losartan-potassium and Malaria

Haemoglobin E-beta thalassaemia (Hb E/β-thalassaemia) is the genotype responsible for approximately one-half of all severe beta-thalassaemia worldwide. The disorder is characterized by marked clinical variability, ranging from a mild and asymptomatic anaemia to a life-threatening disorder requiring transfusions from infancy. The phenotypic variability of Hb E/β-thalassaemia and the paucity of long-term clinical data, present challenges in providing definitive recommendations for the optimal management of patients. Genetic factors influencing the severity of this disorder include the type of beta-thalassaemia mutation, the co-inheritance of alpha-thalassaemia, and polymorphisms associated with increased production of foetal haemoglobin. Other factors, including a variable increase in serum erythropoietin in response to anaemia, previous or ongoing infection with malaria, previous splenectomy and other environmental influences, may be involved. The remarkable variation, and the instability, of the clinical phenotype of Hb E beta-thalassaemia suggests that careful tailoring of treatment is required for each patient, and that therapeutic approaches should be re-assessed over-time.

Topics: alpha-Thalassemia; beta-Thalassemia; Blood Transfusion; Erythropoietin; Fetal Hemoglobin; Genotype; Hemoglobin E; Humans; Malaria; Phenotype; Polymorphism, Genetic; Splenectomy

Death from malaria occurs from the complications of the infection: cerebral manifestations leading to coma and a severe and refractory anemia leading to hypoxia and cardiac decompensation. Several mechanisms have been identified to play a role in the pathogenesis of malarial anemia, such as erythrocyte lysis and phagocytosis, and sequestration of parasitized red blood cells, but recent data indicate that these mechanisms (singly or in combination) do not adequately explain the severity of this anemia. By contrast, hematologic studies have shown that bone marrow suppression and ineffective erythropoiesis contribute importantly to the severe anemia of malaria infection. The host mechanisms responsible for suppression of erythropoiesis may involve an excessive or sustained innate immune response or a pathologic skewing of the T-cell differentiation response with the attendant production of certain proinflammatory cytokines. Experimental data also indicate that severe malarial anemia is associated with the immunologic expression of a circulating inhibitor of erythropoiesis that functionally antagonizes the action of erythropoietin. We review the clinical and experimental basis for these concepts and discuss ongoing experimental and genetic studies aimed at unraveling the molecular basis of this malaria-induced bone marrow suppression.

Topics: Adult; Anemia; Animals; Aotus trivirgatus; Bone Marrow; Child; Child, Preschool; Cytokines; Erythropoiesis; Erythropoietin; Genetic Predisposition to Disease; Heart Failure; Humans; Hypoxia; Infant; Inflammation Mediators; Malaria; Malaria Vaccines; T-Lymphocyte Subsets

It has been proposed that the basis of severe malarial anaemia, a major cause of morbidity and mortality in endemic areas, is multifactorial. Inappropriately low reticulocytosis is observed in malaria patients suggesting that insufficient erythropoiesis is a major factor. Clinical studies provide conflicting data concerning the production of adequate levels of erythropoietin (EPO) during malaria. Plasmodium chabaudi AS causes non-lethal infection in resistant C57BL/6 mice, and lethal infection in susceptible A/J mice. In P. chabaudi AS infected C57BL/6 and A/J mice, which experience varying degrees of severity of anaemia, kidney EPO production is appropriate to the severity of anaemia and is regulated by haematocrit level. Neutralisation of endogenous EPO during infection leads to lethal anaemia while timely administration of exogenous EPO rescues mice although reticulocytosis is suppressed in proportion to the parasitemia level. Characterisation of alterations in splenic erythroid compartments in naive and P. chabaudi AS infected A/J mice revealed that infection, with or without EPO treatment, leads to sub-optimal increases in TER119+ erythroblasts compared to EPO-treated naive mice. A lower percentage of TER119+ erythroblasts in infected mice undergo terminal differentiation to become mature haemoglobin-producing cells. Furthermore, there is a shift in transferrin receptor (CD71) expression from TER119+ cells to a non-erythroid population. Deficiencies in the number and maturation of TER119+ erythroblasts during infection coincide with blunted proliferation to EPO stimulation in vitro by splenocytes, although a high frequency express EPO receptor (EPOR). Together, these data suggest that during malaria, EPO-induced proliferation of early EPOR+ erythroid progenitors is suppressed, leading to sub-optimal generation of TER119+ erythroblasts. Moreover, a shift in CD71 expression may result in impaired terminal maturation of erythroblasts. Thus, suppressed proliferation, differentiation, and maturation of erythroid precursors in association with inadequate reticulocytosis may be the basis of insufficient erythropoiesis during malaria.

Topics: Anemia; Animals; Disease Models, Animal; Erythropoiesis; Erythropoietin; Humans; Kidney; Malaria; Mice; Reticulocytosis

In order to be transmitted by their mosquito vector, malaria parasites undergo sexual reproduction, which occurs between specialized male and female parasites (gametes) within the blood meal in the mosquito. Nothing was known about how Plasmodium determines the sex of its gametocytes (gamete precursors), which are produced in the vertebrate host. Recently, erythropoietin, the vertebrate hormone controlling erythropoiesis in response to anaemia, was implicated in Plasmodium sex determination in animal models of malaria. This review examines the available information and addresses the relevance of such a sex determining mechanism for Plasmodium falciparum transmission to mosquitoes, with special reference to low gametocytaemias.

