scholarly journals Resistance to Plasmodium falciparum in sickle cell trait erythrocytes is driven by oxygen-dependent growth inhibition

2018 ◽  
Vol 115 (28) ◽  
pp. 7350-7355 ◽  
Author(s):  
Natasha M. Archer ◽  
Nicole Petersen ◽  
Martha A. Clark ◽  
Caroline O. Buckee ◽  
Lauren M. Childs ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Low Oxygen ◽  
Partial Protection ◽  
Infected Rbcs ◽  
Specific Stage ◽  
Mechanistic Basis ◽  
Dependent Growth

Sickle cell trait (AS) confers partial protection against lethal Plasmodium falciparum malaria. Multiple mechanisms for this have been proposed, with a recent focus on aberrant cytoadherence of parasite-infected red blood cells (RBCs). Here we investigate the mechanistic basis of AS protection through detailed temporal mapping. We find that parasites in AS RBCs maintained at low oxygen concentrations stall at a specific stage in the middle of intracellular growth before DNA replication. We demonstrate that polymerization of sickle hemoglobin (HbS) is responsible for this growth arrest of intraerythrocytic P. falciparum parasites, with normal hemoglobin digestion and growth restored in the presence of carbon monoxide, a gaseous antisickling agent. Modeling of growth inhibition and sequestration revealed that HbS polymerization-induced growth inhibition following cytoadherence is the critical driver of the reduced parasite densities observed in malaria infections of individuals with AS. We conclude that the protective effect of AS derives largely from effective sequestration of infected RBCs into the hypoxic microcirculation.

Cell-mediated immune responses to Plasmodium falciparum purified soluble antigens in sickle-cell trait subjects

1990 ◽  
Vol 25 (1-3) ◽  
pp. 243-249 ◽  
Author(s):  
R.A. Bayoumi ◽  
Y.A. Abu-Zeid ◽  
N.H. Abdulhadi ◽  
B.O. Saeed ◽  
T.G. Theander ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Sickle Cell ◽  
Sickle Cell Trait

Fine Temporal Mapping of Plasmodium Falciparum growth Inhibition in Hypoxic Sickle Cell Trait Erythrocytes

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 924-924
Author(s):  
Natasha Archer ◽  
Nicole Petersen ◽  
Martha Clark ◽  
Manoj Duraisingh
Keyword(s):  
Flow Cytometry ◽  
Carbon Monoxide ◽  
Dna Replication ◽  
Oxygen Tension ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
High Oxygen ◽  
Low Oxygen ◽  
Trophozoite Stage ◽  
Sickle Hemoglobin

Abstract Background: Despite the global acceptance of Haldane's hypothesis that individuals with sickle cell trait (AS) are protected against malaria, an exact mechanism of resistance remains unknown. Several theories to explain the resistance such as increased splenic destruction, impaired hemoglobin digestion, reduced cytoadherence and specific translocation of host specific microRNAs have been proposed. Here we carefully examine the influence of hypoxia and its relation to parasite cytoadherence and growth in AS and normal (AA) human red blood cells (RBCs). Materials and Methods: To assess the influence of oxygen tension on parasite proliferation in AS RBCs, we followed the proliferation of tightly synchronized P. falciparum within AS and AA RBCs at 1, 5, 10, and 17% oxygen by flow cytometry and microscopy. Carbon monoxide (CO) studies were performed by introducing 100% CO gas into our enclosed chamber system every 21 hours to prevent sickling at low oxygen. Results: Flow cytometry assessment of DNA content confirms the absence of DNA replication within parasites in AS erythrocytes at low oxygen, however normal DNA replication is observed in the presence of high oxygen tension and when CO is introduced at low oxygen. Moving parasites from high to low oxygen tension greatly influences the extent of parasite maturity; parasites moved at 16 and 20 hours post invasion (hpi) do not mature beyond that of the late ring/early trophozoite stage while parasites moved at 24, 28, and 32 hpi develop increasingly more merozoites. Conclusion: Here, we show that in hypoxic conditions parasites in AS erythrocytes stall at the late ring/early trophozoite stage and do not replicate their DNA. We also show that treatment of AS erythrocytes with high oxygen tension or carbon monoxide, a potent inhibitor of sickle hemoglobin polymerization, reverses this phenotype. We propose that the mechanism of AS protection is largely due to P.falciparum's inability to digest polymerized sickle hemoglobin once the parasite sequesters in the hypoxic microvasculature. This is likely a key driver of the reduced parasite densities observed in actual infections in AS individuals. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evidence for both innate and acquired mechanisms of protection from Plasmodium falciparum in children with sickle cell trait

