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1
Klotz, F. W., J. D. Chulay, W. Daniel, and L. H. Miller. "Invasion of mouse erythrocytes by the human malaria parasite, Plasmodium falciparum." Journal of Experimental Medicine 165, no. 6 (June 1, 1987): 1713–18. http://dx.doi.org/10.1084/jem.165.6.1713.
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Plasmodium falciparum malaria merozoites require erythrocyte sialic acid for optimal invasion of human erythrocytes. Since mouse erythrocytes have the form of sialic acid found on human erythrocytes (N-acetyl neuraminic acid), mouse erythrocytes were tested for invasion in vitro. The Camp and 7G8 strains of P. falciparum invaded mouse erythrocytes at 17-45% of the invasion rate of human erythrocytes. Newly invaded mouse erythrocytes morphologically resembled parasitized human erythrocytes as shown on Giemsa-stained blood films and by electron microscopy. The rim of parasitized mouse erythrocytes contained the P. falciparum 155-kD protein, which is on the rim of ring-infected human erythrocytes. Camp but not 7G8 invaded rat erythrocytes, indicating receptor heterogeneity. These data suggest that it may be possible to adapt the asexual erythrocytic stage of P. falciparum to rodents. The development of a rodent model of P. falciparum malaria could facilitate vaccine development.
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Orwa, Titus Okello, Rachel Waema Mbogo, and Livingstone Serwadda Luboobi. "Mathematical Model for Hepatocytic-Erythrocytic Dynamics of Malaria." International Journal of Mathematics and Mathematical Sciences 2018 (July 2, 2018): 1–18. http://dx.doi.org/10.1155/2018/7019868.
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Human malaria remains a major killer disease worldwide, with nearly half (3.2 billion) of the world’s population at risk of malaria infection. The infectious protozoan disease is endemic in tropical and subtropical regions, with an estimated 212 million new cases and 429,000 malaria-related deaths in 2015. An in-host mathematical model ofPlasmodium falciparummalaria that describes the dynamics and interactions of malaria parasites with the host’s liver cells (hepatocytic stage), the red blood cells (erythrocytic stage), and macrophages is reformulated. By a theoretical analysis, an in-host basic reproduction numberR0is derived. The disease-free equilibrium is shown to be locally and globally asymptotically stable. Sensitivity analysis reveals that the erythrocyte invasion rateβr, the average number of merozoites released per bursting infected erythrocyteK, and the proportion of merozoites that cause secondary invasions at the blood phaseζare the most influential parameters in determining the malaria infection outcomes. Numerical results show that macrophages have a considerable impact in clearing infected red blood cells through phagocytosis. Moreover, the density of infected erythrocytes and hence the severity of malaria are shown to increase with increasing density of merozoites in the blood. Concurrent use of antimalarial drugs and a potential erythrocyte invasion-avoidance vaccine would minimize the density of infected erythrocytes and hence malaria disease severity.
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Baum, Jake, Margaret Pinder, and David J. Conway. "Erythrocyte Invasion Phenotypes of Plasmodiumfalciparum in The Gambia." Infection and Immunity 71, no. 4 (April 2003): 1856–63. http://dx.doi.org/10.1128/iai.71.4.1856-1863.2003.
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ABSTRACT In vitro experimentation with Plasmodium falciparum has determined that a number of different receptor-ligand interactions are involved in the invasion of erythrocytes. Most culture-adapted parasite isolates use a mechanism of invasion that depends primarily on the erythrocyte sialoglycoprotein glycophorin A (GYPA) and erythrocyte-binding antigen 175 (EBA-175) of the parasite blood-stage merozoite. However, a minority of culture-adapted parasites and a majority of Indian field isolates can apparently invade by other means. Here, erythrocyte invasion phenotypes of P. falciparum field isolates in Africa were studied. For 38 Gambian isolates, invasion of neuraminidase-treated and trypsin-treated erythrocytes was inhibited, on average, by more than 60 and 85%, respectively, indicating a high level of dependence on sialic acid and trypsin-sensitive proteins on the erythrocyte surface. These results support the hypothesis that African P. falciparum parasites use GYPA as a primary receptor for invasion. However, the considerable variation among isolates confirms the idea that alternative receptors are also used by many parasites. Three amino acid polymorphisms in the GYPA-binding region of EBA-175 (region II) were not significantly associated with invasion phenotype. There was variation among isolates in the selectivity index (i.e., a statistical tendency toward aggregation or multiple invasions of host erythrocytes), but this variation did not correlate with enzyme-determined invasion phenotype or with eba-175 alleles. Overall, these invasion phenotypes in Africa support a vaccine strategy of inhibiting EBA-175 binding to GYPA but suggest that parasites with alternative phenotypes would be selected for if this strategy were used alone.
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Tham, Wai-Hong, Danny W. Wilson, Linda Reiling, Lin Chen, James G. Beeson, and Alan F. Cowman. "Antibodies to Reticulocyte Binding Protein-Like Homologue 4 Inhibit Invasion of Plasmodium falciparum into Human Erythrocytes." Infection and Immunity 77, no. 6 (March 23, 2009): 2427–35. http://dx.doi.org/10.1128/iai.00048-09.
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ABSTRACT Plasmodium falciparum invasion into human erythrocytes relies on the interaction between multiple parasite ligands and their respective erythrocyte receptors. The sialic acid-independent invasion pathway is dependent on the expression of P. falciparum reticulocyte binding protein-like homologue 4 (PfRh4), as disruption of the gene abolishes the ability of parasites to switch to this pathway. We show that PfRh4 is present as an invasion ligand in culture supernatants as a 160-kDa proteolytic fragment. We confirm that PfRh4 binds to the surfaces of erythrocytes through recognition of an erythrocyte receptor that is neuraminidase resistant but trypsin and chymotrypsin sensitive. Serum antibodies from malaria-exposed individuals show reactivity against the binding domain of PfRh4. Purified immunoglobulin G raised in rabbits against the binding domain of PfRh4 blocked the binding of native PfRh4 to the surfaces of erythrocytes and inhibited erythrocyte invasion of parasites using sialic acid-independent invasion pathways and grown in neuraminidase-treated erythrocytes. Our results suggest PfRh4 is a potential vaccine candidate.
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Shaw, M. K., and L. G. Tilney. "The entry of Theileria parva merozoites into bovine erythrocytes occurs by a process similar to sporozoite invasion of lymphocytes." Parasitology 111, no. 4 (November 1995): 455–61. http://dx.doi.org/10.1017/s0031182000065951.
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SUMMARYThe entry of Theileria parva merozoites into bovine erythrocytes in vivo is described and compared to sporozoite invasion of lymphocytes. Merozoites make initial contact with erythrocytes with any part of their surface and invasion of the host cell does not require the re-orientation of the apical end of the merozoite towards the surface of the erythrocyte. After the initial attachment the merozoite and host cell membranes form a continual close junction with the two apposed membranes separated by a 6–8 nm gap containing moderately dense material. The progressive circumferential ‘zippering’ of these closely apposed membranes leads to the movement of the parasite into the erythrocyte. The newly internalized merozoite which is completely surrounded by the erythrocyte plasma membrane escapes from this enclosing membrane by a process involving the discharge of at least the rhoptries; whether the merozoite also contain other types of secretory organelles (e.g. micronemes, microspheres or dense bodies) remains to be determined. Morphologically, the events involved in merozoite invasion of erythrocytes are almost identical to the process of sporozoite invasion of lymphocytes but differ significantly from the entry process of the invasive stages of other Apicomplexan parasites.
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ZINTL, A., C. WESTBROOK, H. E. SKERRETT, J. S. GRAY, and G. MULCAHY. "Chymotrypsin and neuraminidase treatment inhibits host cell invasion by Babesia divergens (Phylum Apicomplexa)." Parasitology 125, no. 1 (July 2002): 45–50. http://dx.doi.org/10.1017/s0031182002001798.
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The process of host cell invasion by Babesia divergens is poorly understood and improved knowledge of the mechanism involved could lead to development of measures effective in disease prevention. To investigate parasite ligands on the erythrocyte surface, B. divergens cultures in bovine erythrocytes were transferred into enzyme-treated bovine, human, ovine and equine erythrocytes. Parasite invasion of bovine erythrocytes was not affected by trypsin treatment while treatment with alpha-chymotrypsin led to a reduction in parasite growth of 20–40%. Treatment of bovine and non-bovine erythrocytes with neuraminidase decreased their susceptibility to invasion by up to 97% implicating sialic acid as an important erythrocyte ligand for babesia, but the addition of either bovine or human N-acetylneuraminyl-lactose to B. divergens cultures in bovine erythrocytes had no inhibitory effect.
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Barnwell, J. W., M. E. Nichols, and P. Rubinstein. "In vitro evaluation of the role of the Duffy blood group in erythrocyte invasion by Plasmodium vivax." Journal of Experimental Medicine 169, no. 5 (May 1, 1989): 1795–802. http://dx.doi.org/10.1084/jem.169.5.1795.
