Cerebral malaria is associated with IgG2 and IgG4 antibody responses to recombinant Plasmodium falciparum RIFIN antigen

Schreiber, Nadine; Brattig, Norbert W.; Evans, Jennifer; Agbenyega, Tsiri; Horstmann, Rolf D.; May, Jürgen; Klinkert, Mo‐Quen

doi:10.1016/j.micinf.2005.12.007

Cited by 19 publications

(20 citation statements)

References 32 publications

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“…However, relating immune responses to malaria resistance is not straightforward since exposed individuals are typically infected repeatedly throughout life, and develop diversified immune responses against multiple antigens, in many cases without comprehensible relevance to disease severity. Multiple studies have sought to relate seroreactivity with disease susceptibility in young African children [38]–[44], but no candidate antigens for a severe malaria vaccine have been identified. While seroreactivity studies are useful for defining the immunoepidemiology of existing vaccine candidate antigens [30],[45], functional assays may be essential for the discovery of novel vaccine candidates.…”

Section: Discussionmentioning

confidence: 99%

High Throughput Functional Assays of the Variant Antigen PfEMP1 Reveal a Single Domain in the 3D7 Plasmodium falciparum Genome that Binds ICAM1 with High Affinity and Is Targeted by Naturally Acquired Neutralizing Antibodies

et al. 2009

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Plasmodium falciparum–infected erythrocytes bind endothelial receptors to sequester in vascular beds, and binding to ICAM1 has been implicated in cerebral malaria. Binding to ICAM1 may be mediated by the variant surface antigen family PfEMP1: for example, 6 of 21 DBLβC2 domains from the IT4 strain PfEMP1 repertoire were shown to bind ICAM1, and the PfEMP1 containing these 6 domains are all classified as Group B or C type. In this study, we surveyed binding of ICAM1 to 16 DBLβC2 domains of the 3D7 strain PfEMP1 repertoire, using a high throughput Bioplex assay format. Only one DBL2βC2 domain from the Group A PfEMP1 PF11_0521 showed strong specific binding. Among these 16 domains, DBL2βC2PF11_0521 best preserved the residues previously identified as conserved in ICAM1-binding versus non-binding domains. Our analyses further highlighted the potential role of conserved residues within predominantly non-conserved flexible loops in adhesion, and, therefore, as targets for intervention. Our studies also suggest that the structural/functional DBLβC2 domain involved in ICAM1 binding includes about 80 amino acid residues upstream of the previously suggested DBLβC2 domain. DBL2βC2PF11_0521 binding to ICAM1 was inhibited by immune sera from east Africa but not by control US sera. Neutralizing antibodies were uncommon in children but common in immune adults from east Africa. Inhibition of binding was much more efficient than reversal of binding, indicating a strong interaction between DBL2βC2PF11_0521 and ICAM1. Our high throughput approach will significantly accelerate studies of PfEMP1 binding domains and protective antibody responses.

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Section: Discussionmentioning

confidence: 99%

High Throughput Functional Assays of the Variant Antigen PfEMP1 Reveal a Single Domain in the 3D7 Plasmodium falciparum Genome that Binds ICAM1 with High Affinity and Is Targeted by Naturally Acquired Neutralizing Antibodies

et al. 2009

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“…The following antisera were applied in this study: rat anti-A RIF40 [29], mouse anti-B RIFΔNC [64], rat anti-RIF44 [29], mouse anti-STEVOR [65] and rabbit anti-PP5 [32]. Mouse anti-SBP1 was kindly provided by Catherine Braun-Breton (Institute Pasteur, Paris), mouse anti-PfCCP1 was kindly provided by Gabriele Pradel (University of Würzburg), rabbit anti-Pfg27 was a kind gift from Pietro Alano (Istituto Superiore di Sanità, Rome).…”

Section: Methodsmentioning

confidence: 99%

Diverse Expression Patterns of Subgroups of the rif Multigene Family during Plasmodium falciparum Gametocytogenesis

