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John W Barnwell - One of the best experts on this subject based on the ideXlab platform.
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analysis of erythrocyte dynamics in rhesus macaque monkeys during infection with plasmodium cynomolgi
Malaria Journal, 2018Co-Authors: John W Barnwell, Luis L Fonseca, Chester J Joyner, Celia L Saney, Alberto MorenoAbstract:Malaria is a major mosquito transmitted, blood-borne parasitic disease that afflicts humans. The disease causes anaemia and other clinical complications, which can lead to death. Plasmodium vivax is known for its Reticulocyte host cell specificity, but many gaps in disease details remain. Much less is known about the closely related species, Plasmodium cynomolgi, although it is naturally acquired and causes zoonotic malaria. Here, a computational model is developed based on longitudinal analyses of P. cynomolgi infections in nonhuman primates to investigate the erythrocyte dynamics that is pertinent to understanding both P. cynomolgi and P. vivax malaria in humans. A cohort of five P. cynomolgi infected Rhesus macaques (Macaca mulatta) is studied, with individuals exhibiting a plethora of clinical outcomes, including varying levels of anaemia. A discrete recursive model with age structure is developed to replicate the dynamics of P. cynomolgi blood-stage infections. The model allows for parasitic Reticulocyte preference and assumes an age preference among the mature RBCs. RBC senescence is modelled using a hazard function, according to which RBCs have a mean lifespan of 98 ± 21 days. Based on in vivo data from three cohorts of macaques, the computational model is used to characterize the Reticulocyte lifespan in circulation as 24 ± 5 h (n = 15) and the rate of RBC production as 2727 ± 209 cells/h/µL (n = 15). Analysis of the host responses reveals a pre-patency increase in the number of Reticulocytes. It also allows the quantification of RBC removal through the bystander effect. The evident pre-patency increase in Reticulocytes is due to a shift towards the release of younger Reticulocytes, which could result from a parasite-induced factor meant to increase Reticulocyte availability and satisfy the parasite’s tropism, which has an average value of 32:1 in this cohort. The number of RBCs lost due to the bystander effect relative to infection-induced RBC losses is 62% for P. cynomolgi infections, which is substantially lower than the value of 95% previously determined for another simian species, Plasmodium coatneyi.
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Analysis of erythrocyte dynamics in Rhesus macaque monkeys during infection with Plasmodium cynomolgi
BMC, 2018Co-Authors: Luis L Fonseca, Mary R Galinski, John W Barnwell, Chester J Joyner, Celia L Saney, Alberto Moreno, The Mahpic Consortium, Eberhard O. VoitAbstract:Abstract Background Malaria is a major mosquito transmitted, blood-borne parasitic disease that afflicts humans. The disease causes anaemia and other clinical complications, which can lead to death. Plasmodium vivax is known for its Reticulocyte host cell specificity, but many gaps in disease details remain. Much less is known about the closely related species, Plasmodium cynomolgi, although it is naturally acquired and causes zoonotic malaria. Here, a computational model is developed based on longitudinal analyses of P. cynomolgi infections in nonhuman primates to investigate the erythrocyte dynamics that is pertinent to understanding both P. cynomolgi and P. vivax malaria in humans. Methods A cohort of five P. cynomolgi infected Rhesus macaques (Macaca mulatta) is studied, with individuals exhibiting a plethora of clinical outcomes, including varying levels of anaemia. A discrete recursive model with age structure is developed to replicate the dynamics of P. cynomolgi blood-stage infections. The model allows for parasitic Reticulocyte preference and assumes an age preference among the mature RBCs. RBC senescence is modelled using a hazard function, according to which RBCs have a mean lifespan of 98 ± 21 days. Results Based on in vivo data from three cohorts of macaques, the computational model is used to characterize the Reticulocyte lifespan in circulation as 24 ± 5 h (n = 15) and the rate of RBC production as 2727 ± 209 cells/h/µL (n = 15). Analysis of the host responses reveals a pre-patency increase in the number of Reticulocytes. It also allows the quantification of RBC removal through the bystander effect. Conclusions The evident pre-patency increase in Reticulocytes is due to a shift towards the release of younger Reticulocytes, which could result from a parasite-induced factor meant to increase Reticulocyte availability and satisfy the parasite’s tropism, which has an average value of 32:1 in this cohort. The number of RBCs lost due to the bystander effect relative to infection-induced RBC losses is 62% for P. cynomolgi infections, which is substantially lower than the value of 95% previously determined for another simian species, Plasmodium coatneyi