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A short-term in vitro culture system that allows for significant re-invasion of target erythrocytes by Plasmodium vivax was used to study the role of the Duffy blood group antigen as a ligand for merozoite invasion by this human malaria species. Using human Duffy-positive and -negative erythrocytes, various primate erythrocytes, enzymatic modification of erythrocytes, and mAb that defines a new Duffy determinant (Fy6) we conclude that the erythrocyte glycoprotein carrying Duffy determinants is required as a ligand for the invasion of human erythrocytes by P. vivax merozoites. Blockade of invasion by Fab fragments of the anti-Fy6 mAb equal to that of the intact molecule and the correlation of P. vivax susceptibility with the presence of the Fy6 determinant suggests this epitope or a nearby domain may be an active site on the Duffy glycoprotein. However, as for P. knowlesi, there is evidence that an alternate pathway for P. vivax invasion of simian erythrocytes may exist.
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Schülein, Ralf, Anja Seubert, Christian Gille, Christa Lanz, Yves Hansmann, Yves Piémont, and Christoph Dehio. "Invasion and Persistent Intracellular Colonization of Erythrocytes." Journal of Experimental Medicine 193, no. 9 (May 7, 2001): 1077–86. http://dx.doi.org/10.1084/jem.193.9.1077.
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The expanding genus Bartonella includes zoonotic and human-specific pathogens that can cause a wide range of clinical manifestations. A productive infection allowing bacterial transmission by blood-sucking arthropods is marked by an intraerythrocytic bacteremia that occurs exclusively in specific human or animal reservoir hosts. Incidental human infection by animal-adapted bartonellae can cause disease without evidence for erythrocyte parasitism. A better understanding of the intraerythrocytic lifestyle of bartonellae may permit the design of strategies to control the reservoir and transmittable stages of these emerging pathogens. We have dissected the process of Bartonella erythrocyte parasitism in experimentally infected animals using a novel approach for tracking blood infections based on flow cytometric quantification of green fluorescent protein–expressing bacteria during their interaction with in vivo–biotinylated erythrocytes. Bacteremia onset occurs several days after inoculation by a synchronous wave of bacterial invasion into mature erythrocytes. Intracellular bacteria replicate until reaching a stagnant number, which is sustained for the remaining life span of the infected erythrocyte. The initial wave of erythrocyte infection is followed by reinfection waves occurring at intervals of several days. Our findings unravel a unique bacterial persistence strategy adapted to a nonhemolytic intracellular colonization of erythrocytes that preserves the pathogen for efficient transmission by blood-sucking arthropods.
9
Murphy, Sean C., Souvik Bhattacharjee, Travis Harrison, and Kasturi Haldar. "Accessing the Erythrocyte Cytoplasm: A Method for Manipulating the Intracellular Environment of Erythrocytes for the Study of Malaria Invasion, Trafficking and Growth." Blood 104, no. 11 (November 16, 2004): 3688. http://dx.doi.org/10.1182/blood.v104.11.3688.3688.
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Abstract Invasion of erythrocytes by malaria parasites requires participation of both parasite ligands and host determinants. Further recent studies show that erythrocyte G protein signaling regulates malarial infection. Many of the Gs-associated signaling components reside on the cytoplasmic leaflet of the erythrocyte plasma membrane, rendering them inaccessible to most extracellular probes. Since erythrocytes are enucleated and terminally differentiated, they cannot be transfected to express exogenous transgenes. We have modified methods of hypotonic lysis and isotonic resealing to generate loaded erythrocyte ghosts that can be efficiently infected by Plasmodium falciparum and sustain normal levels of intraerythrocytic parasite growth and replication. Further, we show that these ghosts can be filled with various membrane-impermeable peptides or other proteinaceous cargoes for studying signaling and transport events inside the erythrocyte. Resealed ghosts morphologically resemble normal erythrocytes, albeit with reduced hemoglobin content. Other measures of erythrocyte function and malarial infection are being investigated. Studies will be presented on the use of ‘reconstituted’ erythrocytes in elucidating mechanisms parasite invasion as well as parasite protein trafficking in erythrocytes infected by P. falciparum.
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Okoyeh, Jude Nnaemeka, C. R. Pillai, and Chetan E. Chitnis. "Plasmodium falciparum Field Isolates Commonly Use Erythrocyte Invasion Pathways That Are Independent of Sialic Acid Residues of Glycophorin A." Infection and Immunity 67, no. 11 (November 1, 1999): 5784–91. http://dx.doi.org/10.1128/iai.67.11.5784-5791.1999.
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ABSTRACT Erythrocyte invasion by malaria parasites is mediated by specific molecular interactions. Sialic acid residues of glycophorin A are used as invasion receptors by Plasmodium falciparum. In vitro invasion studies have demonstrated that some cloned P. falciparum lines can use alternate receptors independent of sialic acid residues of glycophorin A. It is not known if invasion by alternate pathways occurs commonly in the field. In this study, we used in vitro growth assays and erythrocyte invasion assays to determine the invasion phenotypes of 15 P. falciparum field isolates. Of the 15 field isolates tested, 5 multiply in both neuraminidase and trypsin-treated erythrocytes, 3 multiply in neuraminidase-treated but not trypsin-treated erythrocytes, and 4 multiply in trypsin-treated but not neuraminidase-treated erythrocytes; 12 of the 15 field isolates tested use alternate invasion pathways that are not dependent on sialic acid residues of glycophorin A. Alternate invasion pathways are thus commonly used by P. falciparum field isolates. Typing based on two polymorphic markers, MSP-1 and MSP-2, and two microsatellite markers suggests that only 1 of the 15 field isolates tested contains multiple parasite genotypes. Individual P. falciparum lines can thus use multiple invasion pathways in the field. These observations have important implications for malaria vaccine development efforts based on EBA-175, the P. falciparumprotein that binds sialic acid residues of glycophorin A during invasion. It may be necessary to target parasite ligands responsible for the alternate invasion pathways in addition to EBA-175 to effectively block erythrocyte invasion by P. falciparum.
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Thiam, Laty G., Yaw Aniweh, Evelyn B. Quansah, Jacob K. Donkor, Theresa M. Gwira, Kwadwo A. Kusi, Makhtar Niang, and Gordon A. Awandare. "Cell trace far-red is a suitable erythrocyte dye for multi-color Plasmodium falciparum invasion phenotyping assays." Experimental Biology and Medicine 245, no. 1 (January 2020): 11–20. http://dx.doi.org/10.1177/1535370219897393.
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Plasmodium falciparum erythrocyte invasion phenotyping assays are a very useful tool for assessing parasite diversity and virulence, and for characterizing the formation of ligand–receptor interactions. However, such assays need to be highly sensitive and reproducible, and the selection of labeling dyes for differentiating donor and acceptor erythrocytes is a critical factor. We investigated the suitability of cell trace far-red (CTFR) as a dye for P. falciparum invasion phenotyping assays. Using the dyes carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) and dichloro dimethyl acridin one succinimidyl ester (DDAO-SE) as comparators, we used a dye-dilution approach to assess the limitations and specific staining procedures for the applicability of CTFR in P. falciparum invasion phenotyping assays. Our data show that CTFR effectively labels acceptor erythrocytes and provides a stable fluorescent intensity at relatively low concentrations. CTFR also yielded a higher fluorescence intensity relative to DDAO-SE and with a more stable fluorescence intensity over time. Furthermore, CTFR did not affect merozoites invasion of erythrocytes and was not toxic to the parasite’s intraerythrocytic development. Additionally, CTFR offers flexibility in the choice of combinations with several other DNA dyes, which broaden its usage for P. falciparum erythrocyte invasion assays, considering a wider range of flow cytometers with various laser settings. Impact statement In recent years, flow cytometry has become a cornerstone in investigating P. falciparum phenotypic diversity using multiple dyes to discriminate between donor and acceptor erythrocytes. To broaden the applicability of such assays, we optimized the staining conditions of a newly developed cytoplasmic dye, cell trace far-red (CTFR), and assessed its suitability for use in P. falciparum invasion phenotyping assays. We showed that CTFR has a very narrow emission peak excited by red lasers. Furthermore, CTFR labeling of target erythrocytes, achieved even at low concentrations, is stable over time and did not impair parasite development. P. falciparum erythrocyte invasion phenotyping assays revealed that CTFR is suitable for use in combination with several DNA dyes in multiplex assays. This will allow for high throughput phenotyping of parasites as well as facilitate the evaluation of preference of erythrocytes by merozoites. Altogether, these make screening for potential invasion-blocking interventions possible.
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Swardson-Olver, Christine J., Tracey C. Dawson, Robert C. Burnett, Stephen C. Peiper, Nobuyo Maeda, and Anne C. Avery. "Plasmodium yoelii uses the murine Duffy antigen receptor for chemokines as a receptor for normocyte invasion and an alternative receptor for reticulocyte invasion." Blood 99, no. 8 (April 15, 2002): 2677–84. http://dx.doi.org/10.1182/blood.v99.8.2677.