Topics: Anemia; Animals; Chronic Disease; Culicidae; Environment; Erythropoietin; Female; Germ Cells; Humans; Malaria; Male; Plasmodium; Plasmodium falciparum; Sex Determination Processes; Sex Ratio

Topics: Adolescent; Adult; Anemia; Anemia, Hypochromic; Anemia, Megaloblastic; Animals; Child; Child, Preschool; Dapsone; Drug Combinations; Erythropoietin; Female; Hookworm Infections; Humans; Infant; Iron-Dextran Complex; Leishmaniasis, Visceral; Macaca mulatta; Malaria; Male; Mice; Middle Aged; Protein-Energy Malnutrition; Pyrimethamine; Schistosomiasis; Socioeconomic Factors; Tropical Medicine; Trypanosomiasis, African

Topics: Adenocarcinoma; Amidines; Anemia; Antimalarials; Clinical Trials as Topic; Colonic Neoplasms; Erythropoietin; Humans; Levamisole; Malaria; Mefloquine; Pentamidine; Pneumonia, Pneumocystis; Quinolines; Recombinant Proteins

Anaemia in pregnancy is common in underdeveloped countries, and malaria remains the predominant cause of the condition in Ghana. Anti-erythropoietin (anti-EPO) antibody production may be implicated in the pathogenesis of Plasmodium falciparum malaria-related anaemia in pregnancy. This study ascertained the prevalence of anti-EPO antibody production and evaluated the antibodies' relationship with Plasmodium falciparum malaria and malaria-related anaemia in pregnancy.. This hospital-based case-control study recruited a total of 85 pregnant women (55 with Plasmodium falciparum malaria and 30 controls without malaria). Venous blood was taken from participants for thick and thin blood films for malaria parasite microscopy. Complete blood count (CBC) analyses were done using an automated haematology analyzer. Sandwich enzyme-linked immunosorbent assay (ELISA) was used to assess serum erythropoietin (EPO) levels and anti-EPO antibodies. Data were analyzed using IBM SPSS version 22.0.. Haemoglobin (p<0.001), RBC (p<0.001), HCT (p = 0.006) and platelet (p<0.001) were significantly lower among pregnant women infected with Plasmodium falciparum. Of the 85 participants, five (5.9%) had anti-EPO antibodies in their sera, and the prevalence of anti-EPO antibody production among the Plasmodium falciparum-infected pregnant women was 9.1%. Plasmodium falciparum-infected pregnant women with anti-EPO antibodies had lower Hb (p<0.001), RBC (p<0.001), and HCT (p<0.001), but higher EPO levels (p<0.001). Younger age (p = 0.013) and high parasite density (p = 0.004) were significantly associated with Plasmodium falciparum-related anti-EPO antibodies production in pregnancy. Also, younger age (p = 0.039) and anti-EPO antibody production (p = 0.012) related to the development of Plasmodium falciparum malaria anaemia in pregnancy.. The prevalence of anti-EPO antibodies among pregnant women with Plasmodium falciparum malaria was high. Plasmodium falciparum parasite density and younger age could stimulate the production of anti-EPO antibodies, and the antibodies may contribute to the development of malarial anaemia in pregnancy. Screening for anti-EPO antibodies should be considered in pregnant women with P. falciparum malaria.

Topics: Anemia; Case-Control Studies; Erythropoietin; Female; Ghana; Humans; Malaria; Malaria, Falciparum; Plasmodium falciparum; Pregnancy; Pregnant Women

Fetal anemia is common in malaria-endemic areas and a risk factor for anemia as well as mortality during infancy. Placental malaria (PM) and red cell abnormalities have been proposed as possible etiologies, but the relationship between PM and fetal anemia has varied in earlier studies, and the role of red cell abnormalities has not been studied in malaria-endemic areas. In a Tanzanian birth cohort study designed to elucidate the pathogenesis of severe malaria in young infants, we performed a cross-sectional analysis of risk factors for fetal anemia. We determined PM status, newborn red cell abnormalities, and maternal and cord blood levels of iron regulatory proteins, erythropoietin (EPO), cytokines and cytokine receptors. We examined the relationship between these factors and fetal anemia. Fetal anemia was present in 46.2% of the neonates but was not related to PM. Maternal iron deficiency was common (81.6%), most frequent in multigravidae, and interacted with parity to modify risk of fetal anemia, but it was not directly related to risk. Among offspring of iron-deficient women, the odds of fetal anemia increased with fetal α

Topics: Adult; alpha-Thalassemia; Anemia; Biomarkers; Cross-Sectional Studies; Cytokines; Erythropoietin; Female; Fetal Diseases; Fetus; Hemoglobins; Humans; Infant, Newborn; Iron; Iron Deficiencies; Malaria; Male; Maternal Health; Parity; Placenta; Pregnancy; Pregnancy Complications, Parasitic; Risk Assessment; Risk Factors; Tanzania; Transferrin; Young Adult

The pathophysiology of malarial anemia is multifactorial and incompletely understood. We assessed mechanistic and risk factors for post-malarial anemia in Ghanaian and Gabonese children with severe P. falciparum malaria treated with parenteral artesunate followed by an oral artemisinin-combination therapy. We analyzed data from two independent studies in which children were followed on Days 7,14, and 28 after treatment with artesunate. Specific hematological parameters included the presence of hemoglobinopathies and erythropoietin. Presence of once-infected erythrocytes was assessed by flow cytometry in a sub-population. Of 143 children with a geometric mean parasitemia of 116,294/µL (95% CI: 95,574-141,505), 91 (88%) had anemia (Hb < 10 g/dL) at presentation. Hemoglobin increased after Day 7 correlating with increased erythropoiesis through adequate erythropoietin stimulation. 22 children (24%) remained anemic until Day 28. Post-artesunate delayed hemolysis was detected in 7 children (5%) with only minor differences in the dynamics of once-infected erythrocytes. Hyperparasitemia and hemoglobin at presentation were associated with anemia on Day 14. On Day 28 only lower hemoglobin at presentation was associated with anemia. Most children showed an adequate erythropoiesis and recovered from anemia within one month. Post-artesunate delayed hemolysis (PADH) and hyperparasitemia are associated with early malarial anemia and pre-existing anemia is the main determinant for prolonged anemia.

