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Antibody Levels to Plasmodium falciparum Erythrocyte Membrane Protein 1-DBLγ11 and DBLδ-1 Predict Reduction in Parasite Density.

ABSTRACT: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a variant surface antigen family expressed on infected red blood cells that plays a role in immune evasion and mediates adhesion to vascular endothelium. PfEMP1s are potential targets of protective antibodies as suggested by previous seroepidemiology studies. Here, we used previously reported proteomic analyses of PfEMP1s of clinical parasite isolates collected from Malian children to identify targets of immunity. We designed a peptide library representing 11 PfEMP1 domains commonly identified on clinical isolates by membrane proteomics and then examined peptide-specific antibody responses in Malian children. The number of previous malaria infections was associated with development of PfEMP1 antibodies to peptides from domains CIDRα1.4, DBLγ11, DBLβ3, and DBLδ1. A zero-inflated negative binomial model with random effects (ZINBRE) was used to identify peptide reactivities that were associated with malaria risk. This peptide selection and serosurvey strategy revealed that high antibody levels to peptides from DBLγ11 and DBLδ1 domains correlated with decreased parasite burden in future infections, supporting the notion that specific PfEMP1 domains play a role in protective immunity. IMPORTANCE Plasmodium infection causes devastating disease and high mortality in young children. Immunity develops progressively as children acquire protection against severe disease, although reinfections and recrudescences still occur throughout life in areas of endemicity, partly due to parasite immunoevasion via switching of variant proteins such as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the infected erythrocyte surface. Understanding the mechanisms behind antibody protection can advance development of new therapeutic interventions that address this challenge. PfEMP1 domain-specific antibodies have been linked to reduction in severe malaria; however, the large diversity of PfEMP1 domains in circulating parasites has not been fully investigated. We designed representative peptides based on B cell epitopes of PfEMP1 domains identified in membranes of clinical parasite isolates and surveyed peptide-specific antibody responses among young Malian children in a longitudinal birth cohort. We examined previous infections and age as factors contributing to antibody acquisition and identified antibody specificities that predict malaria risk.

SUBMITTER: Araj BN

PROVIDER: S-EPMC8269226 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Plasmodium falciparum malaria remains one of the most deadly infections worldwide. The pathogenesis of the infection results from the sequestration of infected erythrocytes (IRBC) in vital organs, including the brain, with resulting impairment of blood flow, hypoxia, and lactic acidosis. Sequestration occurs through the adhesion of IRBC to host receptors on microvascular endothelium by Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a large family of variant surface antigens, each with up to seven extracellular domains that can bind to multiple host receptors. Consequently, antiadhesive therapies directed at single endothelial adhesion molecules may not be effective. In this study, we demonstrated that the serine protease thrombin, which is pivotal in the activation of the coagulation cascade, cleaved the major parasite adhesin on the surface of IRBC. As a result, adhesion under flow was dramatically reduced, and already adherent IRBC were detached. Thrombin cleavage sites were mapped to the Duffy binding-like δ1 (DBLδ1) domain and interdomains 1 and 2 in the PfEMP1 of the parasite line IT4var19. Furthermore, we observed an inverse correlation between the presence of thrombin and IRBC in cerebral malaria autopsies of children. We investigated a modified (R67A) thrombin and thrombin inhibitor, hirugen, both of which inhibit the binding of substrates to exosite I, thereby reducing its proinflammatory properties. Both approaches reduced the barrier dysfunction induced by thrombin without affecting its proteolytic activity on PfEMP1, raising the possibility that thrombin cleavage of variant PfEMP1 may be exploited as a broadly inhibitory antiadhesive therapy. Plasmodium falciparum malaria is the third leading cause of mortality due to a pathogen, with 214 million people infected and 438,000 deaths annually. The adhesion of Plasmodium falciparum-infected erythrocytes (IRBC) to microvascular endothelium is a major pathological process in severe malaria. While the recent implementation of artemisinin-based antimalarial therapy for severe malaria improves patient survival by targeting all parasite stages, antiparasite drugs alone may not immediately reverse pathophysiological processes in occluded vessels. Here we show that thrombin, an enzyme intimately involved in the clotting process, cleaves the main parasite adhesin expressed on the surface of IRBC, thereby preventing and reversing the binding of IRBC to endothelial cells. This beneficial effect of thrombin can be achieved by modified thrombins that cause significantly less clotting and vessel leakage while preserving the ability to cleave the parasite protein. Our results provide the basis for using modified thrombins as adjunctive therapy in severe malaria.

Project description:UnlabelledMembers of the clonally variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediate adhesion of infected erythrocytes (IEs) to vascular receptors. PfEMP1 expression is normally confined to nanoscale knob protrusions on the IE surface membrane. To investigate the relationship between the densities of these IE surface knobs and the PfEMP1 variant expressed, we used specific antibody panning to generate three sublines of the P. falciparum clone IT4, which expresses the PfEMP1 variants IT4VAR04, IT4VAR32b, and IT4VAR60. The knob density in each subline was then determined by atomic force microscopy (AFM) and scanning electron microscopy (SEM) and compared to PfEMP1 and knob-associated histidine-rich protein (KAHRP) expression. Selection for uniform expression of IT4VAR04 produced little change in knob density, compared to unselected IEs. In contrast, selection for IT4VAR32b expression increased knob density approximately 3-fold, whereas IEs selected for IT4VAR60 expression were essentially knobless. When IT4VAR60(+) IEs were subsequently selected to express IT4VAR04 or IT4VAR32b, they again displayed low and high knob densities, respectively. All sublines expressed KAHRP regardless of the PfEMP1 expressed. Our study documents for the first time that knob density is related to the PfEMP1 variant expressed. This may reflect topological requirements to ensure optimal adhesive properties of the IEs.ImportanceInfections with Plasmodium falciparum malaria parasites are still responsible for many deaths, especially among children and pregnant women. New interventions are needed to reduce severe illness and deaths caused by this malaria parasite. Thus, a better understanding of the mechanisms behind the pathogenesis is essential. A main reason why Plasmodium falciparum malaria is more severe than disease caused by other malaria species is its ability to express variant antigens on the infected erythrocyte surface. These antigens are presented on membrane protrusions known as knobs. This study set out to investigate the interplay between different variant antigens on the surface of P. falciparum-infected erythrocytes and the density of the knobs on which the antigens are expressed. Such a direct analysis of this relationship has not been reported before but adds to the important understanding of the complexity of malaria antigen presentation.

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Antibody Levels to Plasmodium falciparum Erythrocyte Membrane Protein 1-DBLγ11 and DBLδ-1 Predict Reduction in Parasite Density.

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