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.

Expression and self-regulatory function of cardiac interleukin-6 during endotoxemia

2000 ◽  
Vol 279 (5) ◽  
pp. H2241-H2248 ◽  
Author(s):  
Hiroshi Saito ◽  
Cam Patterson ◽  
Zhaoyong Hu ◽  
Marschall S. Runge ◽  
Ulka Tipnis ◽  
...  
Keyword(s):  
Feedback Mechanism ◽  
Intercellular Adhesion Molecule ◽  
Regulatory Function ◽  
Heart Cells ◽  
Intercellular Adhesion Molecule 1 ◽  
Negative Feedback Mechanism ◽  
Proinflammatory Mediators ◽  
Tnf Α

Interleukin (IL)-6 reportedly has negative inotropic and hypertrophic effects on the heart. Here, we describe endotoxin-induced IL-6 in the heart that has not previously been well characterized. An intraperitoneal injection of a bacterial lipopolysaccharide into C57BL/6 mice induced IL-6 mRNA in the heart more strongly than in any other tissue examined. Induction of mRNA for two proinflammatory cytokines, IL-1β and tumor necrosis factor (TNF)-α, occurred rapidly before the induction of IL-6 mRNA and protein. Although stimulation of isolated rat neonatal myocardial cells with IL-1β or TNF-α induced IL-6 mRNA in vitro, nonmyocardial heart cells produced higher levels of IL-6 mRNA upon stimulation with IL-1β. In situ hybridization and immunohistochemical analyses localized the IL-6 expression primarily in nonmyocardial cells in vivo. Endotoxin-induced expression of cardiac IL-1β, TNF-α, and intercellular adhesion molecule 1 was augmented in IL-6-deficient mice compared with control mice. Thus cardiac IL-6, expressed mainly by nonmyocardial cells via IL-1β action during endotoxemia, is likely to suppress expression of proinflammatory mediators and to regulate itself via a negative feedback mechanism.

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.

Thymic emigrants isolated by a new method possess unique phenotypic and functional properties

Blood ◽  
2001 ◽  
Vol 97 (5) ◽  
pp. 1360-1369 ◽  
Author(s):  
Chong-kil Lee ◽  
Kyungjae Kim ◽  
Lisbeth A. Welniak ◽  
William J. Murphy ◽  
Kathrin Muegge ◽  
...  
Keyword(s):  
T Cells ◽  
Severe Combined Immunodeficiency ◽  
Cell Receptor ◽  
Intercellular Adhesion Molecule ◽  
Graft Versus Host Reaction ◽  
Intercellular Adhesion Molecule 1 ◽  
Heat Stable Antigen ◽  
Heterogeneous Expression

T cells that emigrate from the thymus have primarily been studied in vivo using fluorescent dye injection of the thymus. This study examined the properties of thymocytes that emigrate from cultured thymic lobes in organ culture. Under these conditions, thymic emigrants displayed the expected phenotype, that of mature thymocytes expressing high levels of T-cell receptor (TCR-αβ) and either CD4 or CD8, and were observed to emigrate within 24 hours of positive selection. Emigration was inhibited by cytochalasin D, pertussis toxin, orClostridium difficile toxin B, implicating an active motility process. Most of the surface markers on αβ-thymic emigrants (Thy1, CD44, CD69, CD25, leukocyte functional antigen-1, intercellular adhesion molecule-1, α4-integrin, α5-integrin, CD45, and CD28) were expressed at a surface density similar to that on mature intrathymic cells and peripheral splenic T cells. Heterogeneous expression of L-selectin and heat-stable antigen (HSA) suggested that subsets emerge from the thymus with a commitment to different migration patterns. The only marker on emigrants not found on either intrathymic cells or mature spleen T cells was CTLA-4, which could dampen the response of emigrants to peripheral antigens. Antigen responsivenes measured in vitro against allogeneic dendritic cells showed a proliferative response comparable to that of splenic T cells. In vivo, however, thymic emigrants failed to induce an acute graft-versus-host reaction in allogeneic severe combined immunodeficiency recipients. This suggests that a mechanism operating in vivo, perhaps tolerance or migration pattern, attenuates the response of emigrants against antigens that did not induce their deletion in the thymus.