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Abstract Erythrocyte invasion by malaria parasites is a complex multistep process involving parasite and erythrocyte receptors. It is a critical stage in the parasite life cycle and, therefore, a logical step in which to intervene to prevent or ameliorate disease. Rodent models of malaria, commonly Plasmodium yoelii, are frequently used for studies of malaria pathogenesis. Little is known, however, about the invasion machinery of rodent malaria parasites. We have found previously that mice congenic for a region of chromosome 1, containing the Duffy antigen/receptor for chemokines (DARC), have different susceptibility to P yoelii infection. Because P vivax, a human parasite, and P knowlesi, a simian parasite, use DARC to enter human erythrocytes, we sought to identify the role of the murine DARC in P yoelii invasion. Using a novel in vivo invasion assay and DARC knock-out mice, we found that DARC knock-out normocytes (mature erythrocytes) had negligible levels of P yoelii invasion compared with wild-type normocytes, demonstrating that DARC is a receptor for invasion of murine erythrocytes. In contrast, DARC knock-out reticulocytes were invaded at a rate similar to that for wild-type reticulocytes. We conclude that there is a DARC- independent pathway for reticulocyte invasion. These findings represent the first identification of a murine malaria receptor on erythrocytes and the first determination that different pathways of invasion exist on normocytes and reticulocytes. Because we show conservation of host–receptor interactions between rodent and human malaria, we can now use this model to identify how immunity can interfere with the invasion process.
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Mosqueda, Juan, Terry F. McElwain, and Guy H. Palmer. "Babesia bovis Merozoite Surface Antigen 2 Proteins Are Expressed on the Merozoite and Sporozoite Surface, and Specific Antibodies Inhibit Attachment and Invasion of Erythrocytes." Infection and Immunity 70, no. 11 (November 2002): 6448–55. http://dx.doi.org/10.1128/iai.70.11.6448-6455.2002.
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ABSTRACT The Babesia bovis merozoite surface antigen 2 (MSA-2) locus encodes four proteins, MSA-2a1, -2a2, -2b, and -2c. With the use of specific antibodies, each MSA-2 protein was shown to be expressed on the surface of live extracellular merozoites and coexpression on single merozoites was confirmed. Individual antisera against MSA-2a, MSA-2b, and MSA-2c significantly inhibited merozoite invasion of bovine erythrocytes. As tick-derived sporozoites also directly invade erythrocytes, expression of each MSA-2 protein on the sporozoite surface was examined and verified. Finally, statistically significant inhibition of sporozoite binding to the erythrocytes was demonstrated by using antisera specific for MSA-2a, MSA-2b, and MSA-2c. These results indicate an important role for MSA-2 proteins in the initial binding and invasion of host erythrocytes and support the hypothesis that sporozoites and merozoites use common surface molecules in erythrocyte invasion.
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Mosqueda, Juan, Terry F. McElwain, David Stiller, and Guy H. Palmer. "Babesia bovis Merozoite Surface Antigen 1 and Rhoptry-Associated Protein 1 Are Expressed in Sporozoites, and Specific Antibodies Inhibit Sporozoite Attachment to Erythrocytes." Infection and Immunity 70, no. 3 (March 2002): 1599–603. http://dx.doi.org/10.1128/iai.70.3.1599-1603.2002.
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ABSTRACT We examined Babesia bovis sporozoites for the expression of two molecules, merozoite surface antigen 1 (MSA-1) and rhoptry-associated protein 1 (RAP-1), that are postulated to be involved in the invasion of host erythrocytes. Both MSA-1 and RAP-1 were transcribed and expressed in infectious sporozoites. Importantly, monospecific MSA-1 and RAP-1 antisera each inhibited sporozoite invasion of erythrocytes in vitro. This is the first identification of antigens expressed in Babesia sp. sporozoites and establishes that, at least in part, sporozoites and merozoites share common targets of antibody mediated inhibition of erythrocyte invasion.
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Boyle, Michelle J., Christine Langer, Jo-Anne Chan, Anthony N. Hodder, Ross L. Coppel, Robin F. Anders, and James G. Beeson. "Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum." Infection and Immunity 82, no. 3 (November 11, 2013): 924–36. http://dx.doi.org/10.1128/iai.00866-13.
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ABSTRACTPlasmodium falciparumcauses malaria disease during the asexual blood stages of infection when merozoites invade erythrocytes and replicate. Merozoite surface proteins (MSPs) are proposed to play a role in the initial binding of merozoites to erythrocytes, but precise roles remain undefined. Based on electron microscopy studies of invadingPlasmodiummerozoites, it is proposed that the majority of MSPs are cleaved and shed from the surface during invasion, perhaps to release receptor-ligand interactions. In this study, we demonstrate that there is not universal cleavage of MSPs during invasion. Instead, there is sequential and coordinated cleavage and shedding of proteins, indicating a diversity of roles for surface proteins during and after invasion. While MSP1 and peripheral surface proteins such as MSP3, MSP7, serine repeat antigen 4 (SERA4), and SERA5 are cleaved and shed at the tight junction between the invading merozoite and erythrocyte, the glycosylphosphatidylinositol (GPI)-anchored proteins MSP2 and MSP4 are carried into the erythrocyte without detectable processing. Following invasion, MSP2 rapidly degrades within 10 min, whereas MSP4 is maintained for hours. This suggests that while some proteins that are shed upon invasion may have roles in initial contact steps, others function during invasion and are then rapidly degraded, whereas others are internalized for roles during intraerythrocytic development. Interestingly, anti-MSP2 antibodies did not inhibit invasion and instead were carried into erythrocytes and maintained for approximately 20 h without inhibiting parasite development. These findings provide new insights into the mechanisms of invasion and knowledge to advance the development of new drugs and vaccines against malaria.
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ZINTL, A., C. WESTBROOK, G. MULCAHY, H. E. SKERRETT, and J. S. GRAY. "Invasion, and short- and long-term survival of Babesia divergens (Phylum Apicomplexa) cultures in non-bovine sera and erythrocytes." Parasitology 124, no. 6 (June 2002): 583–88. http://dx.doi.org/10.1017/s0031182002001622.
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In order to explore the feasibility of producing a Babesia divergens live vaccine free of bovine material contaminants the parasite's ability to grow in human, sheep and horse erythrocytes and serum and serum-free medium was investigated. B. divergens was successfully maintained in bovine erythrocytes overlaid with serum-free HL-1 medium. Supplementation of the culture medium with bovine or sheep serum improved parasite growth (monitored by measuring parasitaemia and uptake of tritiated hypoxanthine) whereas horse and human sera reduced parasite growth. As assessed by Giemsa's stained and FITC-labelled blood smears, the parasite invaded all erythrocyte types. Polyparasitism was less common in sheep and horse erythrocytes than in bovine and human erythrocytes. Accole stages were observed in bovine, human and sheep but not in horse erythrocytes. Proliferation following invasion was higher in human but lower in horse and sheep erythrocytes compared with bovine erythrocytes. Long-term cultures of B. divergens reached similar peak parasitaemias in human, sheep and bovine erythrocytes. Attempts to establish long-term cultures in horse erythrocytes failed. These results suggest that B. divergens is not host specific at the level of host cell attachment and invasion. Instead, parasite survival appears to be decided once the organism has gained access into the cell.
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Deans, Anne-Marie, Susana Nery, David J. Conway, Oscar Kai, Kevin Marsh, and J. Alexandra Rowe. "Invasion Pathways and Malaria Severity in Kenyan Plasmodium falciparum Clinical Isolates." Infection and Immunity 75, no. 6 (April 16, 2007): 3014–20. http://dx.doi.org/10.1128/iai.00249-07.
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ABSTRACT The invasion of erythrocytes by Plasmodium falciparum occurs through multiple pathways that can be studied in vitro by examining the invasion of erythrocytes treated with enzymes such as neuraminidase, trypsin, and chymotrypsin. We have studied the invasion pathways used by 31 Kenyan P. falciparum isolates from children with uncomplicated or severe malaria. Six distinct invasion profiles were detected, out of eight possible profiles. The majority of isolates (23 of 31) showed neuraminidase-resistant, trypsin-sensitive invasion, characteristic of the pathway mediated by an unknown parasite ligand and erythrocyte receptor “X.” The neuraminidase-sensitive, trypsin-sensitive phenotype consistent with invasion mediated by the binding of parasite ligand erythrocyte binding antigen 175 to glycophorin A, the most common invasion profile in a previous study of Gambian field isolates, was seen in only 3 of 31 Kenyan isolates. No particular invasion profile was associated with severe P. falciparum malaria, and there was no significant difference in the levels of inhibition by the various enzyme treatments between isolates from children with severe malaria and those from children with uncomplicated malaria (P, >0.1 for all enzymes; Mann-Whitney U test). These results do not support the hypothesis that differences in invasion phenotypes play an important role in malaria virulence and indicate that considerable gaps remain in our knowledge of the molecular basis of invasion pathways in natural P. falciparum infections.
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Ito, Daisuke, Tomoyuki Hasegawa, Kazutoyo Miura, Tsutomu Yamasaki, Thangavelu U. Arumugam, Amporn Thongkukiatkul, Satoru Takeo, et al. "RALP1 Is a Rhoptry Neck Erythrocyte-Binding Protein of Plasmodium falciparum Merozoites and a Potential Blood-Stage Vaccine Candidate Antigen." Infection and Immunity 81, no. 11 (September 3, 2013): 4290–98. http://dx.doi.org/10.1128/iai.00690-13.
