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Biomedical subjects

G V Brown

Publications and source records attributed to G V Brown.

At least 37 records · Page 2Linked to original sources
PubMed2000

Identification of glycosaminoglycan binding domains in Plasmodium falciparum erythrocyte membrane protein 1 of a chondroitin sulfate A-adherent parasite.

Accumulation of Plasmodium falciparum-infected erythrocytes in the placenta is a key feature of maternal malaria. This process is mediated in part by the parasite ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1) at the surface of the infected erythrocyte interacting with the host receptor chondroitin sulfate A (CSA) on the placental lining. We have localized CSA binding activity to two adjacent domains in PfEMP1 of an adherent parasite line and shown the presence of at least three active glycosaminoglycan binding sites. A putative CSA binding sequence was identified in one domain, but nonlinear binding motifs are also likely to be present, since binding activity in the region was shown to be dependent on conformation. Characterization of this binding region provides an opportunity to investigate further its potential as a target for antiadhesion therapy.

Amino Acid Sequence↗
PubMed1999

Human phase I vaccine trials of 3 recombinant asexual stage malaria antigens with Montanide ISA720 adjuvant.

Two phase I vaccine trials were conducted to test the immunogenicity and safety of a vaccine containing three recombinant malaria antigens from the asexual stage of Plasmodium falciparum. The three antigens are a fragment of MSP1 (190LCS.T3); MSP2 and a portion of RESA and were formulated in Montanide ISA720 adjuvant. These trials investigated the dose response of each antigen for eliciting both antibody and T-cell responses and the immunogenicity of a mixture of the antigens compared with the antigens injected separately. All three antigens elicited both antibody and T-cell responses. Strong T-cell responses were observed with 190LCS.T3 and RESA with stimulation indices exceeding 100 for peripheral blood leucocytes in some individuals. The antibody responses were generally weak. The human antibody responses observed with MSP2 in Montanide ISA720 were not significantly different from those obtained in an earlier trial which used MSP2 with alum as the adjuvant. No antigenic competition was observed: volunteers receiving a mixture of antigens had similar responses to those receiving the three antigens at separate sites. Tenderness and pain at the injection site were common over the first few days following immunization. In some volunteers, especially those receiving the highest doses tested, there was a delayed reaction at the injection site with pain and swelling occurring approximately 10 days after injection.

Adjuvants, Immunologic↗
PubMed1999

The adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane protein 1.

Chondroitin sulfate A (CSA) is an important receptor for the sequestration of Plasmodium falciparum in the placenta, but the parasite ligand involved in adhesion has not previously been identified. Here we report the identification of a var gene transcribed in association with binding to CSA and present evidence that the P. falciparum erythrocyte membrane protein 1 product of the gene is the parasite ligand mediating CSA binding. Description of this gene and the implication of P. falciparum erythrocyte membrane protein 1 as the parasite ligand paves the way to a more detailed understanding of the pathogenesis of placental infection and potential therapeutic strategies targeting the interaction.

Animals↗
PubMed1999

Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties.

Plasmodium falciparum malaria during pregnancy is an important cause of maternal and infant morbidity and mortality. Accumulation of large numbers of P. falciparum-infected erythrocytes in the maternal blood spaces of the placenta may be mediated by adhesion of infected erythrocytes to molecules presented on the syncytiotrophoblast surface. In this study, isolates from placentas and peripheral blood of infected pregnant women and from children were tested for binding to purified receptors and for agglutination with adult sera. Results suggest that adhesion to chondroitin sulfate A may be involved in placental parasite sequestration in most cases, but other factors are also likely to be important. Agglutination assay results suggest that parasites infecting pregnant women are antigenically distinct from those common in childhood disease. The prevalence of agglutinating antibodies to pregnancy isolates was generally low, but it was highest in multigravidae who are likely to have had the greatest exposure.

Adult↗
PubMed1999

Progress in the development of malaria vaccines: context and constraints.

Major technical advances in the field of vaccine development have culminated in an impressive array of prototype vaccines that may well provide 'proof of principle' that vaccines against all life-cycle stages may induce a degree of protection against malaria. As the mechanisms responsible for protection against this disease are not known, and vaccines for populations at greatest risk will be applied in the presence of ongoing infection and a degree of concomitant immunity, it is essential for us to learn from the 'experiments of nature' about acquired and ongoing immunity in order to determine when and how these vaccines may be applied. Successful interventions with chemoprophylaxis or vector control have provided obvious lessons and highlight the importance of recognising the lack of correlation between infection, clinical disease and mortality. Vaccines inducing sterile immunity raise concerns about rebound mortality in populations who will undoubtedly be re-challenged later in life, hence the need to review supplementary or alternative strategies for reducing disease through immune responses to toxins or molecules inducing pathology by adherence to host endothelium. Following antigen selection there are many challenges in choosing methods of antigen delivery and adjuvants, and measuring vaccine efficacy. A successful vaccine would need to be delivered through a national programme in the context of implementation of a wide range of components required for an effective control strategy.

Humans↗
PubMed1999

The need to 'maintain the rage'.

Personal reflections are presented on the need to ensure that appropriate attention is given to malaria. The importance of political and financial commitments is stressed and the investment in people is considered a major priority.

Delivery of Health Care↗
PubMed1998

Adhesive proteins of the malaria parasite.

Malaria infection of the host cells requires host-parasite recognition events mediated by adhesion and signaling molecules. Recent development of systems for stable transformation and targeted integration of exogenous DNA in malaria parasites provides a powerful tool to study the structure and function of Plasmodium attachment motifs, and their role in infection and disease.

Amino Acid Sequence↗
PubMed1998

Detection of an aberrant motile larval form in the brain of a patient with neurocysticercosis.

Neurocysticercosis is the most common parasitic infection of the central nervous system in humans. The adult pork tape worm, Taenia solium, resides in the lumen of the intestine, and the only structural element of an adult worm usually found within a tissue cyst in the brain or in muscle is a single invaginated scolex. We report a highly unusual, and perhaps unique, occurrence of neurocysticercosis in which an aberrant worm-like larval form, 12.5 cm in length, was found within a cyst in brain parenchyma.

Animals↗
PubMed1998

Inhibition of binding of malaria-infected erythrocytes by a tetradecasaccharide fraction from chondroitin sulfate A.

Adherence of parasite-infected erythrocytes (IEs) to the microvascular endothelium of various organs, a process known as sequestration, is a feature of Plasmodium falciparum malaria. This event is mediated by specific adhesive interactions between parasite proteins, expressed on the surface of IEs, and host molecules. P. falciparum IEs can bind to purified chondroitin sulfate A (CS-A), to the proteoglycan thrombomodulin through CS-A side chains, and to CS-A present on the surface of brain and lung endothelial cells and placental syncytiotrophoblasts. In order to identify structural characteristics of CS-A important for binding, oligosaccharide fragments ranging in size from 2 to 20 monosaccharide units were isolated from CS-A and CS-C, following controlled chondroitin lyase digestion, and used as competitive inhibitors of IE binding to immobilized ligands. Inhibition of binding to CS-A was highly dependent on molecular size: a CS-A tetradecasaccharide fraction was the minimum length able to almost completely inhibit binding. The effect was dose dependent and similar to that of the parent polysaccharide, and the same degree of inhibition was not found with the CS-C oligosaccharides. There was no effect on binding of IEs to other ligands, e.g., CD36 and intercellular adhesion molecule 1. Hexadeca- and octadecasaccharide fractions of CS-A were required for maximum inhibition of binding to thrombomodulin. Analyses of oligosaccharide fractions and polysaccharides by electrospray mass spectrometry and high-performance liquid chromatography suggest that the differences between the activities of CS-A and CS-C oligosaccharides can be attributed to differences in sulfate content and sulfation pattern and that iduronic acid is not involved in IE binding.

