scholarly journals Natural and Vaccine-Induced Acquisition of Cross-Reactive IgG-Inhibiting ICAM-1-Specific Binding of a Plasmodium falciparum PfEMP1 Subtype Associated Specifically with Cerebral Malaria

2018 ◽  
Vol 86 (4) ◽  
Author(s):  
Rebecca W. Olsen ◽  
Gertrude Ecklu-Mensah ◽  
Anja Bengtsson ◽  
Michael F. Ofori ◽  
John P. A. Lusingu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cerebral Malaria ◽  
Specific Binding ◽  
Intercellular Adhesion Molecule ◽  
Enzyme Linked Immunosorbent Assay ◽  
Intercellular Adhesion Molecule 1 ◽  
Content Type ◽  
Protein Receptor ◽  
Specific Igg

ABSTRACT Cerebral malaria (CM) is a potentially deadly outcome of Plasmodium falciparum malaria that is precipitated by sequestration of infected erythrocytes (IEs) in the brain. The adhesion of IEs to brain endothelial cells is mediated by a subtype of parasite-encoded erythrocyte membrane protein 1 (PfEMP1) that facilitates dual binding to host intercellular adhesion molecule 1 (ICAM-1) and endothelial protein receptor C (EPCR). The PfEMP1 subtype is characterized by the presence of a particular motif (DBLβ_motif) in the constituent ICAM-1-binding DBLβ domain. The rate of natural acquisition of DBLβ_motif-specific IgG antibodies and the ability to induce such antibodies by vaccination are unknown, and the aim of this study was to provide such data. We used an enzyme-linked immunosorbent assay (ELISA) to measure DBLβ-specific IgG in plasma from Ghanaian children with malaria. The ability of human immune plasma and DBLβ-specific rat antisera to inhibit the interaction between ICAM-1 and DBLβ was assessed using ELISA and in vitro assays of IE adhesion under flow. The acquisition of DBLβ_motif-specific IgG coincided with age-specific susceptibility to CM. Broadly cross-reactive antibodies inhibiting the interaction between ICAM-1 and DBLβ_motif domains were detectable in immune plasma and in sera of rats immunized with specific DBLβ_motif antigens. Importantly, antibodies against the DBLβ_motif inhibited ICAM-1-specific in vitro adhesion of erythrocytes infected by four of five P. falciparum isolates from cerebral malaria patients. We conclude that natural exposure to P. falciparum as well as immunization with specific DBLβ_motif antigens can induce cross-reactive antibodies that inhibit the interaction between ICAM-1 and a broad range of DBLβ_motif domains. These findings raise hope that a vaccine designed specifically to prevent CM is feasible.

Characterization of Plasmodium falciparum-Infected Erythrocyte and P-Selectin Interaction Under Flow Conditions

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4803-4809 ◽  
Author(s):  
May Ho ◽  
Tineke Schollaardt ◽  
Xiaofei Niu ◽  
Sornchai Looareesuwan ◽  
Kamala D. Patel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Adhesion Molecule ◽  
Sialic Acid Residue ◽  
Intercellular Adhesion Molecule ◽  
Flow Conditions ◽  
Intercellular Adhesion Molecule 1 ◽  
Adhesive Interaction ◽  
Lectin Domain

Abstract Plasmodium falciparum-infected erythrocytes (IRBC) roll on the adhesion molecule P-selectin in vitro under flow conditions that approximate the shear stress in capillary and postcapillary venules in which cytoadherence occurs in vivo. The pathological significance of this adhesive interaction is currently unknown. In this study, we further investigated the molecular interactions between IRBC and P-selectin by using a laminar flow system that allowed for the direct visualization of IRBC-substratum interactions. The results showed that the IRBC–P-selectin interaction was Ca2+-dependent and involved the lectin domain of P-selectin and a sialic acid residue on IRBC. The sialylated P-selectin ligand was trypsin-sensitive, which suggests that it could be part of the parasite antigen PfEMP1 that interacts with CD36 and intercellular adhesion molecule-1 (ICAM-1), but different from a trypsin-resistant IRBC ligand that adheres selectively to chondroitin sulfate A. Studies on the rolling and adhesion of IRBC on activated platelets that express both CD36 and P-selectin showed that inhibition of rolling on P-selectin reduced the adhesion of some clinical parasite isolates to CD36, whereas other parasite isolates appeared to interact directly with CD36. Thus, cytoadherence under physiological flow conditions may be mediated by multiple IRBC ligands that interact with different adhesion molecules in a cooperative fashion. These findings underscore the complexity of the interactions betweeen IRBC and vascular endothelium.

