Immunization with PfEMP1-DBL1alpha generates antibodies that disrupt rosettes and protect against the sequestration of Plasmodium falciparum-infected erythrocytes.
A family of parasite antigens known as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is believed to play an important role in the binding of infected erythrocytes to host receptors in the micro-vasculature. Available data advocates the existence of a subset of very adhesive (rosetting, auto-agglutinating) and antigenic PfEMP1s implicated as virulence factors. Serum antibodies that disrupt rosettes are rarely found in children with severe malaria but are frequent in those with mild disease suggesting that they may be protective. Here we have developed a Semliki forest virus (SFV) vaccine construct with a recombinant gene (mini-var gene) encoding a mini-PfEMP1 (DBL1alpha-TM-ATS) obtained from a particularly antigenic and rosetting parasite (FCR3S1.2). The mini-PfEMP1 is presented to the host mimicking the location of the native molecule at the infected erythrocyte surface. Antibodies generated by a regimen of priming with SFV RNA particles and boosting with a recombinant protein recognize the infected erythrocyte surface (immuno-fluorescence/rosette-disruption) and prevent the sequestration of P. falciparum-infected erythrocytes in an in vivo model of severe malaria. The data prove the involvement of DBL1alpha in the adhesion of infected- and uninfected erythrocytes and the role of rosette-disruptive antibodies in preventing these cellular interactions. The work supports the use of DBL1alpha in a vaccine again severe malaria.
Chen
Qijun
Q
Microbiology and Tumorbiology Centre, Karolinska Institutet, Box 280, SE-171 77 Stockholm, Sweden. qijun.chen@smi.ki.se
Pettersson
Fredrik
F
Vogt
Anna M
AM
Schmidt
Berit
B
Ahuja
Sanjay
S
Liljeström
Peter
P
Wahlgren
Mats
M
D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis* / Q000276:immunology*; D003001:Cloning, Molecular; D017931:DNA Primers; D004912:Erythrocytes / Q000469:parasitology*; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D005453:Fluorescence; D015151:Immunoblotting; D017780:Malaria Vaccines / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000096:biosynthesis / Q000276:immunology*; D012367:RNA, Viral / Q000096:biosynthesis; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012397:Rosette Formation; D012672:Semliki forest virus / Q000276:immunology; D014614:Vaccines, Synthetic / Q000096:biosynthesis / Q000276:immunology; D014760:Viral Fusion Proteins / Q000276:immunology
D000913:Antibodies, Protozoan; D017931:DNA Primers; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D012367:RNA, Viral; D014614:Vaccines, Synthetic; D014760:Viral Fusion Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum