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.

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 Immunization with Recombinant Plasmodium falciparum Erythrocyte Membrane Protein 1 CIDRα1 Domains Induces Domain Subtype Inhibitory Antibodies

2018 ◽  
Vol 86 (11) ◽  
Author(s):  
Louise Turner ◽  
Thor G. Theander ◽  
Thomas Lavstsen
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Protein ◽  
Erythrocyte Membrane ◽  
Sequence Similarity ◽  
Optimal Choice ◽  
Immune Recognition ◽  
Endothelial Protein C Receptor ◽  
Content Type ◽  
Erythrocyte Membrane Protein ◽  
Inhibitory Antibodies

ABSTRACT Plasmodium falciparum malaria pathogenesis is tied to the sequestration of parasites in the microvasculature. Parasite sequestration leading to severe malaria is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1) binding to endothelial protein C receptor (EPCR) via its CIDRα1 domains. CIDRα1 domains are targets of naturally acquired immunity, and a vaccine eliciting antibodies inhibiting the EPCR binding of CIDRα1 could potentially prevent disease and death from malaria. CIDRα1 domains have diversified in sequence to escape immune recognition but preserved structure to maintain EPCR binding. The EPCR-binding CIDRα1 domains separate into six major sequence types predicted to form a conserved structure in which only the amino acids essential for EPCR binding are highly conserved. Here, we investigated whether antibodies elicited by vaccination with single or multiple recombinant CIDRα1 domains are able to bind and inhibit diverse CIDRα1 domains. We found that EPCR binding-inhibitory antibodies to CIDRα1 variants closely related to those used for vaccination are readily elicited, whereas antibodies binding distant CIDRα1 variants are sporadically generated and are rarely inhibitory. Despite this, sequence similarity correlated poorly with the ability of induced antibodies to inhibit across diverse variants, and no continuous sequence regions of importance for cross-inhibitory antibodies could be identified. This suggested that epitopes of cross-variant inhibitory antibodies were predominantly conformational. Vaccination with immunogens engineered to focus immune responses to specific epitopes or an optimal choice of multiple CIDRα1 variants may improve elicitation of broadly reactive and inhibitory antibody responses.

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 Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Catherine J. Mitran ◽  
Angie Mena ◽  
Sedami Gnidehou ◽  
Shanna Banman ◽  
Eliana Arango ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Molecular Mechanism ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Placental Malaria ◽  
Content Type ◽  
Heterologous Immunity ◽  
Cryptic Epitopes

ABSTRACT Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit antibodies to cryptic epitopes that are not under immune pressure. We previously discovered that antibodies to the Plasmodium vivax invasion protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related virulence factor that mediates placental malaria. Here, we describe the molecular mechanism underlying this cross-species immunity. We identified an epitope in subdomain 1 (SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive antibodies to VAR2CSA and show that human antibodies affinity purified against a synthetic SD1 peptide block parasite adhesion to chondroitin sulfate A (CSA) in vitro. The epitope in SD1 is subdominant and highly conserved in PvDBP, and in turn, SD1 antibodies target cryptic epitopes in P. falciparum VAR2CSA. The epitopes in VAR2CSA recognized by vivax-derived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5ε domain of VAR2CSA that are recognized by SD1 antibodies. Both peptides map to regions outside the immunodominant sites, and antibodies to these peptides are not elicited following immunization with VAR2CSA or natural infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target epitopes. IMPORTANCE In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium. Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic epitopes in surface antigens to evade immunity to that parasite. This alternative immune pathway can be exploited to protect pregnant women from falciparum placental malaria by designing vaccines to cryptic epitopes that elicit broadly inhibitory antibodies against variant parasite strains.

scholarly journals mSphere of Influence: Going Native, or the Risk of Overreliance on Recombinant Antigens

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Mary Lopez-Perez
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Recombinant Proteins ◽  
Antibody Responses ◽  
Recombinant Antigens ◽  
Content Type ◽  
Link Type ◽  
Functional Antibodies ◽  
Going Native

ABSTRACT Mary Lopez-Perez works on immunology and pathogenesis of malaria. In this mSphere of Influence article, she reflects on how the paper “Functional antibodies against VAR2CSA in nonpregnant populations from Colombia exposed to Plasmodium falciparum and Plasmodium vivax” by S. Gnidehou, J. Doritchamou, E. M. Arango, A. Cabrera, et al. (Infect Immun 82:2565−2573, 2014, https://doi.org/10.1128/IAI.01594-14) made her cautious of relying exclusively on recombinant proteins when evaluating antibody responses.

scholarly journals Antibodies That Inhibit Binding of Plasmodium falciparum-Infected Erythrocytes to Chondroitin Sulfate A and to the C Terminus of Merozoite Surface Protein 1 Correlate with Reduced Placental Malaria in Cameroonian Women

2004 ◽  
Vol 72 (3) ◽  
pp. 1603-1607 ◽  
Author(s):  
Diane Wallace Taylor ◽  
Aniong Zhou ◽  
Lauren E. Marsillio ◽  
Lucy W. Thuita ◽  
Efua B. Leke ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Placental Malaria ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Liver Stage ◽  
Merozoite Surface Protein 1 ◽  
Erythrocyte Surface ◽  
Antibody Levels ◽  
Chondroitin Sulfate A

ABSTRACT Plasmodium falciparum-infected erythrocytes often sequester in the placenta of pregnant women, producing placental malaria, a condition that can compromise the health of the developing fetus. Scientists are hopeful that a vaccine can be developed to prevent this condition. Immunological mechanisms responsible for eliminating parasites from the placenta remain unclear, but antibodies to the carboxyl-terminal 19-kDa segment of the merozoite surface protein 1 (MSP1-19), the ring-infected erythrocyte surface antigen (RESA), and an erythrocyte-surface ligand that binds chondroitin sulfate A (CSA-L) have been implicated. In addition, antibodies to sporozoite and liver-stage antigens could reduce initial parasite burdens. This study sought to determine if antibodies to the circumsporozoite protein (CSP), liver-stage antigen 1 (LSA1), RESA, MSP1-19, or CSA-L correlated with either the absence of placental parasites or low placental parasitemias. Using a frequency-matched case-control study design, we compared antibody levels in women (gravidity 1 to 11) with and without placental malaria. Results showed that women who were antibody negative for MSP1-19 were at a higher risk of having placental malaria than women with antibodies (P < 0.007). Furthermore, an association between high levels of antibodies that blocked the binding of infected erythrocytes to CSA and low placental parasitemias was observed (P = 0.02). On the other hand, women with high antibody levels at term to CSP, LSA1, and RESA were more likely to have placental malaria than antibody-negative women. Since antibodies to MSP1-19 and CSA-L were associated with reduced placental malaria, both antigens show promise for inclusion in a vaccine for women of child-bearing age.

scholarly journals Multiple Plasmodium falciparum Erythrocyte Membrane Protein 1 Variants per Genome Can Bind IgM via Its Fc Fragment Fcμ

2015 ◽  
Vol 83 (10) ◽  
pp. 3972-3981 ◽  
Author(s):  
Anine Jeppesen ◽  
Sisse Bolm Ditlev ◽  
Vladyslav Soroka ◽  
Liz Stevenson ◽  
Louise Turner ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Protein ◽  
Erythrocyte Membrane ◽  
Placental Malaria ◽  
Clinical Manifestations ◽  
Content Type ◽  
Erythrocyte Membrane Protein ◽  
C Terminus ◽  
Adhesive Proteins ◽  
New Evidence