Blood ◽  
2012 ◽  
Vol 119 (16) ◽  
pp. 3808-3814 ◽  
Author(s):  
Lauren Gong ◽  
Catherine Maiteki-Sebuguzi ◽  
Philip J. Rosenthal ◽  
Alan E. Hubbard ◽  
Chris J. Drakeley ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Relative Density ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Plasmodium Falciparum Malaria ◽  
Force Of Infection ◽  
Symptomatic Malaria ◽  
Molecular Force ◽  
High Parasite Density ◽  
Within Subjects

AbstractSickle cell trait (HbAS) is known to be protective against Plasmodium falciparum malaria, but it is unclear when during the course of infection this protection occurs and whether protection is innate or acquired. To address these questions, a cohort of 601 children 1-10 years of age were enrolled in Kampala, Uganda, and followed for 18 months for symptomatic malaria and asymptomatic parasitemia. Genotyping was used to detect and follow individual parasite clones longitudinally within subjects. Children with HbAS were protected against the establishment of parasitemia, as assessed by the molecular force of infection at older but not younger ages (at 2 years of age: incidence rate ratio [IRR] = 1.16; 95% confidence interval [95% CI], 0.62-2.19; P = .6; at 9 years of age: IRR = 0.50; 95% CI, 0.28-0.87; P = .01), suggesting an acquired mechanism of protection. Once parasitemic, children with HbAS were less likely to progress to symptomatic malaria, with protection again being the most pronounced at older ages (at 2 years of age: relative risk [RR] = 0.92; 95% CI, 0.77-1.10; P = .3; at 9 years of age: RR = 0.68; 95% CI, 0.51-0.91; P = .008). Conversely, the youngest children were best protected against high parasite density (at 2 years of age: relative density = 0.24; 95% CI, 0.10-0.54; P = .001; at 9 years of age: relative density = 0.59; 95% CI, 0.30-1.19; P = .14), suggesting an innate mechanism of protection against this end point.

scholarly journals Sickle Cell Trait Modulates the Proteome and Phosphoproteome of Plasmodium falciparum-Infected Erythrocytes

2021 ◽  
Vol 11 ◽  
Author(s):  
Margaux Chauvet ◽  
Cerina Chhuon ◽  
Joanna Lipecka ◽  
Sébastien Dechavanne ◽  
Célia Dechavanne ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Erythrocyte Membrane ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Protein Complexes ◽  
Human Populations ◽  
Red Cell Membrane ◽  
High Prevalence ◽  
Erythrocyte Surface ◽  
Human Proteins

The high prevalence of sickle cell disease in some human populations likely results from the protection afforded against severe Plasmodium falciparum malaria and death by heterozygous carriage of HbS. P. falciparum remodels the erythrocyte membrane and skeleton, displaying parasite proteins at the erythrocyte surface that interact with key human proteins in the Ankyrin R and 4.1R complexes. Oxidative stress generated by HbS, as well as by parasite invasion, disrupts the kinase/phosphatase balance, potentially interfering with the molecular interactions between human and parasite proteins. HbS is known to be associated with abnormal membrane display of parasite antigens. Studying the proteome and the phosphoproteome of red cell membrane extracts from P. falciparum infected and non-infected erythrocytes, we show here that HbS heterozygous carriage, combined with infection, modulates the phosphorylation of erythrocyte membrane transporters and skeletal proteins as well as of parasite proteins. Our results highlight modifications of Ser-/Thr- and/or Tyr- phosphorylation in key human proteins, such as ankyrin, β-adducin, β-spectrin and Band 3, and key parasite proteins, such as RESA or MESA. Altered phosphorylation patterns could disturb the interactions within membrane protein complexes, affect nutrient uptake and the infected erythrocyte cytoadherence phenomenon, thus lessening the severity of malaria symptoms.