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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.
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Boyle, Michelle J., Jack S. Richards, Paul R. Gilson, Wengang Chai, and James G. Beeson. "Interactions with heparin-like molecules during erythrocyte invasion by Plasmodium falciparum merozoites." Blood 115, no. 22 (June 3, 2010): 4559–68. http://dx.doi.org/10.1182/blood-2009-09-243725.
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AbstractDuring erythrocyte invasion, Plasmodium falciparum merozoites use multiple receptor-ligand interactions in a series of coordinated events, but current knowledge of these interactions is limited. Using real-time imaging of invasion, we established that heparin-like molecules block early, and essential, events in erythrocyte invasion by merozoites. All P falciparum isolates tested, and parasites using different invasion pathways were inhibited to comparable levels. Furthermore, it was not possible to select for heparin-resistant parasites. Heparin-like molecules occur naturally on the surface of human erythrocytes, where they may act as receptors for binding of merozoite surface proteins. Consistent with this, we demonstrated that MSP1-42, a processed form of merozoite surface protein 1 (MSP1) involved in invasion, bound heparin in a specific manner; furthermore, binding was observed with the secondary processing fragment MSP1-33, but not MSP1-19. We defined key structural requirements of heparin-like molecules for invasion inhibition and interactions with MSP1-42. Optimal activity required a degree of sulfation more than or equal to 2, disulfation of the N-acetylglucosamine or hexuronic acid residue, and a minimum chain length of 6 monosaccharides. These findings have significant implications for understanding P falciparum invasion of erythrocytes and the development of novel therapeutics and vaccines.
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LANTOS, P. M., A. D. AHOUIDI, A. K. BEI, C. V. JENNINGS, O. SARR, O. NDIR, D. F. WIRTH, S. MBOUP, and M. T. DURAISINGH. "Erythrocyte invasion profiles are associated with a common invasion ligand polymorphism in Senegalese isolates ofPlasmodium falciparum." Parasitology 136, no. 1 (January 2009): 1–9. http://dx.doi.org/10.1017/s0031182008005167.
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SUMMARYPlasmodium falciparumparasites use multiple ligand-receptor interactions to invade human erythrocytes. Variant expression levels of members of the PfRh and PfEBA ligand families are associated with the use of different erythrocyte receptors, defining invasion pathways. Here we analyse a major polymorphism, a large sequence deletion in the PfRh2b ligand, and erythrocyte invasion profiles in uncultured Senegalese isolates. Parasites vary considerably in their use of sialic acid-containing and protease-sensitive erythrocyte receptors for invasion. The erythrocyte selectivity index was not related to invasion pathway usage, while parasite multiplication rate was associated with enhanced use of a trypsin-resistant invasion pathway. PfRh2b protein was expressed in all parasite isolates, although the PfRh2b deletion was present in a subset (~68%). Parasites with the PfRh2b deletion were found to preferentially utilize protease-resistant pathways for erythrocyte invasion. Sialic acid-independent invasion is reduced in parasites with the PfRh2b deletion, but only in isolates derived from blood group O patients. Our results suggest a significant role for PfRh2b sequence polymorphism in discriminating between alternative erythrocyte receptors for invasion and as a possible determinant of virulence.
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Cowman, Alan F., Drew Berry, and Jake Baum. "The cellular and molecular basis for malaria parasite invasion of the human red blood cell." Journal of Cell Biology 198, no. 6 (September 17, 2012): 961–71. http://dx.doi.org/10.1083/jcb.201206112.
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Malaria is a major disease of humans caused by protozoan parasites from the genus Plasmodium. It has a complex life cycle; however, asexual parasite infection within the blood stream is responsible for all disease pathology. This stage is initiated when merozoites, the free invasive blood-stage form, invade circulating erythrocytes. Although invasion is rapid, it is the only time of the life cycle when the parasite is directly exposed to the host immune system. Significant effort has, therefore, focused on identifying the proteins involved and understanding the underlying mechanisms behind merozoite invasion into the protected niche inside the human erythrocyte.
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Chitnis, C. E., and L. H. Miller. "Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion." Journal of Experimental Medicine 180, no. 2 (August 1, 1994): 497–506. http://dx.doi.org/10.1084/jem.180.2.497.
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Plasmodium vivax and the related monkey malaria, P. knowlesi, require interaction with the Duffy blood group antigen, a receptor for a family of chemokines that includes interleukin 8, to invade human erythrocytes. One P. vivax and three P. knowlesi proteins that serve as erythrocyte binding ligands in such interactions share sequence homology. Expression of different regions of the P. vivax protein in COS7 cells identified a cysteine-rich domain that bound Duffy blood group-positive but not Duffy blood group-negative human erythrocytes. The homologous domain of the P. knowlesi proteins also bound erythrocytes, but had different specificities. The P. vivax and P. knowlesi binding domains lie in one of two regions of homology with the P. falciparum sialic acid binding protein, another erythrocyte binding ligand, indicating conservation of the domain for erythrocyte binding in evolutionarily distant malaria species. The binding domains of these malaria ligands represent potential vaccine candidates and targets for receptor-blockade therapy.
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Narum, David L., J. David Haynes, Steven Fuhrmann, Kathy Moch, Hong Liang, Stephen L. Hoffman, and B. Kim Lee Sim. "Antibodies against the Plasmodium falciparum Receptor Binding Domain of EBA-175 Block Invasion Pathways That Do Not Involve Sialic Acids." Infection and Immunity 68, no. 4 (April 1, 2000): 1964–66. http://dx.doi.org/10.1128/iai.68.4.1964-1966.2000.
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ABSTRACT The 175-kDa Plasmodium falciparum erythrocyte binding protein (EBA-175) binds to its receptor, sialic acids on glycophorin A. The binding region within EBA-175 is a cysteine-rich region identified as region II. Antibodies against region II block the binding of native EBA-175 to erythrocytes. We identified a P. falciparum strain, FVO, that could not invade erythrocytes devoid of sialic acids due to prior neuraminidase treatment, and in addition, we used a strain, 3D7, that could invade such sialic acid-depleted erythrocytes. We used these two strains to study the capacity of anti-region II antibodies to inhibit FVO and 3D7 parasite development in vitro. Analysis of growth-inhibitory effects of purified FVO anti-region II immunoglobulin G (IgG) with the FVO and 3D7 strains resulted in similar levels of growth inhibition. FVO and 3D7 strains were inhibited between 28 and 56% compared to control IgG. There appeared to be no intracellular growth retardation or killing of either isolate, suggesting that invasion was indeed inhibited. Incubation of recombinant region II with anti-region II IgG reversed the growth inhibition. These results suggest that antibodies against region II can also interfere with merozoite invasion pathways that do not involve sialic acids. The fact that EBA-175 has such a universal and yet susceptible role in erythrocyte invasion clearly supports its inclusion in a multivalent malaria vaccine.
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LACOMBE, J. M., B. FERRARI, R. ANDRIAMANANPISOA, and A. A. PAVIA. "Malaria invasion of human erythrocytes." International Journal of Peptide and Protein Research 32, no. 2 (January 12, 2009): 104–16. http://dx.doi.org/10.1111/j.1399-3011.1988.tb00670.x.
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Hermentin, P. "Malaria invasion of human erythrocytes." Parasitology Today 3, no. 2 (February 1987): 52–55. http://dx.doi.org/10.1016/0169-4758(87)90214-6.
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Gaur, Deepak, Jill R. Storry, Marion E. Reid, John W. Barnwell, and Louis H. Miller. "Plasmodium falciparum Is Able To InvadeErythrocytes through a Trypsin-Resistant Pathway Independent ofGlycophorinB." Infection and Immunity 71, no. 12 (December 2003): 6742–46. http://dx.doi.org/10.1128/iai.71.12.6742-6746.2003.
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ABSTRACT Plasmodium falciparum invades erythrocytes through multiple ligand-receptor interactions, with redundancies in each pathway. One such alternate pathway is the trypsin-resistant pathway that enables P. falciparum to invade trypsin-treated erythrocytes. Previous studies have shown that this trypsin-resistant pathway is dependent on glycophorin B, as P. falciparum strains invade trypsin-digested glycophorin B-deficient erythrocytes at a highly reduced efficiency. Furthermore, in a recent study, the P. falciparum 7G8 strain did not invade glycophorin B-deficient erythrocytes, a finding that was not confirmed in the present study. To analyze the degree of dependence on glycophorin B for invasion by P. falciparum through the trypsin-resistant pathway, we have studied the invasion phenotypes of five parasite strains, 3D7, HB3, Dd2, 7G8, and Indochina I, on trypsin-treated normal and glycophorin B-deficient erythrocytes. Invasion was variably reduced in glycophorin B-deficient erythrocytes. Four strains, 3D7, HB3, Dd2, and Indochina I, invaded trypsin-treated erythrocytes, while invasion by the 7G8 strain was reduced by 90%. Among the four strains, invasion by 3D7, HB3, and Dd2 of trypsin-digested glycophorin B-deficient erythrocytes was further reduced. However, Indochina I invaded trypsin-digested glycophorin B-deficient erythrocytes at the same efficiency as its invasion of trypsin-digested normal erythrocytes. This strongly suggests that the Indochina I strain of P. falciparum is not dependent on glycophorin B to invade through a trypsin-resistant pathway as are the strains 3D7, HB3, and Dd2. Thus, P. falciparum is able to invade erythrocytes through a glycophorin B-independent, trypsin-resistant pathway.
