Cytoadhesion to gC1qR through Plasmodium falciparum erythrocyte membrane protein 1 in severe malaria
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Cytoadhesion to gC1qR through Plasmodium falciparum erythrocyte membrane protein 1 in severe malaria. / Magallón-Tejada, Ariel; Machevo, Sónia; Cisteró, Pau; Lavstsen, Thomas; Aide, Pedro; Rubio, Mercedes; Jiménez, Alfons; Turner, Louise; Valmaseda, Aida; Gupta, Himanshu; De Las Salas, Briegel; Mandomando, Inacio; Wang, Christian W; Petersen, Jens E V; Muñoz, Jose; Gascón, Joaquim; Macete, Eusebio; Alonso, Pedro L; Chitnis, Chetan E; Bassat, Quique; Mayor, Alfredo.
I: PLOS Pathogens, Bind 12, Nr. 11, e1006011, 11.11.2016.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Cytoadhesion to gC1qR through Plasmodium falciparum erythrocyte membrane protein 1 in severe malaria
AU - Magallón-Tejada, Ariel
AU - Machevo, Sónia
AU - Cisteró, Pau
AU - Lavstsen, Thomas
AU - Aide, Pedro
AU - Rubio, Mercedes
AU - Jiménez, Alfons
AU - Turner, Louise
AU - Valmaseda, Aida
AU - Gupta, Himanshu
AU - De Las Salas, Briegel
AU - Mandomando, Inacio
AU - Wang, Christian W
AU - Petersen, Jens E V
AU - Muñoz, Jose
AU - Gascón, Joaquim
AU - Macete, Eusebio
AU - Alonso, Pedro L
AU - Chitnis, Chetan E
AU - Bassat, Quique
AU - Mayor, Alfredo
PY - 2016/11/11
Y1 - 2016/11/11
N2 - Cytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed by static binding assays and qPCR the cytoadhesion and var gene transcriptional profile of 86 P. falciparum isolates from Mozambican children with severe and uncomplicated malaria, as well as of a P. falciparum 3D7 line selected for binding to gC1qR (Pf3D7gC1qR). Transcript levels of DC8 correlated positively with cytoadhesion to gC1qR (rho = 0.287, P = 0.007), were higher in isolates from children with severe anemia than with uncomplicated malaria, as well as in isolates from Europeans presenting a first episode of malaria (n = 21) than Mozambican adults (n = 25), and were associated with an increased IgG recognition of infected erythrocytes by flow cytometry. Pf3D7gC1qR overexpressed the DC8 type PFD0020c (5.3-fold transcript levels relative to Seryl-tRNA-synthetase gene) compared to the unselected line (0.001-fold). DBLβ12 from PFD0020c bound to gC1qR in ELISA-based binding assays and polyclonal antibodies against this domain were able to inhibit binding to gC1qR of Pf3D7gC1qR and four Mozambican P. falciparum isolates by 50%. Our results show that DC8-type PfEMP1s mediate binding to gC1qR through conserved surface epitopes in DBLβ12 domain which can be inhibited by strain-transcending functional antibodies. This study supports a key role for gC1qR in malaria-associated endovascular pathogenesis and suggests the feasibility of designing interventions against severe malaria targeting this specific interaction.
AB - Cytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed by static binding assays and qPCR the cytoadhesion and var gene transcriptional profile of 86 P. falciparum isolates from Mozambican children with severe and uncomplicated malaria, as well as of a P. falciparum 3D7 line selected for binding to gC1qR (Pf3D7gC1qR). Transcript levels of DC8 correlated positively with cytoadhesion to gC1qR (rho = 0.287, P = 0.007), were higher in isolates from children with severe anemia than with uncomplicated malaria, as well as in isolates from Europeans presenting a first episode of malaria (n = 21) than Mozambican adults (n = 25), and were associated with an increased IgG recognition of infected erythrocytes by flow cytometry. Pf3D7gC1qR overexpressed the DC8 type PFD0020c (5.3-fold transcript levels relative to Seryl-tRNA-synthetase gene) compared to the unselected line (0.001-fold). DBLβ12 from PFD0020c bound to gC1qR in ELISA-based binding assays and polyclonal antibodies against this domain were able to inhibit binding to gC1qR of Pf3D7gC1qR and four Mozambican P. falciparum isolates by 50%. Our results show that DC8-type PfEMP1s mediate binding to gC1qR through conserved surface epitopes in DBLβ12 domain which can be inhibited by strain-transcending functional antibodies. This study supports a key role for gC1qR in malaria-associated endovascular pathogenesis and suggests the feasibility of designing interventions against severe malaria targeting this specific interaction.
U2 - 10.1371/journal.ppat.1006011
DO - 10.1371/journal.ppat.1006011
M3 - Journal article
C2 - 27835682
VL - 12
JO - P L o S Pathogens
JF - P L o S Pathogens
SN - 1553-7366
IS - 11
M1 - e1006011
ER -
ID: 169061738