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a Reticulocyte binding protein complex of plasmodium vivax merozoites
Cell, 1992Co-Authors: Mary R Galinski, Claudia Corredor Medina, Paul Ingravallo, John W BarnwellAbstract:Plasmodium vivax merozoites primarily invade Reticulocytes. The basis of this restricted host cell preference has been debated. Here we introduce two novel P. vivax proteins that comigrate on reducing SDS-polyacrylamide gels, colocalize at the apical pole of merozoites, and adhere specifically to Reticulocytes. The genes encoding these proteins, P. vivax Reticulocyte-binding proteins 1 and 2 (PvRBP-1 and PvRBP-2), have been cloned and analyzed. Homologous genes are evident in the closely related simian malaria parasite, P. cynomolgi, which also prefers to invade Reticulocytes, but are not evident in the genome of another related simian malaria parasite, P. knowlesi, which invades all red blood cell subpopulations. Native PvRBP-1 is likely a transmembrane-anchored disulfide-linked protein, and along with PvRBP-2 may function as an adhesive protein complex. We propose that the RBPs of P. vivax, and homologous proteins of P. cynomolgi, function to target the Reticulocyte subpopulation of red blood cells for invasion.
Benoit Malleret - One of the best experts on this subject based on the ideXlab platform.
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rodent malaria erythrocyte preference assessment by an ex vivo tropism assay
Elements, 2021Co-Authors: Yew Wai Leong, Erica Qian Hui Lee, Laurent Renia, Benoit MalleretAbstract:Circulating red blood cells consist of young erythrocytes (early and late Reticulocytes) and mature erythrocytes (normocytes). The human malaria parasites, Plasmodium falciparum and P. vivax, have a preference to invade Reticulocytes during blood-stage infection. Rodent malaria parasites that also prefer Reticulocytes could be useful tools to study human malaria Reticulocyte invasion. However, previous tropism studies of rodent malaria are inconsistent from one another, making it difficult to compare cell preference of different parasite species and strains. In vivo measurements of cell tropism are also subjected to many confounding factors. Here we developed an ex vivo tropism assay for rodent malaria with highly purified fractions of murine Reticulocytes and normocytes. We measured invasion into the different erythrocyte populations using flow cytometry and evaluated the tropism index of the parasite strains. We found that P. berghei ANKA displayed the strongest Reticulocyte preference, followed by P. yoelii 17X1.1, whereas P. chabaudi AS and P. vinckei S67 showed mixed tropism. These preferences are intrinsic and were maintained at different Reticulocyte and normocyte availabilities. Our study shed light on the true erythrocyte preference of the parasites and paves the way for future investigations on the receptor-ligand interactions mediating erythrocyte tropism.
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transferrin receptor 1 is a Reticulocyte specific receptor for plasmodium vivax
Science, 2018Co-Authors: Jakub Gruszczyk, Benoit Malleret, Usheer Kanjee, Li Jin Chan, Sebastien Menant, Nicholas T Y Lim, Christoph Q Schmidt, Yeefoong MokAbstract:Plasmodium vivax shows a strict host tropism for Reticulocytes. We identified transferrin receptor 1 (TfR1) as the receptor for P. vivax Reticulocyte-binding protein 2b (PvRBP2b). We determined the structure of the N-terminal domain of PvRBP2b involved in red blood cell binding, elucidating the molecular basis for TfR1 recognition. We validated TfR1 as the biological target of PvRBP2b engagement by means of TfR1 expression knockdown analysis. TfR1 mutant cells deficient in PvRBP2b binding were refractory to invasion of P. vivax but not to invasion of P. falciparum . Using Brazilian and Thai clinical isolates, we show that PvRBP2b monoclonal antibodies that inhibit Reticulocyte binding also block P. vivax entry into Reticulocytes. These data show that TfR1-PvRBP2b invasion pathway is critical for the recognition of Reticulocytes during P. vivax invasion.
