Structural and genomic analysis of single nucleotide polymorphisms in human host factor endothelial protein C receptor (EPCR) reveals complex interplay with malaria parasites

Gill, Jasmita; Sharma, Amit

doi:10.1016/j.meegid.2023.105413

Cited by 3 publications

(5 citation statements)

References 31 publications

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“…CIDRα1 is highly polymorphic as has been seen in field isolate studies. The complex interplay between parasites and EPCR based on global mutations has been described earlier [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…This scenario can efficiently retain the binding capability (albeit with a different set of residues) and withstand immune pressure including that of a vaccine. On these lines, CIDR, the neighbouring domain of DBL on the PfEMP1, which binds to human endothelial protein C receptor (EPCR), exhibits high sequence variability (based on 885 field isolates) but has an overall conserved structural architecture in its EPCR-binding region [ 16 , 31 ]. ICAM-1 and EPCR are of significant interest as several studies have strengthened their potential dual role in the pathogenesis of cerebral malaria [ 14 , 15 ].…”

Section: Resultsmentioning

confidence: 99%

“…The involvement of ICAM-1 in two important features of the immune response has been explored, (i) loss of fibrinogen binding by ICAM-1 Kilifi variants (ligand of ICAM-1 for different physiological functions), and (ii) reduced LFA-1 mediated adhesion of leukocytes in the ICAM-1 Kilifi variant resulting in a beneficial immunomodulatory effect [ 21 ]. Understandably, cohort studies on cerebral malaria are required with a focus on genetic surveillance of host factor mutations along with parasite genes that drive cytoadhesion [ 16 ]. Comprehensive data on global mutations can assist in designing experimental and clinical studies to validate the biological significance of mutations in relation to disease severity by possibly linking specific mutations in ICAM-1 with altered malaria susceptibility in particular host populations.…”

Section: Resultsmentioning

confidence: 99%

“…The subclasses of DBLβ domains found in A, B, and C PfEMP1 are known to bind ICAM-1 [ 2 , 3 ]. Studies show that parasites which express PfEMP1 that binds to both ICAM-1 and endothelial protein C receptor (EPCR) (via the neighbouring CIDR domain), are possibly associated with an increased risk of developing cerebral symptoms of P. falciparum infections [ 14 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Profiles of global mutations in the human intercellular adhesion molecule-1 (ICAM-1) shed light on population-specific malaria susceptibility

Gill,

Singh,

Sharma

2023

BMC Genomics

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Plasmodium falciparum is responsible for malaria-related morbidity and mortality. PfEMP1 (P. falciparum erythrocyte membrane protein 1) mediates infected erythrocytes adhesion to various surface vascular receptors, including intercellular adhesion molecule-1 (ICAM-1), associating this interaction with severe malaria in several studies. Genetic variation in host ICAM-1 plays a significant role in determining susceptibility to malaria infection via clinical phenotypes such as the ICAM-1Kilifi variant which has been reported to be associated with susceptibility in populations. Our genomic and structural analysis of single nucleotide polymorphisms (SNPs) in ICAM-1 revealed 9 unique mutations each in its distinct A-type and BC-type PfEMP1 DBLβ-interacting regions. These mutations are noted in only a few field isolates and mainly in the African/African American population. The ICAM-1Kilifi variant lies in a flexible loop proximal to the DBLβ-interacting region. This analysis will assist in establishing functional correlations of reported global mutations via experimental and clinical studies and in the tailored design of population-specific genetic surveillance studies. Understanding host polymorphism as an evolutionary force in diverse populations can help to predict predisposition to disease severity and will contribute towards laying the framework for designing population-specific personalized medicines for severe malaria.

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“…CIDRα1 is highly polymorphic as has been seen in field isolate studies. The complex interplay between parasites and EPCR based on global mutations has been described earlier [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Profiles of global mutations in the human intercellular adhesion molecule-1 (ICAM-1) shed light on population-specific malaria susceptibility

Gill,

Singh,

Sharma

2023

BMC Genomics

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“…In addition, APC, together with protein S (PS), its main cofactor, are crucial physiological inhibitors of FVa and FVIIIa [ 34 ]. The complex formed by TM and thrombin activates protein C (PC), boosting the efficiency of coagulation when the endothelial PC receptor (EPCR) binds to PC’s Gla domain [ 35 ].…”

Section: Hemostasis and Its Regulationmentioning

confidence: 99%

The Magic of Proteases: From a Procoagulant and Anticoagulant Factor V to an Equitable Treatment of Its Inherited Deficiency

Pablo-Moreno

Miguel-Batuecas

Sancha

et al. 2023

IJMS

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Proteostasis, i.e., the homeostasis of proteins, responsible for ensuring protein turnover, is regulated by proteases, which also participate in the etiopathogenesis of multiple conditions. The magic of proteases is such that, in blood coagulation, one same molecule, such as coagulation factor V, for example, can perform both a procoagulant and an anticoagulant function as a result of the activity of proteases. However, this magic has an insidious side to it, as it may also prevent the completion of the clinical value chain of factor V deficiency. This value chain encompasses the discovery of knowledge, the transfer of this knowledge, and its translation to clinical practice. In the case of rare and ultra-rare diseases like factor V deficiency, this value chain has not been completed as the knowledge acquisition phase has dragged out over time, holding up the transfer of knowledge to clinical practice. The reason for this is related to the small number of patients afflicted with these conditions. As a result, new indications must be found to make the therapies cost-effective. In the case of factor V, significant research efforts have been directed at developing a recombinant factor V capable of resisting the action of the proteases capable of inactivating this factor. This is where bioethics and health equity considerations come into the equation.

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

Hviid,

Jensen,

Deitsch

2024

Advances in Parasitology

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Structural and genomic analysis of single nucleotide polymorphisms in human host factor endothelial protein C receptor (EPCR) reveals complex interplay with malaria parasites

Cited by 3 publications

References 31 publications

Profiles of global mutations in the human intercellular adhesion molecule-1 (ICAM-1) shed light on population-specific malaria susceptibility

Profiles of global mutations in the human intercellular adhesion molecule-1 (ICAM-1) shed light on population-specific malaria susceptibility

The Magic of Proteases: From a Procoagulant and Anticoagulant Factor V to an Equitable Treatment of Its Inherited Deficiency

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

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