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BORK, S., S. DAS, K. OKUBO, N. YOKOYAMA, and I. IGARASHI. "Effects of protein kinase inhibitors on thein vitrogrowth ofBabesia bovis." Parasitology 132, no. 6 (February 24, 2006): 775–79. http://dx.doi.org/10.1017/s0031182006009917.
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Staurosporine, Ro-31-7549, and KN-93, which are inhibitors of serine/threonine protein kinase, protein kinase C, and calcium-modulin kinase, respectively, were tested for their effects on thein vitrogrowth ofBabesia bovis. Staurosporine was the most effective inhibitor, completely clearing the parasitaemia as early as the first day of exposure at a concentration of 100 μM. Moreover, staurosporine caused a significant increase in the percentage of extracellular merozoites, most likely due to the inhibition of erythrocyte invasion by the parasite. Although 5 mMRo-31-7549 and KN-93 had a suppressive action, this was not enough to destroy the parasite. Interestingly, concentrations of 0·5 to 5 mMKN-93 influenced the parasitic development within the infected erythrocytes. The present study suggests thatB. bovisrequires, to a certain extent, the phosphorylations mediated by parasite- or host erythrocyte-protein kinases, in particular, for the processes of successful invasion of erythrocytes and intraerythrocytic development.
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Mayer, D. C. Ghislaine, Jian-Bing Mu, Xiaorong Feng, Xin-zhuan Su, and Louis H. Miller. "Polymorphism in a Plasmodium falciparum Erythrocyte-binding Ligand Changes Its Receptor Specificity." Journal of Experimental Medicine 196, no. 11 (November 25, 2002): 1523–28. http://dx.doi.org/10.1084/jem.20020750.
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Recognition of human erythrocytes by Plasmodium species depends in part on Region II of the Duffy binding-like family of parasite ligands, which includes BA erythrocyte binding ligand (BAEBL) of P. falciparum. In previous studies of BAEBL from two clones, Dd2/Nm from Vietnam and E12 from Papua New Guinea (PNG), it was found that BAEBL bound different erythrocyte receptors. Because of variation in binding specificity, we studied the sequence and erythrocyte binding specificity of Region II of BAEBL in P. falciparum clones from different parts of the world. We observed five nucleotide substitutions leading to five amino acid changes and five polymorphisms in Region II of BAEBL in parasites from both PNG and other parts of the world. We expressed four of the polymorphisms on COS cells and determined their binding to enzyme-treated erythrocytes and to Gerbich-negative erythrocytes. We also performed erythrocyte-binding assay using the native protein from radiolabeled culture supernatant. Both assays demonstrated that each of the four polymorphisms in the parasite ligand, BAEBL, bound to a different receptor on erythrocytes. These results suggest that P. falciparum has evolved multiple invasion pathways dependent on polymorphisms in the BAEBL ligand.
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Sim, B. K., P. A. Orlandi, J. D. Haynes, F. W. Klotz, J. M. Carter, D. Camus, M. E. Zegans, and J. D. Chulay. "Primary structure of the 175K Plasmodium falciparum erythrocyte binding antigen and identification of a peptide which elicits antibodies that inhibit malaria merozoite invasion." Journal of Cell Biology 111, no. 5 (November 1, 1990): 1877–84. http://dx.doi.org/10.1083/jcb.111.5.1877.
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The Plasmodium falciparum gene encoding erythrocyte binding antigen-175 (EBA-175), a putative receptor for red cell invasion (Camus, D., and T. J. Hadley. 1985. Science (Wash. DC). 230:553-556.), has been isolated and characterized. DNA sequencing demonstrated a single open reading frame encoding a translation product of 1,435 amino acid residues. Peptides corresponding to regions on the deduced amino acid sequence predicted to be B cell epitopes were assessed for immunogenicity. Immunization of mice and rabbits with EBA-peptide 4, a synthetic peptide encompassing amino acid residues 1,062-1,103, produced antibodies that recognized P. falciparum merozoites in an indirect fluorescent antibody assay. When compared to sera from rabbits immunized with the same adjuvant and carrier protein, sera from rabbits immunized with EBA-peptide 4 inhibited merozoite invasion of erythrocytes in vitro by 80% at a 1:5 dilution. Furthermore, these sera inhibited the binding of purified, authentic EBA-175 to erythrocytes, suggesting that their activity in inhibiting merozoite invasion of erythrocytes is mediated by blocking the binding of EBA-175 to erythrocytes. Since the nucleotide sequence of EBA-peptide 4 is conserved among seven strains of P. falciparum from throughout the world (Sim, B. K. L. 1990. Mol. Biochem. Parasitol. 41:293-296.), these data identify a region of the protein that should be a focus of vaccine development efforts.
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Udomsangpetch, R., J. Carlsson, B. Wåhlin, G. Holmquist, L. S. Ozaki, A. Scherf, D. Mattei, O. Mercereau-Puijalon, S. Uni, and M. Aikawa. "Reactivity of the human monoclonal antibody 33G2 with repeated sequences of three distinct Plasmodium falciparum antigens." Journal of Immunology 142, no. 10 (May 15, 1989): 3620–26. http://dx.doi.org/10.4049/jimmunol.142.10.3620.
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Abstract The human mAb 33G2 has high capacity to inhibit in vitro invasion of erythrocytes by Plasmodium falciparum merozoites and, thus, is of special interest with regard to protective immunity against the parasite. In order to obtain more information about asexual blood stage Ag of P. falciparum that are seen by this antibody, material from synchronized P. falciparum cultures was studied by immunofluorescence, immunoelectron microscopy, and immunoblotting. Reactivity was mainly confined to the membrane of infected erythrocytes. Soon after merozoite invasion the antibody stained the erythrocyte membrane. This membrane-associated staining faded during intracellular development of the parasites. Beginning about 18 h after invasion, a dotted pattern appeared which increased in strength with time and persisted to schizont rupture. Pf155/RESA was the major Ag recognized in immunoblots of parasites collected throughout the entire erythrocytic cycle, although other polypeptides also bound the antibody. Among these was a 260-kDa polypeptide found in late trophozoites and schizonts. The specificity of the antibody was analyzed with synthetic peptides corresponding to repeated sequences in the P. falciparum Ag Pf155/RESA, Pf11.1, and Ag332. Synthetic peptides related to Ag332 were the most efficient inhibitors of antibody binding in immunofluorescence studies and cell ELISA. A beta-galactosidase-Ag332 fusion protein was also efficient in reversing reinvasion inhibition caused by 33G2. These results define a family of cross-reactive P. falciparum Ag recognized by mAb 33G2 and suggest that Ag332 was its original target.
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Sharma, Monal, and Shailja Singh. "Sequence polymorphism within erythrocyte binding domain of EBA175 in Indian and African field isolates." Biotechnology Kiosk 4, no. 1 (January 21, 2022): 1–9. http://dx.doi.org/10.37756/bk.22.4.1.1.
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Invasion of erythrocyte by Plasmodium merozoites is mediated by specific molecular interactions between proteins expressed on merozoite surface and the receptors present on erythrocytes. Erythrocyte binding antigen 175 (EBA175) is one such protein that interacts with the sialic acid residues on glycophorin A present on erythrocytes’ surface during invasion. The FII region (PfFII) of EBA175 has been mapped to be critical for binding to erythrocytes. It is reported that antibodies against FII region blocks binding. Polymorphisms in FII region of EBA175 are already reported. The goal of this study was to investigate whether polymorphism in FII region of African P. falciparum field isolates has any effect on erythrocyte binding and also to find whether antibodies raised against FII region from P. falciparum Malayan Camp strain (Camp) can inhibit erythrocyte binding. Genomic DNA of parasites from the blood samples of P. falciparum infected individuals was isolated and PfFII region from these genomic DNA were amplified, cloned and sequenced. Following sequence analysis, we selected three isolates harboring higher PfFII polymorphisms, expressed them on the surface of COS cells as chimeric proteins using secretory signal and transmembrane segments of Herpex simplex virus glycoprotein D (HSVg D) and tested for their erythrocyte binding ability. We further tested the inhibition of erythrocyte binding of these polymorphic FII regions using anti-campPfF2 antibodies. Our results reveal that the polymorphisms in different field isolates included in this study do not have any significant effect on erythrocyte binding and antibodies raised against FII region of camp strain could inhibit erythrocyte binding by all the polymorphic PfFII. This observation strengthens the possibility that PfFII can be a potential candidate vaccine.
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Gunalan, Karthigayan, Juliana M. Sá, Roberto R. Moraes Barros, Sarah L. Anzick, Ramoncito L. Caleon, J. Patrick Mershon, Kishore Kanakabandi, et al. "Transcriptome profiling ofPlasmodium vivaxinSaimirimonkeys identifies potential ligands for invasion." Proceedings of the National Academy of Sciences 116, no. 14 (March 14, 2019): 7053–61. http://dx.doi.org/10.1073/pnas.1818485116.
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Unlike the case in Asia and Latin America,Plasmodium vivaxinfections are rare in sub-Saharan Africa due to the absence of the Duffy blood group antigen (Duffy antigen), the only known erythrocyte receptor for theP. vivaxmerozoite invasion ligand, Duffy binding protein 1 (DBP1). However,P. vivaxinfections have been documented in Duffy-negative individuals throughout Africa, suggesting thatP. vivaxmay use ligands other than DBP1 to invade Duffy-negative erythrocytes through other receptors. To identify potentialP. vivaxligands, we compared parasite gene expression inSaimiriandAotusmonkey erythrocytes infected withP. vivaxSalvador I (Sal I). DBP1 bindsAotusbut does not bind toSaimirierythrocytes; thus,P. vivaxSal I must invadeSaimirierythrocytes independent of DBP1. Comparing RNA sequencing (RNAseq) data for late-stage infections inSaimiriandAotuserythrocytes when invasion ligands are expressed, we identified genes that belong to tryptophan-rich antigen and merozoite surface protein 3 (MSP3) families that were more abundantly expressed inSaimiriinfections compared withAotusinfections. These genes may encode potential ligands responsible forP. vivaxinfections of Duffy-negative Africans.
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Orjih, Augustine U. "Requirements for Maximal Enrichment of Viable Intraerythrocytic Plasmodium falciparum Rings by Saponin Hemolysis." Experimental Biology and Medicine 233, no. 11 (November 2008): 1359–67. http://dx.doi.org/10.3181/0804-rm-129.
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The purpose of the present study was to confirm the effectiveness of saponin hemolysis for concentrating ring-infected erythrocytes in Plasmodium falciparum cultures and to determine the actual numbers of the enriched parasites, not just percentage parasitemia. This is important because various molecular biology and vaccine development against malaria require useable quantities of pure culture with minimal number of uninfected erythrocytes at all stages. Synchronized cultures of three P. falciparum strains were exposed to 0.015% isotonic saponin solution for 30 minutes on ice. They were centrifuged and the pellets were treated again with saponin solution for 3–7 minutes. Initially, most of the cultures contained approximately 1010 erythrocytes and 1–7% parasitemia, but at the end of the enrichment up to 108 of erythrocytes containing 90–99.8% parasitemia were recovered (maximal enrichment). From microscopic examination of the cells it was calculated that the hemolysis rate of uninfected and infected erythrocytes was circa 27 to 1, which could account for the enrichment. Studies by other investigators have suggested that P. falciparum merozoite invasion decreases erythrocyte membrane lipids, and it has been reported that reduction of membrane cholesterol could make erythrocytes saponin-resistant. The possibility that merozoite invasion made erythrocytes partially resistant to saponin hemolysis was strengthened by the observation that the proportions of multiple infections increased significantly in the enriched cultures. However, mature asexual parasites could not be concentrated by this method, suggesting possible differences between the membranes of erythrocytes containing ring forms and those of trophozoites and schizonts. Ring-infected erythrocytes freshly from malaria patients could also not be concentrated by the method described here, suggesting that the ability to induce saponin resistance in erythrocytes was acquired by the parasites in vitro.
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Haynes, J. D., J. P. Dalton, F. W. Klotz, M. H. McGinniss, T. J. Hadley, D. E. Hudson, and L. H. Miller. "Receptor-like specificity of a Plasmodium knowlesi malarial protein that binds to Duffy antigen ligands on erythrocytes." Journal of Experimental Medicine 167, no. 6 (June 1, 1988): 1873–81. http://dx.doi.org/10.1084/jem.167.6.1873.
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A 135-kD parasite protein, a minor component of the Plasmodium knowlesi malaria radiolabeled proteins released into culture supernatant at the time of merozoite release and reinvasion, specifically bound to human erythrocytes that are invaded and carry a Duffy blood group determinant (Fya or Fyb), but did not bind to human erythrocytes that are not invaded and do not carry a Duffy determinant (FyFy). Specific anti-Duffy antibodies blocked the binding of the 135-kD protein to erythrocytes carrying that specific Duffy determinant. Purified 135-kD protein bound specifically to the 35-45-kD Duffy glycoprotein on a blot of electrophoretically separated membrane proteins from Fya and Fyb erythrocytes but not from FyFy erythrocytes. Binding of the 135-kD protein was consistently greater to Fyb than to Fya both on the blot and on intact erythrocytes. The 135-kD protein also bound to rhesus erythrocytes that are Fyb and are invaded, but not to rabbit or guinea pig erythrocytes that are Duffy-negative and are not invaded. Cleavage of the Duffy determinant by pretreating Fyb human erythrocytes with chymotrypsin greatly reduced both invasion and binding of the 135-kD protein, whereas pretreating Fyb erythrocytes with trypsin had little effect on the Duffy antigen, the 135-kD protein binding, or on invasion. However, instances of invasion of other enzyme-treated erythrocytes that are Duffy-negative and do not bind the 135-kD protein suggest that alternative pathways for invasion do exist.
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Gilberger, Tim-Wolf, Jennifer K. Thompson, Michael B. Reed, Robert T. Good, and Alan F. Cowman. "The cytoplasmic domain of the Plasmodium falciparum ligand EBA-175 is essential for invasion but not protein trafficking." Journal of Cell Biology 162, no. 2 (July 21, 2003): 317–27. http://dx.doi.org/10.1083/jcb.200301046.
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The invasion of host cells by the malaria parasite Plasmodium falciparum requires specific protein–protein interactions between parasite and host receptors and an intracellular translocation machinery to power the process. The transmembrane erythrocyte binding protein-175 (EBA-175) and thrombospondin-related anonymous protein (TRAP) play central roles in this process. EBA-175 binds to glycophorin A on human erythrocytes during the invasion process, linking the parasite to the surface of the host cell. In this report, we show that the cytoplasmic domain of EBA-175 encodes crucial information for its role in merozoite invasion, and that trafficking of this protein is independent of this domain. Further, we show that the cytoplasmic domain of TRAP, a protein that is not expressed in merozoites but is essential for invasion of liver cells by the sporozoite stage, can substitute for the cytoplasmic domain of EBA-175. These results show that the parasite uses the same components of its cellular machinery for invasion regardless of the host cell type and invasive form.
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OKUBO, K., N. YOKOYAMA, N. TAKABATAKE, M. OKAMURA, and I. IGARASHI. "Amount of cholesterol in host membrane affects erythrocyte invasion and replication by Babesia bovis." Parasitology 134, no. 5 (May 2006): 625–30. http://dx.doi.org/10.1017/s0031182006001910.
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SUMMARYCholesterol is a major component of the erythrocyte membrane. In the present study, we investigated the effects of cholesterol reduction in host bovine erythrocytes (RBC) on the growth of Babesia bovis, a major bovine haemoprotozoon. An in vitro growth assay with bovine RBC that had been prepared by pre-treatment with a cholesterol depletion agent (methyl-β-cyclodextrin, MCD) showed that the culture with 5 mm MCD-treated RBC inhibited the growth of B. bovis significantly as compared with that with the control RBC. In further experiments, the treatment with 5 mm MCD was proved to suppress both activities of the parasite, erythrocyte invasion and replication within the infected RBC. In contrast, a slight reduction in the membrane cholesterol by 1 mm MCD treatment promoted both their growth and erythrocyte invasion activity. These results indicate that erythrocyte invasion and replication by B. bovis are affected by the amount of cholesterol in the host erythrocyte membrane.
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Orlandi, P. A., F. W. Klotz, and J. D. Haynes. "A malaria invasion receptor, the 175-kilodalton erythrocyte binding antigen of Plasmodium falciparum recognizes the terminal Neu5Ac(alpha 2-3)Gal- sequences of glycophorin A." Journal of Cell Biology 116, no. 4 (February 15, 1992): 901–9. http://dx.doi.org/10.1083/jcb.116.4.901.
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Plasmodium falciparum malaria parasites invade human erythrocytes by means of a parasite receptor for erythrocytes, the 175-kD erythrocyte binding antigen (EBA-175). Similar to invasion efficiency, binding requires N-acetylneuraminic acid (Neu5Ac) on human erythrocytes, specifically the glycophorins. EBA-175 bound to erythrocytes with receptor-like specificity and was saturable. The specificity of EBA-175 binding was studied to determine if its binding is influenced either by simple electrostatic interaction with the negatively charged Neu5Ac (on the erythrocyte surface); or if Neu5Ac indirectly affected the conformation of an unknown ligand, or if Neu5Ac itself in specific linkage and carbohydrate composition was the primary ligand for EBA-175 as demonstrated for hemagglutinins of influenza viruses. Most Neu5Ac on human erythrocytes is linked to galactose by alpha 2-3 and alpha 2-6 linkages on glycophorin A. Soluble Neu5Ac by itself in solution did not competitively inhibit the binding of EBA-175 to erythrocytes, suggesting that linkage to an underlying sugar is required for binding in contrast to charge alone. Binding was competitively inhibited only by Neu5Ac(alpha 2-3)Gal-containing oligosaccharides. Similar oligosaccharides containing Neu5Ac(alpha 2-6)Gal-linkages had only slight inhibitory effects. Binding inhibition assays with modified sialic acids and other saccharides confirmed that oligosaccharide composition and linkage were primary factors for efficient binding. EBA-175 bound tightly enough to glycophorin A that the complex could be precipitated with an anti-glycophorin A monoclonal antibody. Selective cleavage of O-linked tetrasaccharides clustered at the NH2 terminus of glycophorin A markedly reduced binding in inhibition studies. We conclude that the Neu5Ac(a2,3)-Gal- determinant on O-linked tetrasaccharides of glycophorin A appear to be the preferential erythrocyte ligand for EBA-175.
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Pandey, Alok K., K. Sony Reddy, Tajali Sahar, Sonal Gupta, Hina Singh, E. Jyotheeswara Reddy, Mohd Asad, et al. "Identification of a Potent Combination of Key Plasmodium falciparum Merozoite Antigens That Elicit Strain-Transcending Parasite-Neutralizing Antibodies." Infection and Immunity 81, no. 2 (November 26, 2012): 441–51. http://dx.doi.org/10.1128/iai.01107-12.
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ABSTRACTBlood-stage malaria vaccines that target singlePlasmodium falciparumantigens involved in erythrocyte invasion have not induced optimal protection in field trials. Blood-stage malaria vaccine development has faced two major hurdles, antigenic polymorphisms and molecular redundancy, which have led to an inability to demonstrate potent, strain-transcending, invasion-inhibitory antibodies. Vaccines that target multiple invasion-related parasite proteins may inhibit erythrocyte invasion more efficiently. Our approach is to develop a receptor-blocking blood-stage vaccine againstP. falciparumthat targets the erythrocyte binding domains of multiple parasite adhesins, blocking their interaction with their receptors and thus inhibiting erythrocyte invasion. However, with numerous invasion ligands, the challenge is to identify combinations that elicit potent strain-transcending invasion inhibition. We evaluated the invasion-inhibitory activities of 20 different triple combinations of antibodies mixedin vitroagainst a diverse set of six key merozoite ligands, including the novel ligandsP. falciparumapical asparagine-rich protein (PfAARP), EBA-175 (PfF2),P. falciparumreticulocyte binding-like homologous protein 1 (PfRH1), PfRH2, PfRH4, andPlasmodiumthrombospondin apical merozoite protein (PTRAMP), which are localized in different apical organelles and are translocated to the merozoite surface at different time points during invasion. They bind erythrocytes with different specificities and are thus involved in distinct invasion pathways. The antibody combination of EBA-175 (PfF2), PfRH2, and PfAARP produced the most efficacious strain-transcending inhibition of erythrocyte invasion against diverseP. falciparumclones. This potent antigen combination was selected for coimmunization as a mixture that induced balanced antibody responses against each antigen and inhibited erythrocyte invasion efficiently. We have thus demonstrated a novel two-step screening approach to identify a potent antigen combination that elicits strong strain-transcending invasion inhibition, supporting its development as a receptor-blocking malaria vaccine.
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Pirson, P. J., and M. E. Perkins. "Characterization with monoclonal antibodies of a surface antigen of Plasmodium falciparum merozoites." Journal of Immunology 134, no. 3 (March 1, 1985): 1946–51. http://dx.doi.org/10.4049/jimmunol.134.3.1946.
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Abstract The merozoite, the extracellular form of the erythrocyte stage of the malarial parasite, invades the erythrocyte and develops intracellularly. Cloned hybridoma cell lines secreting monoclonal antibodies directed against the merozoite surface were selected by indirect immunofluorescent assay by using intact isolated merozoites. Monoclonal antibodies to a 200,000 m.w. merozoite surface antigen were selected and were used to characterize this protein and its role in erythrocyte invasion. Immunoelectron microscopy demonstrated that the antigen was located exclusively on the merozoite surface coat, distributed evenly over the entire surface. The 200,000 m.w. protein incorporated [3H]glucosamine, suggesting that it is a glycoprotein and could be purified to homogeneity by using immuno-affinity chromatography. Freshly isolated, invasive merozoites retained the 200,000 m.w. antigen, but the protein was rapidly cleaved to proteins of 90,000 and 50,000 m.w. when the merozoite was extracellular. The 50,000 m.w. fragment was retained the epitope binding to monoclonal antibody 5B1 and were labeled with [3H]glucosamine. Monoclonal antibodies against the 200,000 m.w. antigen partially inhibited merozoite invasion into erythrocytes.
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Takakuwa, Yuich. "Can Erythrocytes Prevent Malaria Parasite Invasion?" MEMBRANE 31, no. 5 (2006): 253–57. http://dx.doi.org/10.5360/membrane.31.253.
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Horzempa, Joseph, Dawn M. O'Dee, Donna Beer Stolz, Jonathan M. Franks, Doris Clay, and Gerard J. Nau. "Invasion of Erythrocytes by Francisella tularensis." Journal of Infectious Diseases 204, no. 1 (July 1, 2011): 51–59. http://dx.doi.org/10.1093/infdis/jir221.
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Blouin, Edmour E., James T. Blankemeyer, Katherine M. Kocan, and S. A. Ewing. "Effect of 4-bromo-calcium ionophore A23187 on release of Anaplasma marginale from bovine erythrocytes in vitro." American Journal of Veterinary Research 54, no. 2 (February 1, 1993): 263–69. http://dx.doi.org/10.2460/ajvr.1993.54.02.263.
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SUMMARY The ionophore A23187 was used to facilitate release and continued development of Anaplasma marginale in short-term erythrocyte cultures. Addition of 10 μM A23187 to the cultures resulted in significant decrease in percentage of parasitized erythrocytes (ppe) by 24 hours after treatment; further development and increase in PPE was not observed. In contrast, the ppe of untreated cultures, those treated with dimethyl sulfoxide (dmso) only and with 1 μM A23187 increased slightly during that time. Total erythrocyte count decreased in treated cultures in excess of that expected after samples of the medium were taken for analysis. The greatest cell loss and increased hemoglobin concentration in culture medium was observed in cultures treated with 10 μM A23187 and with an equivalent volume of dmso. The dmso appeared to cause hemolysis of some erythrocytes, but not of infected cells selectively. Release of A marginale inclusion bodies was seen by electron microscopy in samples from the 10 μM A23187-exposed cultures. At 30 minutes after treatment, free initial bodies were frequently seen. Inclusion body membranes and individual A marginale were associated with membranes of adjacent erythrocytes. Individual rickettsiae were seen in cell depressions and appeared to be entering erythrocytes. However, neither further invasion nor development of the parasite in erythrocytes was observed. Ionophore A23187 appeared to promote release of A marginale from erythrocytes, but did not enhance infection of erythrocytes or development of organisms in vitro.
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Fernandez-Pol, Sebastian, Zdenek Slouka, Souvik Bhattacharjee, Yana Fedotova, Stefan Freed, Xiuli An, Anthony A. Holder, et al. "A Bacterial Phosphatase-Like Enzyme of the Malaria Parasite Plasmodium falciparum Possesses Tyrosine Phosphatase Activity and Is Implicated in the Regulation of Band 3 Dynamics during Parasite Invasion." Eukaryotic Cell 12, no. 9 (July 3, 2013): 1179–91. http://dx.doi.org/10.1128/ec.00027-13.
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ABSTRACT Eukaryotic parasites of the genus Plasmodium cause malaria by invading and developing within host erythrocytes. Here, we demonstrate that PfShelph2, a gene product of Plasmodium falciparum that belongs to the Shewanella -like phosphatase (Shelph) subfamily, selectively hydrolyzes phosphotyrosine, as shown for other previously studied Shelph family members. In the extracellular merozoite stage, PfShelph2 localizes to vesicles that appear to be distinct from those of rhoptry, dense granule, or microneme organelles. During invasion, PfShelph2 is released from these vesicles and exported to the host erythrocyte. In vitro , PfShelph2 shows tyrosine phosphatase activity against the host erythrocyte protein Band 3, which is the most abundant tyrosine-phosphorylated species of the erythrocyte. During P. falciparum invasion, Band 3 undergoes dynamic and rapid clearance from the invasion junction within 1 to 2 s of parasite attachment to the erythrocyte. Release of Pfshelph2 occurs after clearance of Band 3 from the parasite-host cell interface and when the parasite is nearly or completely enclosed in the nascent vacuole. We propose a model in which the phosphatase modifies Band 3 in time to restore its interaction with the cytoskeleton and thus reestablishes the erythrocyte cytoskeletal network at the end of the invasion process.
