scholarly journals Fucosylated Chondroitin Sulfate Inhibits Plasmodium falciparum Cytoadhesion and Merozoite Invasion

2014 ◽  
Vol 58 (4) ◽  
pp. 1862-1871 ◽  
Author(s):  
Marcele F. Bastos ◽  
Letusa Albrecht ◽  
Eliene O. Kozlowski ◽  
Stefanie C. P. Lopes ◽  
Yara C. Blanco ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Parasite Development ◽  
Flow Conditions ◽  
Inhibitory Effects ◽  
Merozoite Invasion ◽  
Content Type ◽  
Life Threatening ◽  
Lung Endothelial Cells

ABSTRACTSequestration ofPlasmodium falciparum-infected erythrocytes (Pf-iEs) in the microvasculature of vital organs plays a key role in the pathogenesis of life-threatening malaria complications, such as cerebral malaria and malaria in pregnancy. This phenomenon is marked by the cytoadhesion of Pf-iEs to host receptors on the surfaces of endothelial cells, on noninfected erythrocytes, and in the placental trophoblast; therefore, these sites are potential targets for antiadhesion therapies. In this context, glycosaminoglycans (GAGs), including heparin, have shown the ability to inhibit Pf-iE cytoadherence and growth. Nevertheless, the use of heparin was discontinued due to serious side effects, such as bleeding. Other GAG-based therapies were hampered due to the potential risk of contamination with prions and viruses, as some GAGs are isolated from mammals. In this context, we investigated the effects and mechanism of action of fucosylated chondroitin sulfate (FucCS), a unique and highly sulfated GAG isolated from the sea cucumber, with respect toP. falciparumcytoadhesion and development. FucCS was effective in inhibiting the cytoadherence of Pf-iEs to human lung endothelial cells and placenta cryosections under static and flow conditions. Removal of the sulfated fucose branches of the FucCS structure virtually abolished the inhibitory effects of FucCS. Importantly, FucCS rapidly disrupted rosettes at high levels, and it was also able to block parasite development by interfering with merozoite invasion. Collectively, these findings highlight the potential of FucCS as a candidate for adjunct therapy against severe malaria.

scholarly journals Identification of Heparin Modifications and Polysaccharide Inhibitors of Plasmodium falciparum Merozoite Invasion That Have Potential for Novel Drug Development

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Michelle J. Boyle ◽  
Mark Skidmore ◽  
Benjamin Dickerman ◽  
Lynsay Cooper ◽  
Anthony Devlin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Development ◽  
Inhibitory Activity ◽  
Sulfated Polysaccharides ◽  
Merozoite Invasion ◽  
Content Type ◽  
Molecular Weights ◽  
Falciparum Merozoite ◽  
Successful Control ◽  
Novel Drug

ABSTRACT Despite recent successful control efforts, malaria remains a leading global health burden. Alarmingly, resistance to current antimalarials is increasing and the development of new drug families is needed to maintain malaria control. Current antimalarials target the intraerythrocytic developmental stage of the Plasmodium falciparum life cycle. However, the invasive extracellular parasite form, the merozoite, is also an attractive target for drug development. We have previously demonstrated that heparin-like molecules, including those with low molecular weights and low anticoagulant activities, are potent and specific inhibitors of merozoite invasion and blood-stage replication. Here we tested a large panel of heparin-like molecules and sulfated polysaccharides together with various modified chemical forms for their inhibitory activity against P. falciparum merozoite invasion. We identified chemical modifications that improve inhibitory activity and identified several additional sulfated polysaccharides with strong inhibitory activity. These studies have important implications for the further development of heparin-like molecules as antimalarial drugs and for understanding merozoite invasion.