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plasmodium vivax restricted tropism and rapid remodeling of cd71 positive Reticulocytes
Blood, 2015Co-Authors: Benoit Malleret, Rossarin Suwanarusk, Cindy S Chu, Rou Zhang, Kevin S W Tan, Carla Claser, Jee Sun Cho, Esther G L KohAbstract:Plasmodium vivax merozoites only invade Reticulocytes, a minor though heterogeneous population of red blood cell precursors that can be graded by levels of transferrin receptor (CD71) expression. The development of a protocol that allows sorting Reticulocytes into defined developmental stages and a robust ex vivo P vivax invasion assay has made it possible for the first time to investigate the fine-scale invasion preference of P vivax merozoites. Surprisingly, it was the immature Reticulocytes (CD71+) that are generally restricted to the bone marrow that were preferentially invaded, whereas older Reticulocytes (CD71−), principally found in the peripheral blood, were rarely invaded. Invasion assays based on the CD71+ Reticulocyte fraction revealed substantial postinvasion modification. Thus, 3 to 6 hours after invasion, the initially biomechanically rigid CD71+ Reticulocytes convert into a highly deformable CD71− infected red blood cell devoid of host reticular matter, a process that normally spans 24 hours for uninfected Reticulocytes. Concurrent with these changes, clathrin pits disappear by 3 hours postinvasion, replaced by distinctive caveolae nanostructures. These 2 hitherto unsuspected features of P vivax invasion, a narrow preference for immature Reticulocytes and a rapid remodeling of the host cell, provide important insights pertinent to the pathobiology of the P vivax infection.
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significant biochemical biophysical and metabolic diversity in circulating human cord blood Reticulocytes
PLOS ONE, 2013Co-Authors: Benoit Malleret, Narla Mohandas, Rossarin Suwanarusk, Cindy S Chu, Juliana Almeida Leite, Kayen Low, Claudia Turner, Kanlaya Sriprawat, Rou ZhangAbstract:Background The transition from enucleated Reticulocytes to mature normocytes is marked by substantial remodeling of the erythrocytic cytoplasm and membrane. Despite conspicuous changes, most studies describe the maturing Reticulocyte as a homogenous erythropoietic cell type. While Reticulocyte staging based on fluorescent RNA stains such as thiazole orange have been useful in a clinical setting; these ‘sub-vital’ stains may confound delicate studies on Reticulocyte biology and may preclude their use in heamoparasite invasion studies.
Manoj T Duraisingh - One of the best experts on this subject based on the ideXlab platform.
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plasmodium vivax infection compromises Reticulocyte stability
Nature Communications, 2021Co-Authors: Martha A Clark, Carlo Brugnara, Usheer Kanjee, Anjali Mascarenhas, Gabriel W Rangel, Laura Chery, Edwin Gomes, Pradipsinh K Rathod, Marcelo U Ferreira, Manoj T DuraisinghAbstract:The structural integrity of the host red blood cell (RBC) is crucial for propagation of Plasmodium spp. during the disease-causing blood stage of malaria infection. To assess the stability of Plasmodium vivax-infected Reticulocytes, we developed a flow cytometry-based assay to measure osmotic stability within characteristically heterogeneous Reticulocyte and P. vivax-infected samples. We find that erythroid osmotic stability decreases during erythropoiesis and Reticulocyte maturation. Of enucleated RBCs, young Reticulocytes which are preferentially infected by P. vivax, are the most osmotically stable. P. vivax infection however decreases Reticulocyte stability to levels close to those of RBC disorders that cause hemolytic anemia, and to a significantly greater degree than P. falciparum destabilizes normocytes. Finally, we find that P. vivax new permeability pathways contribute to the decreased osmotic stability of infected-Reticulocytes. These results reveal a vulnerability of P. vivax-infected Reticulocytes that could be manipulated to allow in vitro culture and develop novel therapeutics. During Plasmodium intra-erythrocytic developmental, parasites compromise the structural integrity of host red-blood cells. Here, Clark et al. develop a flow cytometric osmotic stability assay to show that P. vivax infection destabilizes host Reticulocytes, which are less stable than P. falciparum-infected normocytes.
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molecular and cellular interactions defining the tropism of plasmodium vivax for Reticulocytes
Current Opinion in Microbiology, 2018Co-Authors: Usheer Kanjee, Martha A Clark, Gabriel W Rangel, Manoj T DuraisinghAbstract:Plasmodium vivax is uniquely restricted to invading Reticulocytes, the youngest of red blood cells. Parasite invasion relies on the sequential deployment of multiple parasite invasion ligands. Correct targeting of the host Reticulocyte is mediated by two families of invasion ligands: the Reticulocyte binding proteins (RBPs) and erythrocyte binding proteins (EBPs). The Duffy receptor has long been established as a key determinant for P. vivax invasion. However, recently, the RBP protein PvRBP2b has been shown to bind to transferrin receptor, which is expressed on Reticulocytes but lost on normocytes, implicating the ligand-receptor in the Reticulocyte tropism of P. vivax. Furthermore there is increasing evidence for P. vivax growth and sexual development in Reticulocyte-enriched tissues such as the bone marrow.
Rou Zhang - One of the best experts on this subject based on the ideXlab platform.
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plasmodium vivax restricted tropism and rapid remodeling of cd71 positive Reticulocytes
Blood, 2015Co-Authors: Benoit Malleret, Rossarin Suwanarusk, Cindy S Chu, Rou Zhang, Kevin S W Tan, Carla Claser, Jee Sun Cho, Esther G L KohAbstract:Plasmodium vivax merozoites only invade Reticulocytes, a minor though heterogeneous population of red blood cell precursors that can be graded by levels of transferrin receptor (CD71) expression. The development of a protocol that allows sorting Reticulocytes into defined developmental stages and a robust ex vivo P vivax invasion assay has made it possible for the first time to investigate the fine-scale invasion preference of P vivax merozoites. Surprisingly, it was the immature Reticulocytes (CD71+) that are generally restricted to the bone marrow that were preferentially invaded, whereas older Reticulocytes (CD71−), principally found in the peripheral blood, were rarely invaded. Invasion assays based on the CD71+ Reticulocyte fraction revealed substantial postinvasion modification. Thus, 3 to 6 hours after invasion, the initially biomechanically rigid CD71+ Reticulocytes convert into a highly deformable CD71− infected red blood cell devoid of host reticular matter, a process that normally spans 24 hours for uninfected Reticulocytes. Concurrent with these changes, clathrin pits disappear by 3 hours postinvasion, replaced by distinctive caveolae nanostructures. These 2 hitherto unsuspected features of P vivax invasion, a narrow preference for immature Reticulocytes and a rapid remodeling of the host cell, provide important insights pertinent to the pathobiology of the P vivax infection.
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significant biochemical biophysical and metabolic diversity in circulating human cord blood Reticulocytes
PLOS ONE, 2013Co-Authors: Benoit Malleret, Narla Mohandas, Rossarin Suwanarusk, Cindy S Chu, Juliana Almeida Leite, Kayen Low, Claudia Turner, Kanlaya Sriprawat, Rou ZhangAbstract:Background The transition from enucleated Reticulocytes to mature normocytes is marked by substantial remodeling of the erythrocytic cytoplasm and membrane. Despite conspicuous changes, most studies describe the maturing Reticulocyte as a homogenous erythropoietic cell type. While Reticulocyte staging based on fluorescent RNA stains such as thiazole orange have been useful in a clinical setting; these ‘sub-vital’ stains may confound delicate studies on Reticulocyte biology and may preclude their use in heamoparasite invasion studies.
Soo Hwan Pai - One of the best experts on this subject based on the ideXlab platform.