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Nasibova, G. R., A. S. Gasanov, and K. V. Andriyanova. "BLOOD INDICATORS IN TURKEYS INFECTED WITH DIFFERENT TYPES OF INVASION." Scientific Notes Kazan Bauman State Academy of Veterinary Medicine 247, no. 3 (September 5, 2021): 182–86. http://dx.doi.org/10.31588/2413-4201-1883-247-3-182-186.
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The article talks about mono- and mixed invasions and the intensity of parasites in the body of turkeys, causing changes in various forms in blood parameters. Blood tests of naturally infected birds show that although the number of erythrocytes and hemoglobin in sick birds increased, there was a decrease in leukocytes and an increase in the erythrocyte sedimentation rate. And this was more prominently shown in birds infected with mixed two and three helminths, compared with birds infected with monoinvasions.
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Yadavalli, Raghavendra, John W. Peterson, Judith A. Drazba, and Tobili Y. Sam-Yellowe. "Trafficking and Association of Plasmodium falciparum MC-2TM with the Maurer’s Clefts." Pathogens 10, no. 4 (April 5, 2021): 431. http://dx.doi.org/10.3390/pathogens10040431.
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In this study, we investigated stage specific expression, trafficking, solubility and topology of endogenous PfMC-2TM in P. falciparum (3D7) infected erythrocytes. Following Brefeldin A (BFA) treatment of parasites, PfMC-2TM traffic was evaluated using immunofluorescence with antibodies reactive with PfMC-2TM. PfMC-2TM is sensitive to BFA treatment and permeabilization of infected erythrocytes with streptolysin O (SLO) and saponin, showed that the N and C-termini of PfMC-2TM are exposed to the erythrocyte cytoplasm with the central portion of the protein protected in the MC membranes. PfMC-2TM was expressed as early as 4 h post invasion (hpi), was tightly colocalized with REX-1 and trafficked to the erythrocyte membrane without a change in solubility. PfMC-2TM associated with the MC and infected erythrocyte membrane and was resistant to extraction with alkaline sodium carbonate, suggestive of protein-lipid interactions with membranes of the MC and erythrocyte. PfMC-2TM is an additional marker of the nascent MCs.
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Patarroyo, Manuel Alfonso, Jessica Molina-Franky, Marcela Gómez, Gabriela Arévalo-Pinzón, and Manuel Elkin Patarroyo. "Hotspots in Plasmodium and RBC Receptor-Ligand Interactions: Key Pieces for Inhibiting Malarial Parasite Invasion." International Journal of Molecular Sciences 21, no. 13 (July 2, 2020): 4729. http://dx.doi.org/10.3390/ijms21134729.
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Protein-protein interactions (IPP) play an essential role in practically all biological processes, including those related to microorganism invasion of their host cells. It has been found that a broad repertoire of receptor-ligand interactions takes place in the binding interphase with host cells in malaria, these being vital interactions for successful parasite invasion. Several trials have been conducted for elucidating the molecular interface of interactions between some Plasmodium falciparum and Plasmodium vivax antigens with receptors on erythrocytes and/or reticulocytes. Structural information concerning these complexes is available; however, deeper analysis is required for correlating structural, functional (binding, invasion, and inhibition), and polymorphism data for elucidating new interaction hotspots to which malaria control methods can be directed. This review describes and discusses recent structural and functional details regarding three relevant interactions during erythrocyte invasion: Duffy-binding protein 1 (DBP1)–Duffy antigen receptor for chemokines (DARC); reticulocyte-binding protein homolog 5 (PfRh5)-basigin, and erythrocyte binding antigen 175 (EBA175)-glycophorin A (GPA).
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Schlott, Anja C., Ellen Knuepfer, Judith L. Green, Philip Hobson, Aaron J. Borg, Julia Morales-Sanfrutos, Abigail J. Perrin, et al. "Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion." PLOS Biology 19, no. 10 (October 25, 2021): e3001408. http://dx.doi.org/10.1371/journal.pbio.3001408.
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We have combined chemical biology and genetic modification approaches to investigate the importance of protein myristoylation in the human malaria parasite, Plasmodium falciparum. Parasite treatment during schizogony in the last 10 to 15 hours of the erythrocytic cycle with IMP-1002, an inhibitor of N-myristoyl transferase (NMT), led to a significant blockade in parasite egress from the infected erythrocyte. Two rhoptry proteins were mislocalized in the cell, suggesting that rhoptry function is disrupted. We identified 16 NMT substrates for which myristoylation was significantly reduced by NMT inhibitor (NMTi) treatment, and, of these, 6 proteins were substantially reduced in abundance. In a viability screen, we showed that for 4 of these proteins replacement of the N-terminal glycine with alanine to prevent myristoylation had a substantial effect on parasite fitness. In detailed studies of one NMT substrate, glideosome-associated protein 45 (GAP45), loss of myristoylation had no impact on protein location or glideosome assembly, in contrast to the disruption caused by GAP45 gene deletion, but GAP45 myristoylation was essential for erythrocyte invasion. Therefore, there are at least 3 mechanisms by which inhibition of NMT can disrupt parasite development and growth: early in parasite development, leading to the inhibition of schizogony and formation of “pseudoschizonts,” which has been described previously; at the end of schizogony, with disruption of rhoptry formation, merozoite development and egress from the infected erythrocyte; and at invasion, when impairment of motor complex function prevents invasion of new erythrocytes. These results underline the importance of P. falciparum NMT as a drug target because of the pleiotropic effect of its inhibition.
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Fujioka, H., and M. Aikawa. "Molecular Pathogenesis of Cerebral Malaria." Microscopy and Microanalysis 3, S2 (August 1997): 39–40. http://dx.doi.org/10.1017/s143192760000708x.
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Plasmodium falciparum, the most malignant human malaria, is responsible for 2-3 million deaths annually. These infections often involve blockage of the cerebral microvasculature by P. falciparum-infected erythrocytes (Fig. 1). This aspect is considered the major factor in the pathogenesis of cerebral malaria.Upon invasion of the erythrocyte, P. falciparum immediately begins to remodel the infected erythrocyte. The adherence points of infected erythrocytes, termed knobs (Fig. 2 and 3), contain antigenically diverse 200-350kDa surface proteins (PfEMPl; Fig. 4). The PfEMPl variant surface proteins are encoded by a large and extremely diverse family of genes (var), and switches in the expression of var genes account for rapid changes in the antigenic and adhesive properties of P. falciparum-inkcted erythrocytes (2.4% per generation). Switches in the PfEMPl expression may not only affect the phenotype of the parasite strain but may also change its sequestration to endothelial cells. Genetic reorganization in this protein can lead to binding any of the following endothelial cell receptors; ICAM-1, CD36, thrombospondin, chondroitin sulfate (Fig. 5),2 ELAM-1, or VCAM-1.
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Alves-Rosa, María Fernanda, Nicole M. Tayler, Doriana Dorta, Lorena M. Coronado, and Carmenza Spadafora. "P. falciparum Invasion and Erythrocyte Aging." Cells 13, no. 4 (February 12, 2024): 334. http://dx.doi.org/10.3390/cells13040334.
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Plasmodium parasites need to find red blood cells (RBCs) that, on the one hand, expose receptors for the pathogen ligands and, on the other hand, maintain the right geometry to facilitate merozoite attachment and entry into the red blood cell. Both characteristics change with the maturation of erythrocytes. Some Plasmodia prefer younger vs. older erythrocytes. How does the life evolution of the RBC affect the invasion of the parasite? What happens when the RBC ages? In this review, we present what is known up until now.
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Uchime, Onyinyechukwu, Raul Herrera, Karine Reiter, Svetlana Kotova, Richard L. Shimp, Kazutoyo Miura, Dominique Jones, et al. "Analysis of the Conformation and Function of the Plasmodium falciparum Merozoite Proteins MTRAP and PTRAMP." Eukaryotic Cell 11, no. 5 (March 30, 2012): 615–25. http://dx.doi.org/10.1128/ec.00039-12.
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ABSTRACT Thrombospondin repeat (TSR)-like domains are structures involved with cell adhesion. Plasmodium falciparum proteins containing TSR domains play crucial roles in parasite development. In particular, the preerythrocytic P. falciparum circumsporozoite protein is involved in hepatocyte invasion. The importance of these domains in two other malaria proteins, the merozoite-specific thrombospondin-related anonymous protein (MTRAP) and the thrombospondin-related apical membrane protein (PTRAMP), were assessed using near-full-length recombinant proteins composed of the extracellular domains produced in Escherichia coli . MTRAP is thought to be released from invasive organelles identified as micronemes during merozoite invasion to mediate motility and host cell invasion through an interaction with aldolase, an actin binding protein involved in the moving junction. PTRAMP function remains unknown. In this study, the conformation of recombinant MTRAP (rMTRAP) appeared to be a highly extended protein (2 nm by 33 nm, width by length, respectively), whereas rPTRAMP had a less extended structure. Using an erythrocyte binding assay, rMTRAP but not rPTRAMP bound human erythrocytes; rMTRAP binding was mediated through the TSR domain. MTRAP- and in general PTRAMP-specific antibodies failed to inhibit P. falciparum development in vitro . Altogether, MTRAP is a highly extended bifunctional protein that binds to an erythrocyte receptor and the merozoite motor.