Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria.
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.
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
Ariel
A
Magallón-Tejada
Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.
Sónia
S
Machevo
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
Pau
P
Cisteró
Centre for Medical Parasitology, Department of International Health, Immunology, and Microbiology, Faculty of Health Sciences, University of Copenhagen, and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Thomas
T
Lavstsen
Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.
Pedro
P
Aide
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
Mercedes
http://orcid.org/0000-0002-4331-3280
M
Rubio
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.|Consorcio de Investigación Biomédica y Salud Pública, Madrid, Spain.
Alfons
A
Jiménez
Centre for Medical Parasitology, Department of International Health, Immunology, and Microbiology, Faculty of Health Sciences, University of Copenhagen, and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Louise
L
Turner
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
Aida
http://orcid.org/0000-0001-6739-0996
A
Valmaseda
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
Himanshu
H
Gupta
Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
Briegel
B
De Las Salas
Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.
Inacio
I
Mandomando
Centre for Medical Parasitology, Department of International Health, Immunology, and Microbiology, Faculty of Health Sciences, University of Copenhagen, and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Christian W
CW
Wang
Centre for Medical Parasitology, Department of International Health, Immunology, and Microbiology, Faculty of Health Sciences, University of Copenhagen, and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Jens E V
JE
Petersen
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
Jose
J
Muñoz
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
Joaquim
J
Gascón
Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.
Eusebio
E
Macete
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.|Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.
Pedro L
PL
Alonso
Department of Parasites and Insect Vectors, Institut Pasteur, Paris, France.|Malaria Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
Chetan E
CE
Chitnis
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.|Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.|ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain.
Quique
Q
Bassat
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.|Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.
Alfredo
A
Mayor
D000328:Adult; D002352:Carrier Proteins / Q000378:metabolism*; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000378:metabolism*; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010963:Plasmodium falciparum; D015800:Protozoan Proteins / Q000378:metabolism*
C087299:C1QBP protein, human; D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum