Browsing by Author "Lopez-Perez, M."
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Item Afucosylated Plasmodium falciparum-specific IgG is induced by infection but not by subunit vaccination(NATURE COMMUNICATIONS, 2021) Larsen, M.D.; Lopez-Perez, M.; Dickson, E.K.; Ampomah, P.; Ederveen, H.; Koeleman, C.A.M.; Nouta, J.; Ndam, T.; Mordmüller, B.; Salanti, A.; Nielsen, M.A.; Massougbodji, A.; Schoot, C.E.; Ofori, M.F.; Wuhrer, M.; Hviid, L.; Vidarsson, G.Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family members mediate receptor- and tissue-specific sequestration of infected erythrocytes (IEs) in malaria. Antibody responses are a central component of naturally acquired malaria immunity. PfEMP1-specific IgG likely protects by inhibiting IE sequestration and through IgG-Fc Receptor (FcγR) mediated phagocytosis and killing of antibody-opsonized IEs. The affinity of afucosylated IgG to FcγRIIIa is up to 40-fold higher than fucosylated IgG, resulting in enhanced antibodydependent cellular cytotoxicity. Most IgG in plasma is fully fucosylated, but afucosylated IgG is elicited in response to enveloped viruses and to paternal alloantigens during pregnancy. Here we show that naturally acquired PfEMP1-specific IgG is strongly afucosylated in a stable and exposure-dependent manner, and efficiently induces FcγRIIIa-dependent natural killer (NK) cell degranulation. In contrast, immunization with a subunit PfEMP1 (VAR2CSA) vaccine results in fully fucosylated specific IgG. These results have implications for understanding protective natural- and vaccine-induced immunity to malaria.Item Biomarker of Anopheles exposure in Ghanaian children with hemoglobin S and C(Acta Tropica, 2024) Londono-Renteria, B.; Seidu, Z.; Lamptey, H.; Ofori, M.F.; Hviid, L.; Lopez-Perez, M.Heterozygous carriers of hemoglobin S and C (HbAS and HbAC) have a reduced risk of severe malaria but are not protected from Plasmodium falciparum infection, suggesting that the protection involves acquired immunity. During a blood meal, female Anopheles mosquitoes inject saliva that can elicit a host antibody response, which can serve as a proxy for exposure to Plasmodium infection. Previous studies have shown that the peptide gSG6-P1 of An. gambiae saliva is antigenic and highly Anopheles specific. Here, we used plasma samples from 201 Gha naian children with wild-type hemoglobin (HbAA), HbAS, and HbAC to evaluate antibody levels against gSG6-P1 as a serological biomarker of Anopheles exposure and, therefore of P. falciparum infection risk. Malaria antigen (PfCSP, GLURP, Pfs230, and HB3VAR06)-specific IgG levels, demographic data, and data regarding P. falciparum infection and malaria control practices were also analyzed. Children with active P. falciparum infection had higher antibody levels against all antigens, and those with HbAS and HbAC had significantly higher antibody levels against Pfs230. Pfs230-specific IgG correlated negatively with gSG6-P1-specific IgG in children with HbAC. Our results highlight the importance of studying the role of hemoglobinopathies in malaria transmission to improve control interventions.Item Comprehensive analysis of Fc-mediated IgM binding to the Plasmodium falciparum erythrocyte membrane protein 1 family in three parasite clones(Scientific Reports, 2019-04) Quintana, P.; Ecklu-Mensah, G.; Tcherniuk, S.; Ditlev, S.B.; Oleinikov, A.V.; Hviid, L.; Lopez-Perez, M.PfEMP1 is a family of adhesive proteins expressed on the surface of Plasmodium falciparum-infected erythrocytes (IEs), where they mediate adhesion of IEs to a range of host receptors. Efficient PfEMP1-dependent IE sequestration often depends on soluble serum proteins, including IgM. Here, we report a comprehensive investigation of which of the about 60 var gene-encoded PfEMP1 variants per parasite genome can bind IgM via the Fc part of the antibody molecule, and which of the constituent domains of those PfEMP1 are involved. We erased the epigenetic memory of var gene expression in three distinct P. falciparum clones, 3D7, HB3, and IT4/FCR3 by promoter titration, and then isolated individual IEs binding IgM from malaria-unexposed individuals by fluorescence-activated single-cell sorting. The var gene transcription profiles of sub-clones measured by real-time qPCR were used to identify potential IgM-binding PfEMP1 variants. Recombinant DBL and CIDR domains corresponding to those variants were tested by ELISA and protein arrays to confirm their IgM-binding capacity. Selected DBL domains were used to raise specific rat anti-sera to select IEs with uniform expression of candidate PfEMP1 proteins. Our data document that IgM-binding PfEMP1 proteins are common in each of the three clones studied, and that the binding epitopes are mainly found in DBLε and DBLζ domains near the C-terminus.Item Comprehensive analysis of Fc-mediated IgM binding to the Plasmodium falciparum erythrocyte membrane protein 1 family in three parasite clones(Scientific Reports, 2019) Quintana, M.P.; Ecklu-Mensah, C.; Tcherniuk, S.O.; Ditlev, S.B.; Oleinikov, A.V.; Hviid, L.; Lopez-Perez, M.PfEMP1 is a family of adhesive proteins expressed on the surface of Plasmodium falciparum-infected erythrocytes (IEs), where they mediate adhesion of IEs to a range of host receptors. Efficient PfEMP1-dependent IE sequestration often depends on soluble serum proteins, including IgM. Here, we report a comprehensive investigation of which of the about 60 var gene-encoded PfEMP1 variants per parasite genome can bind IgM via the Fc part of the antibody molecule, and which of the constituent domains of those PfEMP1 are involved. We erased the epigenetic memory of var gene expression in three distinct P. falciparum clones, 3D7, HB3, and IT4/FCR3 by promoter titration, and then isolated individual IEs binding IgM from malaria-unexposed individuals by fluorescence-activated single-cell sorting. The var gene transcription profiles of sub-clones measured by real-time qPCR were used to identify potential IgM-binding PfEMP1 variants. Recombinant DBL and CIDR domains corresponding to those variants were tested by ELISA and protein arrays to confirm their IgM-binding capacity. Selected DBL domains were used to raise specific rat anti-sera to select IEs with uniform expression of candidate PfEMP1 proteins. Our data document that IgM-binding PfEMP1 proteins are common in each of the three clones studied, and that the binding epitopes are mainly found in DBLε and DBLζ domains near the C-terminus. © 2019, The Author(s).