Outcome prediction with serum intercellular adhesion molecule-1 levels after aneurysmal subarachnoid hemorrhage

2002 ◽  
Vol 96 (1) ◽  
pp. 71-75 ◽  
Author(s):  
William J. Mack ◽  
J Mocco ◽  
Daniel J. Hoh ◽  
Judy Huang ◽  
Tanvir F. Choudhri ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Adhesion Molecule ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Enzyme Linked Immunosorbent Assay ◽  
Intercellular Adhesion Molecule 1 ◽  
Content Type ◽  
Hemorrhagic Event ◽  
Fine Print

Object. Although upregulated adhesion molecule expression has been demonstrated in experimental models of subarachnoid hemorrhage (SAH) and in the cerebrospinal fluid of patients with aneurysmal SAH, the clinical significance of these proinflammatory findings remains unclear. The authors hypothesize that 1) serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) are increased in all patients with aneurysmal SAH shortly after the hemorrhagic event, and 2) elevated soluble ICAM-1 values are associated with poor patient outcome, even when controlling for the severity of the initial hemorrhagic insult. Methods. One hundred one patients were prospectively enrolled and stratified according to their admission Hunt and Hess grade and functional status at discharge (modified Rankin Scale [mRS] score). Soluble ICAM-1 levels were determined every other day for 12 days post-SAH by using the enzyme-linked immunosorbent assay. Early soluble ICAM-1 levels (post-SAH Days 2–4) were increased compared with levels in control patients without SAH (p < 0.05). Patients with aneurysmal SAH who had a poor outcome (mRS Grades 4–6) had significantly higher soluble ICAM-1 levels over the first 2 weeks post-SAH compared with patients who had a good outcome (mRS Grades 0–3, p < 0.01). This association with outcome was predicted by late increases (Day 6, p = 0.07; Days 8–12, p < 0.05) rather than early increases (p = not significant) and was best seen in patients with Hunt and Hess Grades I and II, in whom only those with poor outcomes demonstrated delayed ICAM-1 elevations (p < 0.05). Conclusions. These data demonstrate a correlation between soluble ICAM-1 levels and functional outcome following aneurysmal SAH that appears to be, at least in part, independent of the initial hemorrhage.

scholarly journals Knob-independent cytoadherence of Plasmodium falciparum to the leukocyte differentiation antigen CD36.

1990 ◽  
Vol 171 (6) ◽  
pp. 1883-1892 ◽  
Author(s):  
B A Biggs ◽  
L Goozé ◽  
K Wycherley ◽  
D Wilkinson ◽  
A W Boyd ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Peripheral Circulation ◽  
Melanoma Cells ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Differentiation Antigen ◽  
Erythrocyte Surface ◽  
Falciparum Erythrocyte Membrane Protein

The survival of Plasmodium falciparum-infected erythrocytes is enhanced by the sequestration of mature trophozoites and schizonts from the peripheral circulation. Cytoadherence of infected erythrocytes in vivo is associated with the presence of knobs on the erythrocyte surface, but we and others have shown recently that cytoadherence to C32 melanoma cells may occur in vitro in the absence of knobs. We show here that a knobless clone of P. falciparum adheres to the leukocyte differentiation antigen, CD36, suggesting that binding to CD36 is independent of the presence of knobs on the surface of the infected erythrocyte. This clone showed little cytoadherence to immobilized thrombospondin or to endothelial cells expressing the intercellular adhesion molecule 1. Furthermore, an Mr approximately 300-kD trypsin-sensitive protein doublet was immunoprecipitated from knobless trophozoite-infected erythrocytes. Finding a P. falciparum erythrocyte membrane protein 1 (PfEMP1)-like molecule on these infected erythrocytes is consistent with a role for PfEMP1 in cytoadherence to CD36 and C32 melanoma cells.