Placenta cryosections for study of the adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A in flow conditions

2004 ◽  
Vol 6 (3) ◽  
pp. 249-255 ◽  
Author(s):  
Marion Avril ◽  
Boubacar Traoré ◽  
Fabio T.M. Costa ◽  
Catherine Lépolard ◽  
Jürg Gysin
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Flow Conditions ◽  
Chondroitin Sulfate A

scholarly journals Altered Plasmodium falciparum Sensitivity to the Antiretroviral Protease Inhibitor Lopinavir Associated with Polymorphisms in pfmdr1

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Ebere Sonoiki ◽  
Christian Nsanzabana ◽  
Jennifer Legac ◽  
Kirthana M. V. Sindhe ◽  
Joseph DeRisi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protease Inhibitor ◽  
Genome Sequencing ◽  
Copy Number ◽  
Hiv Protease ◽  
Parasite Development ◽  
Whole Genome ◽  
Aspartic Proteases ◽  
Content Type

ABSTRACT The HIV protease inhibitor lopinavir inhibits Plasmodium falciparum aspartic proteases (plasmepsins) and parasite development, and children receiving lopinavir-ritonavir experienced fewer episodes of malaria than those receiving other antiretroviral regimens. Resistance to lopinavir was selected in vitro over ∼9 months, with ∼4-fold decreased sensitivity. Whole-genome sequencing of resistant parasites showed a mutation and increased copy number in pfmdr1 and a mutation in a protein of unknown function, but no polymorphisms in plasmepsin genes.

scholarly journals RALP1 Is a Rhoptry Neck Erythrocyte-Binding Protein of Plasmodium falciparum Merozoites and a Potential Blood-Stage Vaccine Candidate Antigen

2013 ◽  
Vol 81 (11) ◽  
pp. 4290-4298 ◽  
Author(s):  
Daisuke Ito ◽  
Tomoyuki Hasegawa ◽  
Kazutoyo Miura ◽  
Tsutomu Yamasaki ◽  
Thangavelu U. Arumugam ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Vaccine Candidate ◽  
Binding Protein ◽  
Blood Stage ◽  
Merozoite Invasion ◽  
Free System ◽  
Content Type ◽  
Vaccine Candidate Antigen ◽  
Erythrocyte Binding ◽  
Candidate Antigen

ABSTRACTErythrocyte invasion by merozoites is an obligatory stage ofPlasmodiuminfection and is essential to disease progression. Proteins in the apical organelles of merozoites mediate the invasion of erythrocytes and are potential malaria vaccine candidates. Rhoptry-associated, leucine zipper-like protein 1 (RALP1) ofPlasmodium falciparumwas previously found to be specifically expressed in schizont stages and localized to the rhoptries of merozoites by immunofluorescence assay (IFA). Also, RALP1 has been refractory to gene knockout attempts, suggesting that it is essential for blood-stage parasite survival. These characteristics suggest that RALP1 can be a potential blood-stage vaccine candidate antigen, and here we assessed its potential in this regard. Antibodies were raised against recombinant RALP1 proteins synthesized by using the wheat germ cell-free system. Immunoelectron microscopy demonstrated for the first time that RALP1 is a rhoptry neck protein of merozoites. Moreover, our IFA data showed that RALP1 translocates from the rhoptry neck to the moving junction during merozoite invasion. Growth and invasion inhibition assays revealed that anti-RALP1 antibodies inhibit the invasion of erythrocytes by merozoites. The findings that RALP1 possesses an erythrocyte-binding epitope in the C-terminal region and that anti-RALP1 antibodies disrupt tight-junction formation, are evidence that RALP1 plays an important role during merozoite invasion of erythrocytes. In addition, human sera collected from areas in Thailand and Mali where malaria is endemic recognized this protein. Overall, our findings indicate that RALP1 is a rhoptry neck erythrocyte-binding protein and that it qualifies as a potential blood-stage vaccine candidate.

scholarly journals Plasmodium falciparum Founder Populations in Western Cambodia Have Reduced Artemisinin SensitivityIn Vitro

2014 ◽  
Vol 58 (8) ◽  
pp. 4935-4937 ◽  
Author(s):  
Chanaki Amaratunga ◽  
Benoit Witkowski ◽  
Dalin Dek ◽  
Vorleak Try ◽  
Nimol Khim ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Clearance ◽  
Parasite Development ◽  
Ring Stage ◽  
Content Type ◽  
Short Course ◽  
Founder Populations ◽  
Admixed Population ◽  
Survival Assay