CD36 Antigens↗
PubMed1997

The age-specific prevalence of Plasmodium falciparum in migrants to Irian Jaya is not attributable to agglutinating antibody repertoire.

Previous observations have shown that individuals migrating from a malaria free area to a malaria endemic region in North Eastern Irian Jaya quickly acquire anti-parasite immunity, in an age-dependent manner. Sera from migrants and long-term residents in this area were examined for their ability to agglutinate a range of Plasmodium falciparum isolates and to disrupt erythrocyte rosettes. Antibody responses to merozoite surface protein 2 (MSP2) and ring-infected erythrocyte surface antigen (RESA) were also determined. The range of isolates agglutinated by sera from the migrants approached that seen in long-term residents. No difference was found between migrant adults and children in the range of agglutinating antibody, size of agglutinates, nor disruption of rosettes. Anti-MSP2 and anti-RESA antibodies were the only factors examined which showed a correlation with age. We conclude that although antibody to parasite neoantigens expressed on the surface of infected erythrocytes may play a role in the acquisition of immunity, the humoral response to other P. falciparum antigens is more likely to account for the age-dependent prevalence of parasitaemia observed.

Adult↗
PubMed1997

Targeted gene disruption shows that knobs enable malaria-infected red cells to cytoadhere under physiological shear stress.

Knobs at the surface of erythrocytes infected with Plasmodium falciparum have been proposed to be important in adherence of these cells to the vascular endothelium. This structure contains the knob-associated histidine-rich protein (KAHRP) and the adhesion receptor P. falciparum erythrocyte membrane protein 1. We have disrupted the gene encoding KAHRP and show that it is essential for knob formation. Knob-transfectants adhere to CD36 in static assays; when tested under flow conditions that mimic those of postcapillary venules, however, the binding to CD36 was dramatically reduced. These data suggest that knobs on P. falciparum-infected erythrocytes exert an important influence on adherence of parasitized-erythrocytes to microvascular endothelium, an important process in the pathogenesis of P. falciparum infections.

Animals↗
PubMed1997

Airport malaria in Cairns.

We report a patient with Plasmodium vivax malaria that was acquired in Cairns in October 1996. Rather than being "introduced" (i.e., derived from an imported case), we believe this is likely to have been a case of "airport malaria" (i.e., acquired from an infected mosquito imported in an aircraft). It is, to our knowledge, the first report of airport malaria in Australia.

Adult↗
PubMed1997

Plasmodium falciparum-infected erythrocytes adhere to the proteoglycan thrombomodulin in static and flow-based systems.

Plasmodium falciparum-infected erythrocytes can bind to the glycosaminoglycan chondroitin sulfate A. In this paper, we demonstrate that thrombomodulin, a proteoglycan present on endothelial cells and placental syncytiotrophoblasts, supports binding of selected lines of P. falciparum-infected erythrocytes in both static and flow-based assays, and that adhesion is dependent on the presence of the chondroitin sulfate A chain of thrombomodulin. Chondroitinase treatment of thrombomodulin abolished binding, and free chondroitin sulfate A prevented it, whereas other soluble glycosaminoglycans had little or no effect. Soluble thrombomodulin (with, but not without, its chondroitin sulfate chain) inhibited binding at 40 micrograms/ml, but not at physiological concentrations. Parasitized erythrocytes bound to cells expressing thrombomodulin, including human umbilical vein endothelial cells and A549 cells, and binding was inhibited by free chondroitin sulfate A. Established binding to A549 cells or to immobilized thrombomodulin was substantially reversed by chondroitin sulfate A at 10 micrograms/ml. The chondroitin sulfate chain of thrombomodulin is a receptor for malaria-infected erythrocytes in static assays and under physiological flow.

Animals↗
PubMed1997

Chondroitin sulphate A as an adherence receptor for Plasmodium falciparum-infected erythrocytes.

Until recently, the sequestration of erythrocytes infected with Plasmodium falciparum has been thought to be due to one of a number of protein-protein interactions. In this article, Stephen Rogerson and Graham Brown summarize the emerging evidence that, in vitro, infected erythrocytes can also adhere to the glycosaminoglycan chondroitin sulphate A (CSA) expressed on the surface of cells and immobilized on plastic. In vivo, binding of infected erythrocytes to CSA could be crucial to the development of malarial infection of the placenta, and possibly to sequestration in the lung and brain. The consequences of this may include maternal morbidity and mortality, low birth weight in the infant, pulmonary oedema and cerebral malaria. They discuss the need to characterize the molecular basis of this interaction, and to investigate the possible therapeutic role of CSA in malaria. Chondroitin sulphates are nontoxic compounds already in use for other diseases in humans. Vaccines based on inhibiting this receptor-ligand interaction could also be appropriate.

Journal Article↗
PubMed1996

Adhesion of malaria-infected red blood cells to chondroitin sulfate A under flow conditions.

Adhesion of parasitized red blood cells (PRBCs) to microvascular endothelial cells (ECs) is a distinctive feature of Plasmodium falciparum malaria and is a central event in the development of life-threatening complications such as cerebral malaria. PRBCs adhere to several EC-expressed molecules in vitro, but the relative importance of these interactions in vivo remains unclear. Chondroitin sulfate A (CSA) is the most recent EC surface-associated molecule to be implicated in the adhesive process. Accordingly, we have studied adhesion of PRBCs to CSA in vitro using a parallel-plate flow chamber. Under controlled flow conditions, PRBCs adhered to CSA in a concentration-dependent manner at wall-shear stresses up to 0.2 Pa, a value that is within the physiological range for venules. Once adhered, PRBCs remained stationary (rather than rolling) and continued to remain stationary even when the wall-shear stress was raised to supravenular levels. The adhesive interaction was strong and a proportion of adherent PRBCs could withstand detachment at stresses up to 2.5 Pa. Soluble CSA at pharmacological concentrations prevented adhesion of flowing PRBCs in a concentration-dependent manner but failed to reverse established adhesion. Adhesion of PRBCs to CSA could contribute to the pathogenesis of malaria, and soluble CSA may have a useful therapeutic effect.

Cell Adhesion↗
PubMed1996

Antigenic variation and immune evasion in Plasmodium falciparum malaria.

Plasmodium falciparum malaria is responsible for 2 million deaths each year. Even in endemic regions, immunity to malaria builds slowly and is rarely complete. Strategies such as antigenic variation and antigenic diversity are critical to a parasite's ability to evade the host immune response and infect previously exposed individuals. In this short review, the phenomenon of antigenic variation is discussed in relation to immune evasion and its impact on parasite pathogenesis. Recent advances in the understanding of the underlying molecular mechanisms of antigenic variation are examined and questions posed for future research.

Animals↗
PubMed1996

Cytoadherence characteristics of Plasmodium falciparum isolates from Thailand: evidence for chondroitin sulfate a as a cytoadherence receptor.

The association between cytoadherence of Plasmodium falciparum-infected erythrocytes and the severity of malaria has been evaluated. In this study, we investigate adherence to C32 melanoma cells, CD36, intracellular adhesion molecule-1 (ICAM-1), thrombospondin (TSP), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and chondroitin sulfate A (CSA) of 36 P. falciparum isolates from patients suffering from acute falciparum malaria. Adherence to purified adhesion molecules varied greatly among different parasite isolates. All isolates but one adhered to CD36, but none bound to E-selectin and VCAM-1 beyond control levels. Some P. falciparum isolates adhered to ICAM-1 and to CSA, a newly identified receptor for adherence. There was no correlation between in vitro binding to any one receptor and the patients' conditions. In addition, we investigated the characteristics of adherence to CSA and to C32 melanoma cells. Infected erythrocytes continued to adhere after trypsin digestion and soluble CSA inhibited adherence to C32 melanoma cells in a dose-dependent manner. The results imply a role for CSA in the natural infection of P. falciparum.

Adolescent↗