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

Abstract

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.

Erythrocyte type 1 equilibrative nucleoside transporter expression in sickle cell disease and sickle cell trait

“…At present, we do not have any good explanation for this finding. Erythrocyte ENT1 transporter of SCT carriers has been shown to exhibit increased phosphorylation in a comparative quantitative phosphoproteomic analysis of SCT carriers and HbAA subjects 19 . It would be of major interest to determine whether our present observation of reduced ENT1 levels in individuals with SCT is related to their finding.…”

“…Erythrocyte ENT1 transporter of SCT carriers has been shown to exhibit increased phosphorylation in a comparative quantitative phosphoproteomic analysis of SCT carriers and HbAA subjects. 19 It would be of major interest to determine whether our present observation of reduced ENT1 levels in individuals with SCT is related to their finding. Whether reduced expression of erythrocyte ENT1 contributes to the mechanism of SCT resistance to P. falciparum parasite infection remains to be investigated.…”

Malaria: a historical, eminent and persistent problem

“…Assim, a morfologia celular com formato de "foice" é mais frequente em pessoas de ascendência africana do que em outros grupos populacionais. Da mesma forma, a hemoglobina C, a talassemias e deficiência de glicose-6-fosfato desidrogenase são mais prevalentes em áreas endêmicas de malária (MBANEFO et al, 2017;BANYATSUPPASIN et al, 2017;CHAUVET et al, 2021).…”

“…De acordo com WHO, (2023), essa é a primeira vacina contra a malária a atingir um estágio de eficiência suficiente e pode ser uma boa ferramenta amplamente implementável para combater a malária, desde a terapia combinada à base de artemisinina e mosquiteiros. Mesmo o resultado de eficácia sendo relativamente baixo para uma vacina, estimada em 39%, as autoridades consideram um bom resultado, mediante os riscos oferecidos pela doença (RTS, 2015).…”

Decrypting the complexity of the human malaria parasite biology through systems biology approaches

“…They can also reveal parasite-host interactions at play and serve as a diagnostic tool. Using Phos-tag and magnetic TiO 2 beads, comparison of the phosphoproteome of P. falciparum infected and un-infected RBC membrane extracts showed identifiable sickle cell traits along with notable associations with parasite infections, bringing renewed optimism in clinical and diagnostic research (Chauvet et al, 2021). Phosphoproteome capture technology has been refined to increase the specificity, stability, and spatial resolution across different conditions.…”