ABSTRACTReducedPlasmodium falciparumsensitivity to short-course artemisinin (ART) monotherapy manifests as a long parasite clearance half-life. We recently defined three parasite founder populations with long half-lives in Pursat, western Cambodia, where reduced ART sensitivity is prevalent. Using the ring-stage survival assay, we show that these founder populations have reduced ART sensitivityin vitroat the early ring stage of parasite development and that a genetically admixed population contains subsets of parasites with normal or reduced ART sensitivity.

scholarly journals Antibodies to Escherichia coli-Expressed C-Terminal Domains of Plasmodium falciparum Variant Surface Antigen 2-Chondroitin Sulfate A (VAR2CSA) Inhibit Binding of CSA-Adherent Parasites to Placental Tissue

2013 ◽  
Vol 81 (4) ◽  
pp. 1031-1039 ◽  
Author(s):  
Tracy Saveria ◽  
Andrew V. Oleinikov ◽  
Kathryn Wiliamson ◽  
Richa Chaturvedi ◽  
Joe Lograsso ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Surface Antigen ◽  
Transmembrane Protein ◽  
Placental Malaria ◽  
Placental Tissue ◽  
Content Type ◽  
Variant Surface Antigen ◽  
Chondroitin Sulfate A

ABSTRACTPlacental malaria (PM) is characterized by infected erythrocytes (IEs) that selectively bind to chondroitin sulfate A (CSA) and sequester in placental tissue. Variant surface antigen 2-CSA (VAR2CSA), aPlasmodium falciparumerythrocyte membrane protein 1 (PfEMP1) protein family member, is expressed on the surface of placental IEs and mediates adherence to CSA on the surface of syncytiotrophoblasts. This transmembrane protein contains 6 Duffy binding-like (DBL) domains which might contribute to the specific adhesive properties of IEs. Here, we use laboratory isolate 3D7 VAR2CSA DBL domains expressed inEscherichia colito generate antibodies specific for this protein. Flow cytometry results showed that antibodies generated against DBL4ε, DBL5ε, DBL6ε, and tandem double domains of DBL4-DBL5 and DBL5-DBL6 all bind to placental parasite isolates and to lab strains selected for CSA binding but do not bind to children's parasites. Antisera to DBL4ε and to DBL5ε inhibit maternal IE binding to placental tissue in a manner comparable to that for plasma collected from multigravid women. These antibodies also inhibit binding to CSA of several field isolates derived from pregnant women, while antibodies to double domains do not enhance the functional immune response. These data support DBL4ε and DBL5ε as vaccine candidates for pregnancy malaria and demonstrate thatE. coliis a feasible tool for the large-scale manufacture of a vaccine based on these VAR2CSA domains.

scholarly journals The Plasmodium falciparum Artemisinin Susceptibility-Associated AP-2 Adaptin μ Subunit is Clathrin Independent and Essential for Schizont Maturation

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryan C. Henrici ◽  
Rachel L. Edwards ◽  
Martin Zoltner ◽  
Donelly A. van Schalkwyk ◽  
Melissa N. Hart ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Cellular Localization ◽  
Gene Knockout ◽  
Mass Spectrometry Analysis ◽  
Parasite Development ◽  
Content Type ◽  
Spectrometry Analysis ◽  
Fluorescence And Electron Microscopy ◽  
Kelch Domain

ABSTRACT The efficacy of current antimalarial drugs is threatened by reduced susceptibility of Plasmodium falciparum to artemisinin, associated with mutations in pfkelch13. Another gene with variants known to modulate the response to artemisinin encodes the μ subunit of the AP-2 adaptin trafficking complex. To elucidate the cellular role of AP-2μ in P. falciparum, we performed a conditional gene knockout, which severely disrupted schizont organization and maturation, leading to mislocalization of key merozoite proteins. AP-2μ is thus essential for blood-stage replication. We generated transgenic P. falciparum parasites expressing hemagglutinin-tagged AP-2μ and examined cellular localization by fluorescence and electron microscopy. Together with mass spectrometry analysis of coimmunoprecipitating proteins, these studies identified AP-2μ-interacting partners, including other AP-2 subunits, the K10 kelch-domain protein, and PfEHD, an effector of endocytosis and lipid mobilization, but no evidence was found of interaction with clathrin, the expected coat protein for AP-2 vesicles. In reverse immunoprecipitation experiments with a clathrin nanobody, other heterotetrameric AP-complexes were shown to interact with clathrin, but AP-2 complex subunits were absent. IMPORTANCE We examine in detail the AP-2 adaptin complex from the malaria parasite Plasmodium falciparum. In most studied organisms, AP-2 is involved in bringing material into the cell from outside, a process called endocytosis. Previous work shows that changes to the μ subunit of AP-2 can contribute to drug resistance. Our experiments show that AP-2 is essential for parasite development in blood but does not have any role in clathrin-mediated endocytosis. This suggests that a specialized function for AP-2 has developed in malaria parasites, and this may be important for understanding its impact on drug resistance.

