PfEMP1 and var genes – Still of key importance in Plasmodium falciparum malaria pathogenesis and immunity

Background Acquired immunity to Plasmodium falciparum malaria is mainly mediated by immunoglobulin G (IgG) targeting erythrocyte membrane protein 1 (PfEMP1). These adhesins mediate infected erythrocyte (IE) sequestration, protecting IEs from splenic destruction. PfEMP1-specific IgG is therefore thought to protect mainly by inhibiting IE sequestration. VAR2CSA-type PfEMP1 mediates placental IE sequestration, putting pregnant women exposed to P falciparum parasites at risk of placental malaria (PM). Methods Levels and Fc-afucosylation of VAR2CSA-specific plasma IgG were measured by a modified enzyme-linked immunosorbent assay (FEASI). We also measured the ability of the IgG to inhibit IE adhesion and to induce natural killer (NK) cell degranulation. The results were related to parity and clinical pregnancy outcomes. Results Parity was positively correlated with levels and Fc-afucosylation of VAR2CSA-specific IgG, and with birth weight and plasma IgG inhibition of IE adhesion in vitro. Fc-afucosylation of VAR2CSA-specific IgG increased NK–cell degranulation. Women with Fc-afucosylated VAR2CSA–specific IgG had a reduced risk of delivering a low birth weight (LBW) baby, but not of PM or anemia. Conclusions Fc-afucosylated VAR2CSA-specific IgG effectively induced NK–cell degranulation and was associated with protection against LBW, independent of IgG levels. Our study has implications for the development of VAR2CSA-based subunit vaccines, which exclusively induce Fc-fucosylated IgG.

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Single Cells Signal Non-self from Self via ‘XOR’ and ‘NOT EQUALS’ Logic in a Dimer of Dimers

An,

Prakash

2024

Preprint

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The ciliate Tetrahymena thermophila's seven mating types are defined by unique receptor-ligand pairs (Mta/Mtb). While Mta and Mtb are known to participate in a mating signal complex, how they distinguish between oneself and six non-self cell types remains unknown. AlphaFold3 predictions reveal Mta/Mtb as large glycoproteins likely derived from ancient, unisexual, intercellular adhesion molecules. Since homologous binary-type systems perform XOR by switching mtA expression, we show spectrum (n) types naturally extend XOR to multi-bit NOT EQUALS operations via differential affinities of Mta/Mtb dimers. We model kinetics begetting the 'n + 1th' type, demonstrating self-inhibition by trans-homophilic Mtb-Mtb. A computational approach reconciles recent and classical evidence for mating exclusivity, including selfing failures (same type mating). Binding kinetics enables fast, robust intercellular computation across an intermembrane mating space. Thus, Mta/Mtb families are a model system allowing us to derive a 'calculus' of antigenic variation and inspire synthetic designs of XOR logic underlying self/non-self recognition.

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PfEMP1 and var genes – Still of key importance in Plasmodium falciparum malaria pathogenesis and immunity

Cited by 3 publications

References 291 publications

Placental malaria and circumsporozoite protein-specific immunity

Placental malaria and circumsporozoite protein-specific immunity

Fc-Afucosylation of VAR2CSA-Specific Immunoglobulin G and Clinical Immunity to Placental Plasmodium falciparum Malaria

Single Cells Signal Non-self from Self via ‘XOR’ and ‘NOT EQUALS’ Logic in a Dimer of Dimers

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