Structural Conservation Despite Huge Sequence Diversity Allows EPCR Binding by the PfEMP1 Family Implicated in Severe Childhood Malaria

Lau, C.K.; Turner, Louise; Jespersen, Jakob S.; Lowe, E.D.; Petersen, Bent; Wang, Christian W.; Petersen, Jens E.V.; Lusingu, John; Theander, Thor G.; Lavstsen, Thomas; Higgins, Matthew K.

doi:10.1016/j.chom.2014.11.007

Cited by 149 publications

(312 citation statements)

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“…Expression of a subset of PfEMP1s, which contain a specific set of domains, known as CIDRα1 domains, was associated with severe malaria or brain endothelial cell binding [32][33][34][35]. Later, CIDRα1 domains were found to bind to human EPCR [16], thereby preventing EPCR from interacting with its natural ligand, activated protein C [16,36] (Figure 1). The blockage of EPCR-mediated signalling, through PfEMP1 binding, is proposed to lead to localized inflammation and to symptoms of severe disease [12,16,36,37].…”

Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

“…Later, CIDRα1 domains were found to bind to human EPCR [16], thereby preventing EPCR from interacting with its natural ligand, activated protein C [16,36] (Figure 1). The blockage of EPCR-mediated signalling, through PfEMP1 binding, is proposed to lead to localized inflammation and to symptoms of severe disease [12,16,36,37].…”

Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

“…(B) Crystal structure of a CIDR domain (yellow) bound to its human receptor, EPCR (blue). The inset shows the CIDR residues (red) that make direct contact with EPCR and their conservation across 737 EPCR-binding CIDR domains, displayed as a sequence logo [36]. (C) Crystal structure of a DBL domain (green) bound to the first two domains of its human receptor, ICAM-1 (blue).…”

Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

“…Nevertheless, expression of these PfEMP1s is a significant risk factor for the development of severe malaria symptoms and inhibitory antibodies targeting their respective receptor-binding domains are found in surviving patients [36,38]. While there is still much to discover about the PfEMP1s, these groups of domains are therefore highly promising candidates to target in attempts to reduce the devastating symptoms of severe malaria.…”

Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

“…Do the ICAM-1 or EPCR-binding PfEMP1s, associated with severe disease, have the properties of vaccine immunogens? A combination of structural studies and extensive genomic analysis have revealed the degree to which these PfEMP1s remain conserved to allow receptor binding and has further identified regions of the ligand-binding domains that could be mimicked in immunogens [36,38,47] (Figure 1). The residues important for ICAM-1 binding in the DBLβ domains associated with cerebral malaria are remarkably conserved [38].…”

Section: Identifying Conserved Receptor-binding Surfaces On Pfemp1smentioning

confidence: 99%

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Towards an anti-disease malaria vaccine

Lennartz

Lavstsen

Higgins

2017

Emerging Topics in Life Sciences

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Human infective parasites, such as those that cause malaria, are highly adapted to evade clearance by the immune system. In situations where they must maintain prolonged interactions with molecules of their host, they often use parasite surface protein families. These families are highly diverse to prevent immune recognition, and yet, to promote parasite survival, their members must retain the ability to interact with specific human receptors. One of the best understood of the parasite surface protein families is the PfEMP1 proteins of Plasmodium falciparum. These molecules cause infected erythrocytes to adhere to human receptors found on blood vessel and tissue surfaces. This protects the parasite within from clearance by the spleen and also causes symptoms of severe malaria. The PfEMP1 are exposed to the immune system during infection and are therefore excellent vaccine candidates for use in an approach to prevent severe disease. A key question, however, is whether their extensive diversity precludes them from forming components of the malaria vaccines of the future?

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Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

Section: Identifying Conserved Receptor-binding Surfaces On Pfemp1smentioning

confidence: 99%

See 3 more Smart Citations

Towards an anti-disease malaria vaccine

Lennartz

Lavstsen

Higgins

2017

Emerging Topics in Life Sciences

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Signatures of competition and strain structure within the major blood‐stage antigen of Plasmodium falciparum in a local community in Ghana

Rorick

Artzy‐Randrup

Ruybal‐Pesántez

et al. 2018

Ecology and Evolution

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The concept of niche partitioning has received considerable theoretical attention at the interface of ecology and evolution of infectious diseases. Strain theory postulates that pathogen populations can be structured into distinct nonoverlapping strains by frequency‐dependent selection in response to intraspecific competition for host immune space. The malaria parasite Plasmodium falciparum presents an opportunity to investigate this phenomenon in nature, under conditions of high recombination rate and extensive antigenic diversity. The parasite's major blood‐stage antigen, Pf EMP1, is encoded by the hyperdiverse var genes. With a dataset that includes thousands of var DBLα sequence types sampled from asymptomatic cases within an area of high endemicity in Ghana, we address how var diversity is distributed within isolates and compare this to the distribution of microsatellite allelic diversity within isolates to test whether antigenic and neutral regions of the genome are structured differently. With respect to var DBLα sequence types, we find that on average isolates exhibit significantly lower overlap than expected randomly, but that there also exists frequent pairs of isolates that are highly related. Furthermore, the linkage network of var DBLα sequence types reveals a pattern of nonrandom modularity unique to these antigenic genes, and we find that modules of highly linked DBLα types are not explainable by neutral forces related to var recombination constraints, microsatellite diversity, sampling location, host age, or multiplicity of infection. These findings of reduced overlap and modularity among the var antigenic genes are consistent with a role for immune selection as proposed by strain theory. Identifying the evolutionary and ecological dynamics that are responsible for the nonrandom structure in P. falciparum antigenic diversity is important for designing effective intervention in endemic areas.

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Patterns of protective associations differ for antibodies to P. falciparum‐infected erythrocytes and merozoites in immunity against malaria in children

et al. 2017

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Acquired antibodies play an important role in immunity to P. falciparum malaria and are typically directed towards surface antigens expressed by merozoites and infected erythrocytes (IEs). The importance of specific IE surface antigens as immune targets remains unclear. We evaluated antibodies and protective associations in two cohorts of children in Papua New Guinea. We used genetically-modified P. falciparum to evaluate the importance of PfEMP1 and a P. falciparum isolate with a virulent phenotype. Our findings suggested that PfEMP1 was the dominant target of antibodies to the IE surface, including functional antibodies that promoted opsonic phagocytosis by monocytes. Antibodies were associated with increasing age and concurrent parasitemia, and were higher among children exposed to a higher force-of-infection as determined using molecular detection. Antibodies to IE surface antigens were consistently associated with reduced risk of malaria in both younger and older children. However, protective associations for antibodies to merozoite surface antigens were only observed in older children. This suggests that antibodies to IE surface antigens, particularly PfEMP1, play an earlier role in acquired immunity to malaria, whereas greater exposure is required for protective antibodies to merozoite antigens. These findings have implications for vaccine design and serosurveillance of malaria transmission and immunity.

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Structural Conservation Despite Huge Sequence Diversity Allows EPCR Binding by the PfEMP1 Family Implicated in Severe Childhood Malaria

Cited by 149 publications

References 59 publications

Towards an anti-disease malaria vaccine

Towards an anti-disease malaria vaccine

Signatures of competition and strain structure within the major blood‐stage antigen of Plasmodium falciparum in a local community in Ghana

Patterns of protective associations differ for antibodies to P. falciparum‐infected erythrocytes and merozoites in immunity against malaria in children

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