Topics: Anemia; Antimalarials; Artesunate; Blood Transfusion; Child; Child, Preschool; Erythropoietin; Female; Humans; Infant; Infusions, Parenteral; Malaria; Male; Parasitemia

The pathophysiology of malaria-related anaemia is not fully understood although increased destruction of parasitized and nonparasitized erythrocytes, as well as inadequate erythropoiesis, has been proposed. Circulating antierythropoietin (anti-EPO) antibodies have also been implicated in malaria and malaria-related anaemia in mice. However, studies on this association have not been investigated in humans. This study therefore determined the prevalence of anti-EPO antibody production and assessed its association with malaria and malaria-related anaemia in humans.. A total of 86 children aged 1-10 years (57 children with malaria serving as the case group and 29 healthy children serving as control), all residents of Duayaw Nkwanta, Ghana, were recruited for this case-control study. Venous blood was collected for thick and thin films for malaria microscopy, full blood count by automated haematology analyzer, and antierythropoietin antibody and erythropoietin estimation by sandwich ELISA method.. Out of the 86 participants recruited, only 3 (3.5%) were positive for anti-EPO antibody; 2.3% of the case group; and 1.2% of the control group. There was no association between the cases and the controls in the production of anti-EPO antibodies. Erythropoietin concentration was significantly higher in malaria-related anaemic subjects (p=0.032).. Antierythropoietin antibodies are not associated with malaria infection and malaria-related anaemia in humans. Erythropoietin concentration is associated with malaria-related anaemia.

Topics: Anemia; Autoantibodies; Child; Child, Preschool; Erythropoietin; Female; Humans; Infant; Malaria; Male

Malaria patients frequently develop severe anaemia that can persist after Plasmodium infection has been cleared from the circulation. This puzzling phenomenon involves massive death of young uninfected erythrocytes at a time when parasitic infection is very low. We have observed striking similarities in erythrocyte homoeostasis during altitude acclimatisation and Plasmodium infection, both of which initially induce an increase in circulating erythropoietin (Epo). Decreasing levels of Epo after return to low altitudes induce the death of young erythrocytes, a phenomenon called neocytolysis. In a similar way, we propose that Epo, which peaks during acute malaria and decreases after parasite clearance, could be contributing to anaemia causing neocytolysis during recovery from Plasmodium infection.

Topics: Acclimatization; Altitude; Anemia; Cell Death; Erythrocytes; Erythropoietin; Homeostasis; Humans; Malaria; Plasmodium

Malaria continues to be a global health challenge, affecting more than half the world's population and causing approximately 660,000 deaths annually. The majority of malaria cases are caused by Plasmodium falciparum and occur in sub-Saharan Africa. One of the major complications asscociated with malaria is severe anaemia, caused by a cycle of haemoglobin digestion by the parasite. Anaemia due to falciparum malaria in children has multifactorial pathogenesis, which includes suppression of bone marrow activity. Recent studies have shown that haemozoin, which is a by-product of parasite haemoglobin digestion, may play an important role in suppression of haemoglobin production, leading to anaemia. In this study we correlated the levels of erythropoietin (EPO), as an indicator of stimulation of haemoglobin production, to the levels of monocyte acquired haemozoin in children with both severe and uncomplicated malaria. There was a significantly negative correlation between levels of haemozoin-containing monocytes and EPO, which may suggest that haemozoin suppresses erythropoiesis in severe malaria. A multiple linear regression analysis and simple bar was used to investigate associations between various haematological parameters.. To examine the levels of erythropoietin in the age categories, the levels of erythropoietin was measured using a commercial Enyme-Linked Immunosorbent Assay (ELISA). Giemsa-stained blood smears were used to determine percentage pigment containing monocytes. The haemozoin containing monocytes was expressed as a percentage of the total number of monocytes. To obtain the number of haemozoin containing monocytes/μL the percentage of haemozoin containing monocytes was multiplied by the absolute number of monocytes/μL from the automated haematology analyzer.. The levels of erythropoietin in younger children (<3 years) was significantly higher than in older children with a similar degree of malaria anaemia (Hb levels) (p < 0.005). Haemozoin-containing monocytes were relatively higher in severe malaria anaemia patients compared to those with uncomplicated malaria (p < 0.001).. Age purportedly has a direct effect on background levels of erythropoietin. With corresponding decreased levels of erythropoietin in older children with the same degree of severe malarial anaemia, conceivably, the bone marrows of younger children with acute malaria may be less sensitive to erythropoietin.

Topics: Age Factors; Anemia; Child; Erythropoietin; Ghana; Hemeproteins; Humans; Malaria; Monocytes

Severe malaria, a leading cause of mortality among children and nonimmune adults, is a multisystemic disorder characterized by complex clinical syndromes that are mechanistically poorly understood. The interplay of various parasite and host factors is critical in the pathophysiology of severe malaria. However, knowledge regarding the pathophysiological mechanisms and pathways leading to the multisystemic disorders of severe malaria in humans is limited. Here, we systematically investigate infections with Plasmodium coatneyi, a simian malaria parasite that closely mimics the biological characteristics of P. falciparum, and develop baseline data and protocols for studying erythrocyte turnover and severe malaria in greater depth. We show that rhesus macaques (Macaca mulatta) experimentally infected with P. coatneyi develop anemia, coagulopathy, and renal and metabolic dysfunction. The clinical course of acute infections required suppressive antimalaria chemotherapy, fluid support, and whole-blood transfusion, mimicking the standard of care for the management of severe malaria cases in humans. Subsequent infections in the same animals progressed with a mild illness in comparison, suggesting that immunity played a role in reducing the severity of the disease. Our results demonstrate that P. coatneyi infection in rhesus macaques can serve as a highly relevant model to investigate the physiological pathways and molecular mechanisms of malaria pathogenesis in naïve and immune individuals. Together with high-throughput postgenomic technologies, such investigations hold promise for the identification of new clinical interventions and adjunctive therapies.