2008

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BackgroundThe maturation of Plasmodium falciparum gametocytes in the human host takes several days, during which the parasites need to efficiently evade the host immune system. Like asexual stage parasites, immature gametocytes can sequester at various sites in the human body, and only mature sexual stages are found in the circulation. Although the fundamental mechanisms of gametocyte immune evasion are still largely unknown, candidate molecules that may be involved include variant antigens encoded by multigene families in the P. falciparum genome, such as the PfEMP1, STEVOR and RIFIN proteins. While expression of the former two families in sexual stages has been investigated earlier, we report here RIFIN expression during gametocytogenesis.Methodology/Principal FindingsVariants of two previously characterized RIFIN subfamilies (A- and B-type RIFINs) were found to be synthesized in gametocytes. Immunofluorescence experiments showed A-type RIFINs to be accumulated in a crescent-shaped pattern of discrete punctate structures at the infected erythrocyte membrane, while members of the B-type family were associated with the parasite. Transcription analysis demonstrated the existence of diverse transcriptional regulation patterns during sexual differentiation and indicated variant-specific regulation of B-type RIFINs, in contrast to group-specific regulation for A-type RIFINs. Phylogenetic analysis of 5′-upstream regions showed that the rif–gene family falls into five defined clusters, designated rups (rif upstream) A1, A2, AB, B and C. In trophozoites and early gametocytes, rif variants of the rupsA2-type were preferentially expressed.Conclusions/SignificanceIn this work we demonstrate the expression dynamics of the rif-gene family during sexual differentiation and present indications for subgroup specific regulation patterns. Therefore, our data provide a first foundation and point to new directions for future investigations of the potential role of RIFINs in gametocyte immune evasion.

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“…1993). Parasite culture handling and antigen preparation were carried out as described previously (Schreiber et al. 2006).…”

Section: Methodsmentioning

confidence: 99%

Immune responses after single‐dose sulphadoxine–pyrimethamine indicate underestimation of protective efficacy of intermittent preventive treatment in infants

Schreiber

Kobbe

Adjei

et al. 2007

Tropical Med Int Health

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Summaryobjective To assess how intermittent preventive treatment in infants (IPTi) with sulphadoxinepyrimethamine (SP) affects Immunoglobulin (IgG) immune responses against Plasmodium falciparum in infants from rural Ghana.methods Randomized, placebo-controlled and double-blinded clinical trial with participants randomized in blocks of 10 to receive either 250 mg sulphadoxine/2.5 mg pyrimethamine or placebo at the age of 3 (IPTi-1), 9 (IPTi-2) and 15 (IPTi-3) months and followed-up for 21 months. (i) Anti-P. falciparum IgG levels were measured in 180 children at the age of 9 months. (ii) Longitudinal study of the relationship between IgG levels and P. falciparum infections and/or clinical malaria in 17 naive children until they reached the age of 2 years.results IgG antibody levels against crude P. falciparum lysate were dependent on the frequency of preceding infections and significantly lower in children treated with SP.

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Cerebral malaria is associated with IgG2 and IgG4 antibody responses to recombinant Plasmodium falciparum RIFIN antigen

Cited by 19 publications

References 32 publications

High Throughput Functional Assays of the Variant Antigen PfEMP1 Reveal a Single Domain in the 3D7 Plasmodium falciparum Genome that Binds ICAM1 with High Affinity and Is Targeted by Naturally Acquired Neutralizing Antibodies

High Throughput Functional Assays of the Variant Antigen PfEMP1 Reveal a Single Domain in the 3D7 Plasmodium falciparum Genome that Binds ICAM1 with High Affinity and Is Targeted by Naturally Acquired Neutralizing Antibodies

Diverse Expression Patterns of Subgroups of the rif Multigene Family during Plasmodium falciparum Gametocytogenesis

Immune responses after single‐dose sulphadoxine–pyrimethamine indicate underestimation of protective efficacy of intermittent preventive treatment in infants

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