Intercellular adhesion molecule-1-deficient mice have antibody responses but impaired leukocyte recruitment

1997 ◽  
Vol 273 (3) ◽  
pp. L513-L523 ◽  
Author(s):  
C. A. Hatfield ◽  
J. R. Brashler ◽  
G. E. Winterrowd ◽  
F. P. Bell ◽  
R. L. Griffin ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Adhesion Molecule ◽  
Lavage Fluid ◽  
Intercellular Adhesion ◽  
Antibody Responses ◽  
Intercellular Adhesion Molecule ◽  
Enzyme Linked Immunosorbent Assay ◽  
Intercellular Adhesion Molecule 1

The role of intercellular adhesion molecule-1 (ICAM-1) in murine lung inflammation was examined in vivo. Ovalbumin (Ova)-sensitized and -challenged ICAM-1-deficient (KO) mice had decreased accumulation of leukocytes in the bronchoalveolar lavage fluid compared with wild-type (WT) mice. Lung tissue inflammation was also attenuated. Ova immunization and challenge produced equivalent plasma levels of Ova-specific immunoglobulin (Ig) G1 and higher concentrations of IgE in KO versus WT mice. Ova-dependent induction of cytokines in vitro, as measured by enzyme-linked immunosorbent assay, was impaired in splenocytes from KO mice compared with the comparable release of interleukin (IL)-5 and IL-10 from anti-CD3-stimulated WT and KO splenocytes. Methacholine-induced increases in trapped gas in lungs of Ova-sensitized and -challenged WT mice were greater than those of KO mice. The activation of lung tissue nuclear factor-kappa B was diminished in KO mice after Ova provocation. This suggests that ICAM-1 was important for activation of the inflammatory cascade leading to the recruitment of leukocytes but was not critical for the generation of antibody responses in vivo.

scholarly journals Ivermectin Impairs the Development of Sexual and Asexual Stages of Plasmodium falciparum In Vitro

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Lais Pessanha de Carvalho ◽  
Thaisa Lucas Sandri ◽  
Edésio José Tenório de Melo ◽  
Rolf Fendel ◽  
Peter G. Kremsner ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Stage Iv ◽  
Enzyme Linked Immunosorbent Assay ◽  
Parasitic Infections ◽  
High Dose ◽  
Trophozoite Stage ◽  
Content Type ◽  
Blood Sucking

ABSTRACT Ivermectin is the drug of choice for many parasitic infections, with more than one billion doses being distributed in onchocerciasis programs. The drug has been put into focus recently by the malaria community because of its potential to kill blood-sucking mosquitoes, thereby reducing malaria transmission. However, the activity of ivermectin against the malaria parasite itself has been only partly investigated. This study aimed to investigate the in vitro activity of ivermectin against asexual and sexual stages of Plasmodium falciparum. Both asexual and late-stage gametocytes were incubated with ivermectin and control drugs in vitro. The growth-inhibiting effects were assessed for asexual stages of different Plasmodium falciparum laboratory strains and culture-adapted clinical isolates using the histidine-rich protein 2 enzyme-linked immunosorbent assay technique. The effect against stage IV/V gametocytes was evaluated based on ATP quantification. Ivermectin showed activities at nanomolar concentrations against asexual stages (50% inhibitory concentration of ∼100 nM) and stage IV/V gametocytes (500 nM) of P. falciparum. Stage-specific assays suggested that ivermectin arrests the parasite cycle at the trophozoite stage. Ivermectin might add a feature to its “wonder drug” properties with activity against asexual stages of the malaria parasite Plasmodium falciparum. The observed activities might be difficult to reach with current regimens but will be more relevant with future high-dose regimens under investigation. Further studies should be performed to confirm these results in vitro and in vivo.