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.

scholarly journals Receptor Priming of Major Group Human Rhinoviruses for Uncoating and Entry at Mild Low-pH Environments

2003 ◽  
Vol 77 (22) ◽  
pp. 11985-11991 ◽  
Author(s):  
Ghasem Nurani ◽  
Birgitta Lindqvist ◽  
José M. Casasnovas
Keyword(s):  
Inhibitory Effect ◽  
Low Ph ◽  
Proximal Region ◽  
Major Group ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Cell Infection ◽  
Endosomal Acidification

ABSTRACT Receptor priming of low-pH-triggered virus entry has been described for an enveloped virus (15). Here we show with major group human rhinoviruses (HRV) and its intercellular adhesion molecule-1 receptor that nonenveloped viruses follow this novel cell entry principle. In vitro the receptor primed HRV for efficient uncoating at mild low pH (5.5 to 6.0). Agents preventing endosomal acidification reduced or blocked rhinovirus cell infection, while nocodazole had no effect on infection of any serotype tested. The entry inhibitory effect of lysosomotropic agents was overcome by exposing cell-internalized HRV to mild low pH (5.5 to 6.0). We therefore conclude that receptor priming of major group HRV must occur in vivo as well. Cooperation of a cellular receptor and low pH in virus uncoating will polarize the exit of the genome to the receptor-bound, membrane-proximal region of the virus particle during acidification of endosomes. This process must be required for efficient penetration of the cellular membrane by viruses.

scholarly journals Cryptococcal Glucuronoxylomannan Inhibits Adhesion of Neutrophils to Stimulated Endothelium In Vitro by Affecting Both Neutrophils and Endothelial Cells

2002 ◽  
Vol 70 (9) ◽  
pp. 4762-4771 ◽  
Author(s):  
Pauline M. Ellerbroek ◽  
Andy I. M. Hoepelman ◽  
Floor Wolbers ◽  
Jaap Jan Zwaginga ◽  
Frank E. J. Coenjaerts
Keyword(s):  
Capsular Polysaccharide ◽  
Inhibitory Effect ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Blocking Antibodies ◽  
Selectin Binding

ABSTRACT Cryptococcal infections are often characterized by a paucity of leukocytes in the infected tissues. Previous research has shown that the capsular polysaccharide glucuronoxylomannan (GXM) inhibits leukocyte migration. In this study we investigated whether the capsular polysaccharide GXM affects the migration of neutrophils (polymorphonuclear leukocytes [PMN]) through the endothelium by interfering with adhesion in a static adhesion model. Pretreatment of PMN with GXM inhibited PMN adhesion to tumor necrosis factor alpha (TNF-α)-stimulated endothelium up to 44%. Treatment of TNF-α-stimulated endothelium with GXM led to a 27% decrease in PMN adhesion. GXM treatment of both PMN and endothelium did not have an additive inhibitory effect. We demonstrated that GXM-induced L-selectin shedding does not play an important role in the detected inhibition of adhesion. L-selectin was still present on PMN in sufficient amounts after GXM treatment, since it could be further inhibited by blocking antibodies. Furthermore, blocking of GXM-related L-selectin shedding did not abolish the GXM-related inhibition of adhesion. GXM most likely exerts its effect on PMN by interfering with E-selectin-mediated binding. The use of blocking monoclonal antibodies against E-selectin, which was shown to decrease adhesion in the absence of GXM, did not cause additive inhibition of PMN adhesion after GXM pretreatment. The use of blocking antibodies also demonstrated that the inhibiting effect found after GXM treatment of endothelium probably involves interference with both intercellular adhesion molecule-1 and E-selectin binding.

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.

scholarly journals Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1250-1255 ◽  
Author(s):  
S Whitehead ◽  
TE Peto
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Antimalarial Activity ◽  
Clinical Malaria ◽  
Inhibitory Effect ◽  
Parasite Development ◽  
And Control ◽  
Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

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