Topics: Anemia; Animals; Blood Coagulation; Bone Marrow Diseases; Disease Models, Animal; Erythropoiesis; Erythropoietin; Macaca mulatta; Malaria; Male; Monkey Diseases; Plasmodium; Random Allocation; Time Factors

Malaria anaemia is still a major public health problem and its pathogenesis still unclear. Interestingly, the progression of anaemia is at relatively low parasitaemia with some mortality in the semi-immune individuals in the endemic areas despite adequate erythropoietin (EPO) synthesis. A recent study has shown that treatment with exogenous anti-erythropoietin (anti-EPO) antibodies (Ab) of infected mice gives protection against malaria infection, suggesting an important role for anti-EPO Ab in malaria. The objective of the study was to evaluate anti-EPO antibody levels in anaemic condition of different strains of semi-immune mice with malaria.. Semi-immune status was attained in four mice strains (Balb/c, B6, CBA and NZW) by repeated infections with 10⁴Plasmodium berghei ANKA, and treatment with chloroquine/pyrimethamine. ELISA was used to measure anti-EPO Ab, transferrin and EPO while inflammatory cytokines measurement was done using bead-based multiplex assay kit.. The mean anti-EPO Ab levels in the mice strains [Optical Density (OD) values at 450 nm: Balb/c (2.1); B6 (1.3); CBA (1.4) and NZW (1.7)] differed (p = 0.045), and were significantly higher when compared with uninfected controls, p < 0.0001, and mean anti-EPO Ab levels in the mice strains at recovery [OD values at 450 nm: Balb/c (1.8); B6 (1.1); CBA (1.5) and NZW (1.0) also differed (p = 0.0004). Interestingly, EPO levels were significantly high in NZW and low in Balb/c mice (p < 0.05), with those of B6 and CBA of intermediary values. Again, NZW were highly parasitaemic (20.7%) and the other strains (Balb/c, B6 and CBA) ranged between 2.2-2.8% (p = 0.015). Anti-EPO Ab correlated positively with extent of Hb loss (r = 0.5861; p = 0.003). Correlation of anti-EPO antibody with EPO was significant only in Balb/c mice (r = -0.83; p = 0.01). Significant levels of IL6 and IFNγ (p < 0.0001), both known to be associated with erythropoiesis suppression were observed in the Balb/c. Transferrin was significantly lower in Balb/c (p < 0.0001) when compared with the other mice strains (B6, CBA and NZW).. This is the first ever report in estimating endogenous anti-EPO antibodies in malaria anaemia. The data presented here suggest that anti-EPO Ab is produced at infection and is associated with Hb loss. Host factors appear to influence anti-EPO antibody levels in the different strains of mice.

Topics: Anemia; Animals; Autoantibodies; Disease Models, Animal; Erythropoietin; Malaria; Mice; Plasmodium berghei

One of the commonest complications of Plasmodium falciparum malaria is the development of severe malarial anemia (SMA), which is, at least in part, due to malaria-induced suppression of erythropoiesis. Factors associated with suppression of erythropoiesis and development of SMA include accumulation of malarial pigment (hemozoin, PfHz) in bone marrow and altered production of inflammatory mediators, such as tumor necrosis factor (TNF)-α, and nitric oxide (NO). However, studies investigating the specific mechanisms responsible for inhibition of red blood cell development have been hampered by difficulties in obtaining bone marrow aspirates from infants and young children, and the lack of reliable models for examining erythroid development. As such, an in vitro model of erythropoiesis was developed using CD34+ stem cells derived from peripheral blood to examine the effects of PfHz, PfHz-stimulated peripheral blood mononuclear cell (PBMC)-conditioned media (CM-PfHz), TNF-α, and NO on erythroid cell development. PfHz only slightly suppressed erythroid cell proliferation and maturation marked by decreased expression of glycophorin A (GPA). On the other hand, CM-PfHz, TNF-α, and NO significantly inhibited erythroid cell proliferation. Furthermore, decreased proliferation in cells treated with CM-PfHz and NO was accompanied by increased apoptosis of erythropoietin-stimulated CD34+ cells. In addition, NO significantly inhibited erythroid cell maturation, whereas TNF-α did not appear to be detrimental to maturation. Collectively, our results demonstrate that PfHz suppresses erythropoiesis by acting both directly on erythroid cells, and indirectly via inflammatory mediators produced from PfHz-stimulated PBMC, including TNF-α and NO.

Topics: Anemia; Antigens, CD34; Apoptosis; Cell Proliferation; Cells, Cultured; Culture Media, Conditioned; Erythropoiesis; Erythropoietin; Glycophorins; Hematopoietic Stem Cells; Hemeproteins; Humans; Inflammation Mediators; Leukocytes, Mononuclear; Malaria; Malaria, Falciparum; Nitric Oxide; Nitric Oxide Donors; Pigments, Biological; Recombinant Proteins; Tumor Necrosis Factor-alpha

Malaria infection leads to anemia in humans which generally occurs during the chronic phase of the infection. The role that erythropoietic molecules play for anemia during malaria at low parasitemia levels is still controversial due to the lack of suitable animal models which might mimic this condition. In this regard, α-tocopherol transfer protein knockout mice, with undetectable levels of vitamin E in circulation, were possibly used as a model to investigate the role that erythropoietic molecules such as erythropoietin (EPO), erythropoietin receptor (EPOR), and macrophage migration inhibitory factor (MIF) play on the outcome of anemia during uncomplicated malaria infection at low parasitemias. The results indicate that the degree of parasitemia unlikely plays any important effect on mRNA expression of EPO and EPOR in different organs. Moreover, even though EPO and EPOR productions are impaired in the kidney and bone marrow, respectively, other organs such as the liver and spleen intend to compensate production of these cytokines to prevent anemia in the infected animals.

