B-cell epitopes in NTS-DBL1α of PfEMP1 recognized by human antibodies in Rosetting Plasmodium falciparum
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Published on: August 6, 2020
Letusa Albrecht1, Davide Angeletti1, Kirsten Moll1
1Department of Microbiology, Tumor- and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
Abstract:
Plasmodium falciparum is the most lethal of the human malaria parasites. The virulence is associated with the capacity of the infected red blood cell (iRBC) to sequester inside the deep microvasculature where it may cause obstruction of the blood-flow when binding is excessive. Rosetting, the adherence of the iRBC to uninfected erythrocytes, has been found associated with severe malaria and found to be mediated by the NTS-DBL1α-domain of Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1). Here we show that the reactivity of plasma of Cameroonian children with the surface of the FCR3S1.2-iRBC correlated with the capacity to disrupt rosettes and with the antibody reactivity with a recombinant PfEMP1 (NTS-DBL1α of IT4var60) expressed by parasite FCR3S1.2. The plasma-reactivity in a microarray, consisting of 96 overlapping 15-mer long peptides covering the NTS-DBL1α domain from IT4var60 sequence, was compared with their capacity to disrupt rosettes and we identified five peptides where the reactivity were correlated. Three of the peptides were localized in subdomain-1 and 2. The other two peptide-sequences were localized in the NTS-domain and in subdomain-3. Further, principal component analysis and orthogonal partial least square analysis generated a model that supported these findings. In conclusion, human antibody reactivity with short linear-peptides of NTS-DBL1α of PfEMP1 suggests subdomains 1 and 2 to hold anti-rosetting epitopes recognized by anti-rosetting antibodies. The data suggest rosetting to be mediated by the variable areas of PfEMP1 but also to involve structurally relatively conserved areas of the molecule that may induce biologically active antibodies.
Insights
Severe malaria is linked to Plasmodium falciparum rosetting, mediated by PfEMP1. Antibodies targeting specific NTS-DBL1α peptide regions, particularly subdomains 1 and 2, show potential in disrupting this binding.
Area of Science:
- Immunology
- Parasitology
- Molecular Biology
Background:
- Plasmodium falciparum causes severe malaria by sequestering infected red blood cells (iRBCs) in microvasculature.
- Rosetting, iRBCs adhering to uninfected erythrocytes, is associated with severe malaria and mediated by the NTS-DBL1α domain of PfEMP1.
Purpose of the Study:
- To investigate the correlation between human antibody reactivity against specific PfEMP1 NTS-DBL1α peptides and the ability to disrupt rosettes.
- To identify key epitopes within the PfEMP1 NTS-DBL1α domain involved in rosetting.
Main Methods:
- Plasma from Cameroonian children was tested for reactivity against a peptide microarray covering the PfEMP1 NTS-DBL1α domain.
- The capacity of plasma to disrupt FCR3S1.2-iRBC rosettes was measured.
- Statistical analyses including principal component analysis and orthogonal partial least square analysis were employed.
Main Results:
- Plasma reactivity against the NTS-DBL1α domain of PfEMP1 correlated with rosette-disrupting capacity.
- Five specific peptides within the NTS-DBL1α domain showed significant correlation between antibody reactivity and rosette disruption.
- Identified peptides were located in subdomain-1, subdomain-2, the NTS-domain, and subdomain-3.
Conclusions:
- Antibody responses targeting short linear peptides of the PfEMP1 NTS-DBL1α domain, particularly subdomains 1 and 2, are associated with anti-rosetting activity.
- These findings suggest that both variable and conserved regions of PfEMP1 contribute to rosetting and can be targeted by biologically active antibodies.
