pre-erythrocytic stages of malaria infection are acquired in children who are repeatedly exposed toPlasmodiumparasites. This immune response does not prevent them from becoming infected during a malaria transmission season, but might delay the appearance of blood stage parasitaemia. Our approach could not fully separate the effects of pre-erythrocytic-specific and blood-stage-specific antibody-mediated immune responsesin vivo; epidemiological studies powered and designed to address this important question should become a research priority.

Ultrastructural observations on the in vitro cytoadherence of Plasmodium falciparum infected red blood cells

1990 ◽  
Vol 48 (3) ◽  
pp. 914-915
Author(s):  
D.J.P. Ferguson ◽  
A.R. Berendt ◽  
J. Tansey ◽  
K. Marsh ◽  
C.I. Newbold
Keyword(s):  
Plasmodium Falciparum ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Umbilical Vein ◽  
Cell Types ◽  
Amelanotic Melanoma ◽  
Cytoplasmic Process ◽  
Umbilical Vein Endothelial Cells

In human malaria, the most serious clinical manifestation is cerebral malaria (CM) due to infection with Plasmodium falciparum. The pathology of CM is thought to relate to the fact that red blood cells containing mature forms of the parasite (PRBC) cytoadhere or sequester to post capillary venules of various tissues including the brain. This in vivo phenomenon has been studied in vitro by examining the cytoadherence of PRBCs to various cell types and purified proteins. To date, three Ijiost receptor molecules have been identified; CD36, ICAM-1 and thrombospondin. The specific changes in the PRBC membrane which mediate cytoadherence are less well understood, but they include the sub-membranous deposition of electron-dense material resulting in surface deformations called knobs. Knobs were thought to be essential for cytoadherence, lput recent work has shown that certain knob-negative (K-) lines can cytoadhere. In the present study, we have used electron microscopy to re-examine the interactions between K+ PRBCs and both C32 amelanotic melanoma cells and human umbilical vein endothelial cells (HUVEC).We confirm previous data demonstrating that C32 cells possess numerous microvilli which adhere to the PRBC, mainly via the knobs (Fig. 1). In contrast, the HUVEC were relatively smooth and the PRBCs appeared partially flattened onto the cell surface (Fig. 2). Furthermore, many of the PRBCs exhibited an invagination of the limiting membrane in the attachment zone, often containing a cytoplasmic process from the endothelial cell (Fig. 2).

scholarly journals Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1250-1255 ◽  
Author(s):  
S Whitehead ◽  
TE Peto
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Antimalarial Activity ◽  
Clinical Malaria ◽  
Inhibitory Effect ◽  
Parasite Development ◽  
And Control ◽  
Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

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