Topics: Anemia; Animals; Carrier Proteins; Erythropoietin; Gene Knockout Techniques; Malaria; Mice; Mice, Inbred C57BL; Mice, Knockout; Parasitemia; Plasmodium berghei; Receptors, Erythropoietin

Severe malaria is difficult to differentiate from other forms of malaria or other infections with similar symptoms. Any parameter associated to malaria-attributable severe disease could help to improve severe malaria diagnosis.. This study assessed the relation between erythropoietin (EPO) and malaria-attributable severe disease in an area of Mozambique with moderate malaria transmission. 211 children <5 years, recruited at Manhiça District Hospital or in the surrounding villages, were included in one of the following groups: severe malaria (SM, n = 44), hospital malaria without severity (HM, n = 49), uncomplicated malaria (UM, n = 47), invasive bacterial infection without malaria parasites (IBI, n = 39) and healthy community controls (C, n = 32). Malaria was diagnosed by microscopy and IBI by blood/cerebrospinal fluid culture.. Mean EPO concentration in the control group was 20.95 U/l (SD = 2.96 U/l). Values in this group were lower when compared to each of the clinical groups (p = 0.026 C versus UM, p<0.001 C vs HM, p<0.001 C vs SM and p<0.001 C vs IBI). In the 3 malaria groups, values increased with severity [mean = 40.82 U/l (SD = 4.07 U/l), 125.91 U/l (SD = 4.99U/l) and 320.87 U/l (SD = 5.91U/l) for UM, HM and SM, respectively, p<0.001]. The IBI group [mean = 101.75 U/l (SD = 4.12 U/l)] presented lower values than the SM one (p = 0.002). In spite of the differences, values overlapped between study groups and EPO levels were only associated to hemoglobin. Hemoglobin means of the clinical groups were 93.98 g/dl (SD = 14.77 g/dl) for UM, 75.96 g/dl (SD = 16.48 g/dl) for HM, 64.34 g/dl (SD = 22.99 g/dl) for SM and 75.67 g/dl (SD = 16.58 g/dl) for IBI.. Although EPO levels increase according to malaria severity and are higher in severe malaria than in bacteremia, the utility of EPO to distinguish malaria-attributable severe disease is limited due to the overlap of values between the study groups and the main role of hemoglobin in the expression of EPO.

Topics: Bacteremia; Bilirubin; Child, Preschool; Diagnosis, Differential; Erythropoietin; Female; Hemoglobins; Hemolysis; Humans; Infant; L-Lactate Dehydrogenase; Malaria; Male; Mozambique

Topics: Enzyme Inhibitors; Erythropoietin; Fetal Hemoglobin; Humans; Iron; Malaria; Ribonucleotide Reductases

The extent to which the acute phase response (APR) influences iron status indicators in chronic infections is not well documented. We investigated this relationship using reported recent fever and 2 acute phase proteins (APP), C-reactive protein (CRP), and alpha-1-acid glycoprotein (AGP). In a sample of 690 children matched on age and helminth infection status at baseline, we measured plasma for AGP, CRP, ferritin, transferrin receptor (TfR), and erythropoietin (EPO) and whole blood for hemoglobin (Hb) concentration, zinc protoporphyrin (ZPP), and malaria parasite density, and we obtained maternal reports of recent fever. We then examined the influence of the APR on each iron status indicator using regression analysis with Hb as the outcome variable. Ferritin was inversely related to Hb in the APR-unadjusted model. Adjusting for the APR using reported recent fever alone was not sufficient to reverse the inverse Hb-ferritin relationship. However, using CRP and/or AGP resulted in the expected positive relationship. The best fit model included reported recent fever, AGP and CRP (R(2) = 0.241; P < 0.001). The best fit Hb-ZPP, Hb-TfR, and Hb-EPO models included reported recent fever and AGP but not CRP (R(2) = 0.253, 0.310, and 0.292, respectively; P < 0.001). ZPP, TfR, and EPO were minimally influenced by the APR, whereas ferritin was immensely affected. Reported recent fever alone cannot be used as a marker for the APR. Either AGP or CRP is useful for adjusting if only 1 APP can be measured. However, AGP best predicted the APR in this population.

Topics: Acute-Phase Proteins; Appetite; C-Reactive Protein; Clinical Trials as Topic; Erythropoietin; Female; Ferritins; Helminthiasis; Hemoglobins; Humans; Infant; Iron; Iron, Dietary; Malaria; Male; Orosomucoid; Tanzania

Although it is almost certain that alpha(+)-thalassemia protects against malaria, the mechanisms for that are still unknown. It has been suggested that an increased number of young circulating red blood cells in alpha(+)-thalassemic children, as a result of some degree of ineffective erythropoiesis, could be related to the high frequencies of the alpha(+)-thalassemic allele in malaria endemic areas. Reticulocyte evaluation in this condition, however, has been poorly performed so far. Our objective was to determine the reticulocyte number and maturation degree, in addition to the soluble transferrin receptor and serum erythropoietin levels, in alpha(+)-thalassemia heterozygotes, comparing them with normal alpha-genotype controls. One hundred twenty-one alpha(+)-thalassemia carriers (-alpha(3.7)/alphaalpha) and 249 controls (alphaalpha/alphaalpha), all of them with normal serum ferritin levels, were subclassified according to age (1-5, 6-10, 11-15, 16-20, and over 20 years old). Reticulocyte analyzes were carried out by flow cytometry and sTfR and s-Epo levels determined by immunonephelometry and chemiluminescence, respectively. The comparisons did not show any significant difference between thalassemics and controls regarding the reticulocyte parameters [percentages and absolute values, P = 0.2643 and 0.5421; high, medium, and low maturation degree, P = 0.2579, 0.2196, and 0.4192; RET maturity index (RMI), P = 0.2471, respectively], as well as the s-Epo levels (P = 0.5711). The sTfR concentrations were higher in the thalassemic group (P = 0.0001), but statistical significance was due only to the 1-5 and over 20 subgroups (P = 0.0082 and 0.0436, respectively). The results found here are compatible with a compensated erythropoiesis and do not confirm the hypothesis mentioned above.