scholarly journals Imbalanced Distribution of Plasmodium falciparum MSP-1 Genotypes Related to Sickle-Cell Trait

1997 ◽  
Vol 3 (9) ◽  
pp. 581-592 ◽  
Author(s):  
Francine Ntoumi ◽  
Christophe Rogier ◽  
Alioune Dieye ◽  
Jean-François Trape ◽  
Pascal Millet ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Sickle Cell ◽  
Sickle Cell Trait

A PROSPECTIVE STUDY OF THE INFLUENCE OF α-THALASSAEMIA ON MORBIDITY FROM MARLARIA AND IMMUNE RESPONSES TO DEFINED PLASMODIUM FALCIPARUM ANTIGENS IN GAMBIAN CHILDREN

PEDIATRICS ◽  
1995 ◽  
Vol 95 (6) ◽  
pp. 844-844
Author(s):  
S. J. Allen ◽  
P. Rowe ◽  
C. E. M. Allsop
Keyword(s):  
Plasmodium Falciparum ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Stimulation Index ◽  
Malarial Parasite ◽  
Similar Proportion ◽  
Control Group ◽  
Unexpected Finding ◽  
Vitro Assay

α-Thalassaemia is the most common haemoglobinopathy in Africa and is due to a defect in α-globin chain synthesis. Earlier studies have indicated that α-Thalassaemia may provide a selective advantage against Plasmodium falciparum malaria and account for the increased prevalence of α-Thalassaemia in malarial endemic areas. The mechanism by which α-Thalassaemia is protective against malaria is not clear. One hypothesis is that there is a greater binding of immunoglobulin molecules to the surface of thalassaemic red cells resulting in better clearance of parasitized erythrocytes. The present authors conducted a study on children living in two groups of villages in Gambia to test this hypothesis. These studies were conducted once at the beginning of May and once at the end of October, which is the end of the rainy season and a period of intense malaria transmission. In addition to definition of active and asymptomatic malarial infection, the authors conducted a number of studies including genotyping for haemoglobinopathies (specifically α-Thalassaemia and sickle cell), measurement of antibody to a variety of antigens related to malarial parasite, and in vitro cellular immune response to specific malarial antigens. They included a control group of 30 Swedish children who had never been exposed to malaria. They also used PHA, candida, and PPD as control antigens for in vitro stimulation of lymphocytes. They looked at the lymphocyte stimulation index and IFNγ production in vitro in response to various mitogens. The authors did not find an increased parasite rate in children with α-Thalassaemia. A similar proportion of normal and heterozygotes thalassaemia children acquired malaria. This was different from earlier studies conducted in Papua, New Guinea. They also noted a higher rate of infection among children with hemoglobin AS and heterozygote for \g=a\-Thalassaemia than in those with normal hemoglobin and heterozygote for \g=a\-Thalassaemia. There was no difference between children with \g=a\-Thalassaemia and those with normal genes in the prevalence of antibodies to any of the malarial antigens. However, in the in vitro assay they noted greater lymphoproliferative responses to some of the soluble antigens and lower IFN\g=g\ production response to two of the recombinant antigens for merozoite protein in \g=a\-Thalassaemic children compared with normal children. However, considering the number of antigens that were tested, these abnormalities may have been by chance. Although there was no difference in the frequency of malaria among children with \g=a\-Thalassaemia and those with normal haemoglobin genotype, there were few children who had both \g=a\-Thalassaemia and sickle cell trait with fewer clinical episodes of malaria than children with sickle cell trait alone. This is an unexpected finding. This finding may be more important to follow than the original question with which the authors started the study.

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