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Brief Communication: Erythropoietic Activities in Acute Leukemia and in Malignant Lymphoma
2003Co-Authors: Jong Weon Choi, Soo Hwan PaiAbstract:Abstract. Erythropoietic activities and immature Reticulocyte production were investigated in a total of 157 patients (81 men, 76 women, median age = 42 yr, range = 23 to 65 yr) with acute lymphoid leukemia (ALL, n = 31), acute myeloid leukemia (AML, n = 39), or non-Hodgkin’s lymphoma (NHL, n = 87), based on assays of the hemogram, red cell indices, Reticulocyte subpopulations, and intramedullary erythroid precursors. There were no significant differences in red blood cell (RBC) counts, blood hemoglobin levels, or erythroid precursors between ALL and AML patients. Reticulocytes in AML patients averaged 1.7 ± 0.8%, which was higher than in patients with ALL (0.8 ± 0.3%, p <0.01); the proportion of high-fluorescence Reticulocytes (HFR) averaged 4-fold higher in AML versus ALL (p <0.01) and the Reticulocyte maturity index (RMI) was higher in AML (20.8 ± 8.3 %) versus ALL (12.4 ± 6.5%, p <0.01). The RMI was higher in NHL patients with bone marrow (BM) involvement (15.6 ± 9.4%), compared to those without BM involvement (4.3 ± 2.1%, p <0.01). The proportion of HFR averaged 11-fold higher in NHL with BM involvement versus NHL without BM involvement. In summary, erythropoietic activity is significantly more active in patients with AML compared to ALL and in patients with NHL with BM involvement
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Associations between serum transferrin receptor concentrations and erythropoietic activities according to body iron status
2003Co-Authors: Jong Weon Choi, Soo Hwan PaiAbstract:Abstract. This study investigated the associations between serum transferrin receptor (sTfR) concentrations and erythropoietic activities during 3 stages of iron deficiency in humans. Serum iron markers, fluorescent intensity of Reticulocytes, and sTfR concentrations were measured in 227 prepubescent children, age 9 to 12 yr. Reticulocyte subpopulations were analyzed by flow cytometry and sTfR concentrations were measured by enzyme immunoassay. Mean values of middle-fluorescence Reticulocytes (MFR), Reticulocyte maturity index (RMI), and sTfR concentrations were significantly higher in iron-deficiency anemia subjects than in healthy controls. Reticulocyte subpopulations increased gradually, as body iron status diminished; the mean values of MFR and RMI in subjects with serum ferritin concentrations <4.0 µg/L were 3-fold higher than those in healthy controls (p <0.01). Correlation coefficients of MFR and RMI vs log ferritin values (r = 0.43 and r = 0.42) were higher than those of MFR and RMI vs sTfR concentrations (r = 0.24 and r = 0.27) in iron-deficiency anemia subjects. In summary, iron deficiency leads to increased production of immature Reticulocytes. Erythropoietic activity is more closely associated with log ferritin values than with sTf
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Reticulocyte subpopulations and Reticulocyte maturity index rmi rise as body iron status falls
American Journal of Hematology, 2001Co-Authors: Jong Weon Choi, Soo Hwan PaiAbstract:To investigate the influence of body iron status on Reticulocyte subpopulations and Reticulocyte maturity index (RMI), we measured serum iron markers, fluorescent intensity of Reticulocytes, and serum transferrin receptor (sTfR) concentrations in 374 females aged 14-19 years. Reticulocyte subpopulations were analyzed by flow cytometry, and sTfR concentration was measured by enzyme immunoassay. There were no significant differences in the values of Reticulocyte subpopulations and RMI between ferritin alone-depleted group and healthy controls. However, middle- and high-fluorescence Reticulocytes and RMI were significantly higher in both the serum iron- and serum ferritin-depleted groups than in the ferritin alone-depleted group. Middle-fluorescence Reticulocytes and RMI increased gradually as the body iron store was depleted and were 3.4- and 3.6-fold higher, respectively, than normal controls, when the subjects attained a frank iron-deficiency anemia. There were no significant changes in the values of red blood cells or total Reticulocyte counts during iron-depleted states. The mean value of sTfR (3.98 mg/l) in the subjects with RMI > or = 1.5% was significantly higher than that (2.26 mg/l) in the subjects with RMI < 1.5% (P < 0.01). The sTfR concentration correlated significantly with RMI (r = 0.61, P < 0.01) and middle-fluorescence Reticulocytes (r = 0.59, P < 0.01). In short, body iron depletion induces elevation of immature Reticulocyte fractions and RMI.