Topics: Adolescent; Adult; alpha-Thalassemia; Brazil; Child; Child, Preschool; Erythropoiesis; Erythropoietin; Female; Ferritins; Flow Cytometry; Heterozygote; Humans; Infant; Malaria; Male; Nephelometry and Turbidimetry; Receptors, Transferrin; Reticulocyte Count; Reticulocytes

Cerebral involvement during malaria is a complication that leads to seizure, coma, and death. The effect of new neuroprotective therapies has not yet been investigated, although cerebral malaria shares some features with neurological stroke. Erythropoietin (EPO) is one of the more promising drugs in this area. We measured the effect of EPO on the survival of mice infected with Plasmodium berghei ANKA and demonstrated that inoculations of recombinant human EPO at the beginning of the clinical manifestations of cerebral malaria protect >90% of mice from death. This drug has no effect on the course of parasitemia. The effect of EPO was not related to either the inhibition of apoptosis in the brain or the regulation of the increase and decrease of nitric oxide production in the brain and blood, respectively. Tumor necrosis factor-alpha and interferon-gamma mRNA overexpression was inhibited by EPO, and treated mice had fewer brain hemorrhages. EPO has been used in patients with chronic diseases for years, and more recently it has been used to treat acute ischemic stroke. The data presented here provide the first evidence indicating that this cytokine could be useful for the symptomatic prevention of mortality during the acute stage of cerebral malaria.

Topics: Animals; Apoptosis; Brain; Disease Models, Animal; Erythropoietin; Female; Gene Expression; Interferon-gamma; Malaria; Malaria, Cerebral; Mice; Neuroprotective Agents; Nitric Oxide; Parasitemia; Plasmodium berghei; Recombinant Proteins; RNA, Messenger; Survival Analysis; Tumor Necrosis Factor-alpha

Malaria and other haemosporin parasites must undergo a round of sexual reproduction in their insect vector in order to produce stages that can be transmitted to vertebrate hosts. Consequently, it is crucial that parasites produce the sex ratio (proportion of male sexual stages) that will maximize the number of fertilization and thus, transmission to new vertebrate hosts. There is some evidence to show that, consistent with evolutionary theory, the sex ratios of malaria parasites are negatively correlated to their inbreeding rate. However, recent theory has shown that when fertilization success is compromised, parasites should respond by increasing their investment in sexual stages or by producing a less female biased ration than predicted by their inbreeding rate alone. Here, we show that two species of rodent malaria, Plasmodium chabaudi and Plasmodium vinckei petteri, adopt different strategies in response to host anaemia, a factor though to compromise transmission success: P. chabaudi increases investment in sexual stages, whereas P. vinckei produces a less female biased sex ratio. We suggest that these different transmission strategies may be due to marked differences in host cell preference.

Topics: Anemia; Animals; Erythropoietin; Female; Fertility; Inbreeding; Malaria; Male; Mice; Mice, Inbred Strains; Plasmodium; Rodent Diseases; Sex Ratio; Species Specificity

Although maternal anaemia often stems from malaria infection during pregnancy, its effects on foetal haemoglobin levels are not straightforward. Lower-than-expected cord haemoglobin values in malarious versus non-malarious regions were noted by one review, which hypothesized they resulted from foetal immune activation to maternal malaria. This study addressed this idea by examining cord haemoglobin levels in relation to maternal malaria, anaemia, and markers of foetal immune activation.. Cord haemoglobin levels were examined in 32 malaria-infected and 58 uninfected women in Blantyre, Malawi, in relation to maternal haemoglobin levels, malaria status, and markers of foetal haematological status, hypoxia, and inflammation, including TNF-alpha, TGF-beta, and ferritin. All women were HIV-negative.. Although malaria was associated with a reduction in maternal haemoglobin (10.8 g/dL vs. 12.1 g/dL, p < 0.001), no reduction in cord haemoglobin and no significant relationship between maternal and cord haemoglobin levels were found. Cord blood markers of haematological and hypoxic statuses did not differ between malaria-infected and uninfected women. Maternal malaria was associated with decreased TGF-beta and increased cord ferritin, the latter of which was positively correlated with parasitaemia (r = 0.474, p = 0.009). Increased cord ferritin was associated with significantly decreased birth weight and gestational length, although maternal and cord haemoglobin levels and malaria status had no effect on birth outcome.. In this population, cord haemoglobin levels were protected from the effect of maternal malaria. However, decreased TGF-beta and elevated ferritin levels in cord blood suggest foetal immune activation to maternal malaria, which may help explain poor birth outcomes.

Topics: Adolescent; Adult; Cohort Studies; Erythropoietin; Female; Ferritins; Fetal Blood; Hemoglobins; Humans; Infant, Newborn; Malaria; Malawi; Parasitemia; Placenta Diseases; Pregnancy; Pregnancy Complications, Parasitic

We have previously reported that erythropoiesis commences in the liver and spleen after malarial infection, and that newly generated erythrocytes in the liver are essential for infection of malarial parasites as well as continuation of infection. At this time, erythropoietin (EPO) is elevated in the serum. In the present study, we administered EPO or anti-EPO antibody into C57BL/6 (B6) mice to modulate the serum level of EPO. When mice were infected with a non-lethal strain (17NXL) of Plasmodium yoelii (blood-stage infection of 10(4) parasitized erythrocytes per mouse), parasitemia continued for 1 month, showing a peak at day 17. Daily injection of EPO (200 IU/day per mouse) from day five to day 14 prolonged parasitemia, whereas injection of anti-EPO antibody (1.5 mg/day per mouse) every second day from day five to day 28 decreased it. Erythropoiesis was confirmed in the liver, spleen and bone marrow by the appearance of nucleated erythrocytes (TER119+). When anti-EPO antibody was injected by the same protocol into mice infected with a lethal strain (17XL) of P. yoelii, all mice showed decreased parasitemia and recovered from the infection. These results suggest that the use of anti-EPO antibody after malarial infection may be of therapeutic value in severe cases of malaria.