scholarly journals SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells

2021 ◽  
Vol 9 (7) ◽  
pp. 1438
Author(s):  
Francesca Caccuri ◽  
Antonella Bugatti ◽  
Alberto Zani ◽  
Antonella De Palma ◽  
Dario Di Silvestre ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Dysfunction ◽  
Proteome Analysis ◽  
Immunofluorescence Assay ◽  
Direct Role ◽  
Intussusceptive Angiogenesis ◽  
Cytopathic Effects ◽  
Life Threatening ◽  
Lung Endothelial Cells

SARS-CoV-2-associated acute respiratory distress syndrome (ARDS) and acute lung injury are life-threatening manifestations of severe viral infection. The pathogenic mechanisms that lead to respiratory complications, such as endothelialitis, intussusceptive angiogenesis, and vascular leakage remain unclear. In this study, by using an immunofluorescence assay and in situ RNA-hybridization, we demonstrate the capability of SARS-CoV-2 to infect human primary lung microvascular endothelial cells (HL-mECs) in the absence of cytopathic effects and release of infectious particles. Preliminary data point to the role of integrins in SARS-CoV-2 entry into HL-mECs in the absence of detectable ACE2 expression. Following infection, HL-mECs were found to release a plethora of pro-inflammatory and pro-angiogenic molecules, as assessed by microarray analyses. This conditioned microenvironment stimulated HL-mECs to acquire an angiogenic phenotype. Proteome analysis confirmed a remodeling of SARS-CoV-2-infected HL-mECs to inflammatory and angiogenic responses and highlighted the expression of antiviral molecules as annexin A6 and MX1. These results support the hypothesis of a direct role of SARS-CoV-2-infected HL-mECs in sustaining vascular dysfunction during the early phases of infection. The construction of virus-host interactomes will be instrumental to identify potential therapeutic targets for COVID-19 aimed to inhibit HL-mEC-sustained inflammation and angiogenesis upon SARS-CoV-2 infection.

scholarly journals mSphere of Influence: Structural Insights into the Molecular Mechanism Underlying Placental Malaria

mSphere ◽  
2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Maria del Pilar Quintana
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Placental Malaria ◽  
Structural Basis ◽  
Content Type ◽  
Link Type ◽  
Structural Details ◽  
Inhibitory Antibodies ◽  
Structural Insights ◽  
Insight Into

ABSTRACT Maria del Pilar Quintana works on immunology and pathogenesis of severe malaria. In this mSphere of Influence article, she reflects on how the papers “Structural basis for placental malaria mediated by Plasmodium falciparum VAR2CSA” (R. Ma, T. Lian, R. Huang, J. P. Renn, J. D. Petersen, J. Zimmerberg, P. E. Duffy, N. H. Tolia, Nat Microbiol 6:380–391, 2021, https://doi.org/10.1038/s41564-020-00858-9) and “Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding” (K. Wang, R. Dagil, T. Lavsten, S. K. Misra, C. B. Spliid, Y. Wang, T. Gustavsson, D. R. Sandoval, E. E. Vidal-Calvo, S. Choudary, M. O. Agerback, K. Lindorff-Larsen, M. A. Nielsen, T. G. Theander, J. S. Sharp, T. M. Clausen, P. Gourdon, A. Salanti [Research Square preprint], 2021, https://doi.org/10.21203/rs.3.rs-121821/v1) shed light on the precise structural details behind Plasmodium falciparum VAR2CSA binding to chondroitin sulfate A (CSA) in the placenta and how these novel insights have changed the way she will approach her work toward the discovery of new broadly cross-reactive/inhibitory antibodies targeting VAR2CSA.

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