Recombinant PfEMP1 peptide inhibits and reverses cytoadherence of clinical Plasmodium falciparum isolates in vivo

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 331-337 ◽  
Author(s):  
Bryan G. Yipp ◽  
Dror I. Baruch ◽  
Ciaran Brady ◽  
Allan G. Murray ◽  
Sornchai Looareesuwan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Severe Combined Immunodeficiency ◽  
Inhibitory Effect ◽  
Intercellular Adhesion Molecule ◽  
Skin Grafts ◽  
Intercellular Adhesion Molecule 1 ◽  
Recombinant Peptide ◽  
Tnf Α

Abstract The parasite ligand Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and host endothelial receptors represent potential targets for antiadhesive therapy for cytoadherence. In the present study, the major host receptor CD36 was targeted in vitro and in vivo with a recombinant peptide, PpMC-179, corresponding to the minimal CD36-binding domain from the cysteine-rich interdomain region 1 (CIDR1) within the MCvar1 PfEMP1. The in vitro inhibitory effect of PpMC-179 on human dermal microvascular endothelial cells (HDMECs) expressing multiple relevant adhesion molecules was investigated using a parallel-plate flow chamber. Pretreatment of endothelial monolayers with PpMC-179 (2 μM) inhibited the adhesion of infected erythrocytes (IRBCs) from all clinical isolates tested by 84.4% on resting and 62.8% on tumor necrosis factor α (TNF-α)–stimulated monolayers. Adhesion to stimulated cells was further inhibited (90.4%) when PpMC-179 was administered with an inhibitory anti–intercellular adhesion molecule 1 (ICAM-1) monoclonal antibody 84H10 (5 μg/mL). To determine the in vivo effectiveness of PpMC-179, we used a human/severe combined immunodeficiency (SCID) mouse chimeric model that allowed direct visualization of cytoadherence on intact human microvasculature. In unstimulated skin grafts, PpMC-179 inhibited adhesion by 86.3% and by 84.6% in TNF-α–stimulated skin grafts. More importantly, PpMC-179 administration resulted in the detachment of already adherent IRBCs by 80.7% and 83.3% on resting and stimulated skin grafts, respectively. The antiadhesive effect of PpMC-179 was rapid and sustained in vivo for at least 30 minutes. Our data indicate that targeting cytoadhesion in vivo is feasible and may offer a rapid antimalarial therapy.

Characterization of Plasmodium falciparum-Infected Erythrocyte and P-Selectin Interaction Under Flow Conditions

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4803-4809 ◽  
Author(s):  
May Ho ◽  
Tineke Schollaardt ◽  
Xiaofei Niu ◽  
Sornchai Looareesuwan ◽  
Kamala D. Patel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Adhesion Molecule ◽  
Sialic Acid Residue ◽  
Intercellular Adhesion Molecule ◽  
Flow Conditions ◽  
Intercellular Adhesion Molecule 1 ◽  
Adhesive Interaction ◽  
Lectin Domain

Plasmodium falciparum-infected erythrocytes (IRBC) roll on the adhesion molecule P-selectin in vitro under flow conditions that approximate the shear stress in capillary and postcapillary venules in which cytoadherence occurs in vivo. The pathological significance of this adhesive interaction is currently unknown. In this study, we further investigated the molecular interactions between IRBC and P-selectin by using a laminar flow system that allowed for the direct visualization of IRBC-substratum interactions. The results showed that the IRBC–P-selectin interaction was Ca2+-dependent and involved the lectin domain of P-selectin and a sialic acid residue on IRBC. The sialylated P-selectin ligand was trypsin-sensitive, which suggests that it could be part of the parasite antigen PfEMP1 that interacts with CD36 and intercellular adhesion molecule-1 (ICAM-1), but different from a trypsin-resistant IRBC ligand that adheres selectively to chondroitin sulfate A. Studies on the rolling and adhesion of IRBC on activated platelets that express both CD36 and P-selectin showed that inhibition of rolling on P-selectin reduced the adhesion of some clinical parasite isolates to CD36, whereas other parasite isolates appeared to interact directly with CD36. Thus, cytoadherence under physiological flow conditions may be mediated by multiple IRBC ligands that interact with different adhesion molecules in a cooperative fashion. These findings underscore the complexity of the interactions betweeen IRBC and vascular endothelium.

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