ThePlasmodium falciparumerythrocyte membrane protein 1 (PfEMP1) adhesive proteins expressed on the surfaces of infected erythrocytes (IEs) are of key importance in the pathogenesis ofP. falciparummalaria. Several structurally and functionally defined PfEMP1 types have been associated with severe clinical manifestations, such as cerebral malaria in children and placental malaria in pregnant women. PfEMP1 that can bind the Fc part of IgM (Fcμ) characterizes one such type, although the functional significance of this IgM binding to PfEMP1 remains unclear. In this study, we report the identification and functional analysis of five IgM-binding PfEMP1 proteins encoded byP. falciparumNF54. In addition to the VAR2CSA-type PFL0030c protein, already known to bind Fcμ and to mediate chondroitin sulfate A (CSA)-specific adhesion of IEs in the placenta, we found four PfEMP1 proteins not previously known to bind IgM this way. Although they all contained Duffy binding-like ε (DBLε) domains similar to those in VAR2CSA-type PfEMP1, they did not mediate IE adhesion to CSA, and IgM binding did not shield IEs from phagocytosis of IgG-opsonized IEs. In this way, these new IgM-binding PfEMP1 proteins resemble the rosette-mediating and IgM-binding PfEMP1 HB3VAR06, but none of them mediated formation of rosettes. We could map the capacity for Fc-specific IgM binding to DBLε domains near the C terminus for three of the four PfEMP1 proteins tested. Our study provides new evidence regarding Fc-dependent binding of IgM to PfEMP1, which appears to be a common and multifunctional phenotype.

scholarly journals Transfer of Sphingorhabdus marina, Sphingorhabdus litoris, Sphingorhabdus flavimaris and Sphingorhabdus pacifica corrig. into the novel genus Parasphingorhabdus gen. nov. and Sphingopyxis baekryungensis into the novel genus Novosphingopyxis gen. nov. within the family Sphingomonadaceae

2020 ◽  
Vol 70 (3) ◽  
pp. 2147-2154 ◽  
Author(s):  
Guang-Da Feng ◽  
Xian-Jiao Zhang ◽  
Song-Zhen Yang ◽  
An-Zhang Li ◽  
Qing Yao ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Type Species ◽  
New Genus ◽  
The Novel ◽  
New Combinations ◽  
Novel Genus ◽  
Content Type ◽  
Link Type ◽  
The Family ◽  
Insight Into

During a phylogenetic analysis of Sphingorhabdus and its closely related genera in the family Sphingomonadaceae , we found that the genus Sphingorhabdus and the species Sphingopyxis baekryungensis might not be properly assigned in the taxonomy. Phylogenetic, phenotypic and chemotaxonomic characterizations clearly showed that the genus Sphingorhabdus should be reclassified into two genera (Clade I and Clade II), for which the original genus name, Sphingorhabdus , is proposed to be retained only for Clade I, and a new genus named as Parasphingorhabdus gen. nov. is proposed for Clade II with four new combinations: Parasphingorhabdus marina comb. nov., Parasphingorhabdus litoris comb. nov., Parasphingorhabdus flavimaris comb. nov. and Parasphingorhabdus pacifica comb. nov. Moreover, Sphingopyxis baekryungensis should represent a novel genus in the family Sphingomonadaceae , for which the name Novosphingopyxis gen. nov. is proposed, with a combination of Novosphingopyxis baekryungensis comb. nov. The study provides a new insight into the taxonomy of closely related genera in the family Sphingomonadaceae .

scholarly journals Antigenic Characterization of an Intrinsically Unstructured Protein, Plasmodium falciparum Merozoite Surface Protein 2

2012 ◽  
Vol 80 (12) ◽  
pp. 4177-4185 ◽  
Author(s):  
Christopher G. Adda ◽  
Christopher A. MacRaild ◽  
Linda Reiling ◽  
Kaye Wycherley ◽  
Michelle J. Boyle ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Surface Protein ◽  
Variable Region ◽  
Intrinsic Property ◽  
Merozoite Surface Protein ◽  
Surface Proteins ◽  
Structural Basis ◽  
Content Type ◽  
Intrinsically Unstructured Protein ◽  
Unstructured Protein