Topics: Animals; Antibodies; Erythropoiesis; Erythropoietin; Humans; Immunotherapy; Liver; Malaria; Mice; Mice, Inbred C57BL; Plasmodium yoelii

Inappropriately low reticulocytosis may exacerbate malarial anemia, but the under-lying mechanism is not clear. In this study, naive and infected mice were treated with recombinant murine erythropoietin (EPO), and the upstream events of erythropoiesis affected by blood-stage Plasmodium chabaudi AS were investigated. Malaria infection, with or without EPO treatment, led to a suboptimal increase in TER119(+) erythroblasts compared with EPO-treated naive mice. Furthermore, a lower percentage of TER119(+) erythroblasts in infected mice were undergoing terminal differentiation to become mature hemoglobin-producing erythroblasts. The impaired maturation of erythroblasts during infection was associated with a shift in the transferrin receptor (CD71) expression from the TER119(+) population to B220(+) population. Moreover, the suboptimal increase in TER119(+) erythroblasts during infection coincided with a blunted proliferative response by splenocytes to EPO stimulation in vitro, although a high frequency of these splenocytes expressed EPO receptor (EPOR). Taken together, these data suggest that during malaria, EPO-induced proliferation of early EPOR-positive erythroid progenitors is suppressed, which may lead to a suboptimal generation of TER119(+) erythroblasts. The shift in CD71 expression may result in impaired terminal maturation of these erythroblasts. Thus, inadequate reticulocytosis during malaria is associated with suppressed proliferation, differentiation, and maturation of erythroid precursors.

Topics: Anemia; Animals; Cell Differentiation; Cell Division; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Leukocyte Common Antigens; Malaria; Male; Mice; Mice, Inbred Strains; Plasmodium chabaudi; Receptors, Transferrin; Recombinant Proteins; Reticulocytosis; Spleen

Severe anemia is a major life-threatening complication of malaria. The roles of erythropoietin (Epo) and erythropoiesis during blood-stage malaria were investigated. By treating Plasmodium chabaudi AS-infected C57BL/6 (B6) mice, which are resistant to malaria, with polyclonal anti-human Epo neutralizing antibody, we demonstrated that Epo-induced reticulocytosis was important for alleviating malarial anemia and for host survival. By inducing erythropoiesis in A/J mice, which are susceptible to malaria, and in B6 mice at various periods during infection, by use of exogenous recombinant murine Epo, untimely onset of reticulocytosis was shown to augment multiplication of parasites and result in lethal infection. However, timely inducement of reticulocytosis with Epo treatment alleviated malarial anemia and increased survival. Our data reveal the important role of Epo-induced reticulocytosis in modulating the course and outcome of blood-stage malaria. However, the mechanisms underlying the increased mortality associated with untimely treatment with Epo and the increased protection associated with timely treatment with Epo remain to be investigated.

Topics: Animals; Disease Models, Animal; Disease Susceptibility; Epoetin Alfa; Erythropoietin; Malaria; Male; Mice; Mice, Inbred A; Mice, Inbred C57BL; Plasmodium chabaudi; Recombinant Proteins; Reticulocytosis; Treatment Outcome

Renal dysfunction and severe anemia are clinical complications of blood-stage malaria. Erythropoietin (Epo) is a hormone produced by the kidney and plays an essential role in stimulating erythrocyte production. Renal dysfunction in malaria is associated with changes in renal cytokine levels, which may affect the production of Epo and the alleviation of anemia.. Resistant C57BL/6 (B6) and susceptible A/J mice were infected with Plasmodium chabaudi AS. The levels of Epo and cytokines were measured by enzyme-linked immunosorbent assay (ELISA) and the degree of anemia was determined by hematocrit. Regression analyses were employed to estimate the influences of anemia and renal cytokines on the production of Epo during infection.. A/J mice developed higher peak parasitemia, more severe anemia, and succumbed as compared to B6 mice, which survived the infection. B6 mice had higher levels of renal tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-10, whereas A/J mice had higher levels of IL-12p70, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4, and Epo. Regression analyses revealed that kidney Epo levels were influenced most strongly by changes in hematocrit levels. In addition, albeit to a much weaker degree, kidney Epo levels correlated negatively with GM-CSF levels but positively with IL-10 levels.. Blood-stage malaria infection modulates the production of renal pro- and anti-inflammatory cytokines in resistant versus susceptible strains of mice differentially. However, despite the fluctuations of renal cytokines, the degree of anemia is the main determinant for Epo production during blood-stage malaria while kidney cytokines may exert secondary influences.

Topics: Anemia; Animals; Cytokines; Erythropoietin; Female; Humans; Interleukin-10; Interleukin-12; Interleukin-4; Kidney; Malaria; Male; Mice; Mice, Inbred A; Mice, Inbred C57BL; Plasmodium chabaudi; Protein Subunits; Species Specificity; Tumor Necrosis Factor-alpha

A highly sensitive sandwich ELISA specific for murine erythropoietin (mEpo) was developed using commercially available monoclonal anti-mouse Epo antibody and polyclonal anti-human Epo antibody. This newly developed Epo ELISA protocol and the traditional Epo bioassay method were used to analyze Epo production in response to anemia induced during blood-stage Plasmodium chabaudi AS (P. chabaudi AS) malaria infection in C57BL/6 mice. Both methods revealed an inverse correlation between the serum Epo concentration and hematocrit level, but Epo values estimated by the Epo bioassay were between 5- and 20-fold higher than those estimated by the ELISA. Further study demonstrated that the estimated Epo level in bioassay was strongly influenced by other cytokines present in the samples. Therefore, the Epo bioassay detects the net erythropoiesis promoting activities, whereas the ELISA method specifically measures the level of Epo in the samples. Combined with the Epo bioassay, the murine Epo ELISA will be an extremely useful tool in specifically measuring the Epo response and facilitating the understanding of mechanisms involved in the development of anemia-associated diseases using mouse models.