ABSTRACTMerozoite surface protein 2 (MSP2) is an abundant glycosylphosphatidylinositol (GPI)-anchored protein ofPlasmodium falciparum, which is a potential component of a malaria vaccine. As all forms of MSP2 can be categorized into two allelic families, a vaccine containing two representative forms of MSP2 may overcome the problem of diversity in this highly polymorphic protein. Monomeric recombinant MSP2 is an intrinsically unstructured protein, but its conformational properties on the merozoite surface are unknown. This question is addressed here by analyzing the 3D7 and FC27 forms of recombinant and parasite MSP2 using a panel of monoclonal antibodies raised against recombinant MSP2. The epitopes of all antibodies, mapped using both a peptide array and by nuclear magnetic resonance (NMR) spectroscopy on full-length recombinant MSP2, were shown to be linear. The antibodies revealed antigenic differences, which indicate that the conserved N- and C-terminal regions, but not the central variable region, are less accessible in the parasite antigen. This appears to be an intrinsic property of parasite MSP2 and is not dependent on interactions with other merozoite surface proteins as the loss of some conserved-region epitopes seen using the immunofluorescence assay (IFA) on parasite smears was also seen on Western blot analyses of parasite lysates. Further studies of the structural basis of these antigenic differences are required in order to optimize recombinant MSP2 constructs being evaluated as potential vaccine components.

scholarly journals Structural Insights into the Inhibition of the Extended-Spectrum β-Lactamase PER-2 by Avibactam

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Melina Ruggiero ◽  
Krisztina M. Papp-Wallace ◽  
Florencia Brunetti ◽  
Melissa D. Barnes ◽  
Robert A. Bonomo ◽  
...  
Keyword(s):  
Side Chain ◽  
Structural Studies ◽  
Content Type ◽  
Class A ◽  
Extended Spectrum ◽  
Inhibition Constants ◽  
The Rich ◽  
Structural Insights ◽  
Insight Into ◽  
Made In

ABSTRACT The diazabicyclooctane (DBO) avibactam (AVI) reversibly inactivates most serine-β-lactamases. Previous investigations showed that inhibition constants of AVI toward class A PER-2 are reminiscent of values observed for class C and D β-lactamases (i.e., k2/K of ≈103 M−1 s−1) but lower than other class A β-lactamases (i.e., k2/K = 104 to 105 M−1 s−1). Herein, biochemical and structural studies were conducted with PER-2 and AVI to explore these differences. Furthermore, biochemical studies on Arg220 and Thr237 variants with AVI were conducted to gain deeper insight into the mechanism of PER-2 inactivation. The main biochemical and structural observations revealed the following: (i) both amino-acid substitutions in Arg220 and the rich hydrophobic content in the active site hinder the binding of catalytic waters and acylation, impairing AVI inhibition; (ii) movement of Ser130 upon binding of AVI favors the formation of a hydrogen bond with the sulfate group of AVI; and (iii) the Thr237Ala substitution alters the AVI inhibition constants. The acylation constant (k2/K) of PER-2 by AVI is primarily influenced by stabilizing hydrogen bonds involving AVI and important residues such as Thr237 and Arg220. (Variants in Arg220 demonstrate a dramatic reduction in k2/K.) We also observed that displacement of Ser130 side chain impairs AVI acylation, an observation not made in other extended-spectrum β-lactamases (ESBLs). Comparatively, relebactam combined with a β-lactam is more potent against Escherichia coli producing PER-2 variants than β-lactam–AVI combinations. Our findings provide a rationale for evaluating the utility of the currently available DBO inhibitors against unique ESBLs like PER-2 and anticipate the effectiveness of these inhibitors toward variants that may eventually be selected upon AVI usage.

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