Topics: Anemia; Animals; Biological Assay; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Malaria; Male; Mice; Mice, Inbred C57BL; Plasmodium chabaudi; Sensitivity and Specificity

A century ago, W. G. MacCallum identified distinct male and female forms in malaria parasites of both birds and humans. Since then, scientists have been puzzled by the high female-to-male ratios of parasites in Plasmodium infections and by the mechanism of sex determination. The sex ratio of malaria parasites was shown to become progressively more male as conditions that allow motility and subsequent fertilization by the male parasites become adverse. This resulted from an increased immune response against male gametes, which coincides with intense host erythropoietic activity. Natural and artificial induction of erythropoiesis in vertebrate hosts provoked a shift toward male parasite production. This change in parasite sex ratio led to reduced reproductive success in the parasite, which suggests that sex determination is adaptive and is regulated by the hematologic state of the host.

Topics: Aedes; Animals; Chickens; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Malaria; Malaria, Avian; Male; Mice; Plasmodium; Plasmodium gallinaceum; Recombinant Proteins; Reproduction; Reticulocytes; Sex Determination Processes; Sex Ratio

Human falciparum malaria, caused by Plasmodium falciparum infection, results in 1 to 2 million deaths per year, mostly children under the age of 5 years. The two main causes of death are severe anemia and cerebral malaria. Malarial anemia is characterized by parasite red blood cell (RBC) destruction and suppression of erythropoiesis (the mechanism of which is unknown) in the presence of a robust host erythropoietin response. The production of a host-derived erythropoiesis inhibitor in response to parasite products has been implicated in the pathogenesis of malarial anemia. The identity of this putative host factor is unknown, but antibody neutralization studies have ruled out interleukin-1beta, tumor necrosis factor alpha, and gamma interferon while injection of interleukin-12 protects susceptible mice against lethal P. chabaudi infection. In this study, we report that ingestion of P. chabaudi-infected erythrocytes or malarial pigment (hemozoin) induces the release of macrophage migration inhibitory factor (MIF) from macrophages. MIF, a proinflammatory mediator and counter-regulator of glucocorticoid action, inhibits erythroid (BFU-E), multipotential (CFU-GEMM), and granulocyte-macrophage (CFU-GM) progenitor-derived colony formation. MIF was detected in the sera of P. chabaudi-infected BALB/c mice, and circulating levels correlated with disease severity. Liver MIF immunoreactivity increased concomitant with extensive pigment and parasitized RBC deposition. Finally, MIF was elevated three- to fourfold in the spleen and bone marrow of P. chabaudi-infected mice with active disease, as compared to early disease, or of uninfected controls. In summary, the present results suggest that MIF may be a host-derived factor involved in the pathophysiology of malaria anemia.

Topics: Anemia; Animals; Bone Marrow; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Immunohistochemistry; Leukopoiesis; Liver; Macrophage Migration-Inhibitory Factors; Macrophages; Malaria; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Plasmodium chabaudi; Spleen; Time Factors

Malaria parasites proliferate asexually within the vertebrate host but must undergo sexual reproduction for transmission to mosquitoes and hence infection of new hosts. The developmental pathways controlling gametocytogenesis are not known, but several protein kinases and other putative signal transduction elements possibly involved in this phenomenon have been found in Plasmodium. Recently, another developmental pathway, that of Plasmodium sex determination (male or female), has been shown to be triggered by erythropoiesis in the host. Rapid progress is being made in our understanding of the molecular basis of mammalian erythropoiesis, revealing kinase pathways that are essential to cellular responses triggered by the hormone erythropoietin. Although the molecular mechanisms whereby this hormone modulates the sex ratio of malaria parasites remain to be elucidated, it probably activates, within the parasite, transduction pathways similar to those found in other eukaryotes. Indeed, enzymes belonging to protein kinase families known to be involved in the response of mammalian cells to erythropoietin (such as the mitogen-activated protein kinases) have been identified in P. falciparum gametocytes. Some of these enzymes differ markedly from their mammalian homologs; therefore, identification of the transduction pathways of the parasite that are responsible for its developmental response to erythropoietin opens the way to the development of transmission-blocking drugs based on kinase inhibitors.

Topics: Animals; Erythropoiesis; Erythropoietin; Malaria; Plasmodium; Sex Determination Processes; Signal Transduction

Topics: Animals; Bone Marrow; Cell Division; Cells, Cultured; Disease Susceptibility; Erythropoiesis; Erythropoietin; Growth Inhibitors; Hematopoietic Stem Cells; Immunity, Innate; Macrophage Colony-Stimulating Factor; Malaria; Mice; Mice, Inbred A; Mice, Inbred C57BL; Spleen

This paper presents changes in the bone marrow of patients with malaria; it is based primarily on observations of bone marrows of 89 Gambian children with P. falciparum malaria and includes a review of the literature. Erythroid hyperplasia with dyserythropoiesis was found to be more common in patients with severe anemia and low grade parasitemia than in those with acute malaria. The dyserythropoietic changes are illustrated both with light photomicropraphs and with electron micrographs. The significance of the dyserythropoiesis and possible causes are discussed. Other changes in these patients with acute malaria include lymphocytosis in the bone marrow and reactive lymphocytes, monocytosis and mild neutrophilia in the peripheral blood. Giant metamyelocytes were also commonly seen in bone marrow of patients but were thought to be part of dysmyelopoiesis and not due to B12 or folate deficiency. Phagocytosis of erythrocytes, parasitized cells and nucleated cells was more commonly seen in macrophages in acute malaria, while phagocytosis of small particles such as merozoites was observed in neutrophils. Megakaryocytes were found to be increased in number in patients with acute malaria; a proportion of these cells had rounded nuclei, probably indicating accelerated platelet turnover.

Topics: Bone Marrow; Erythroblasts; Erythrocyte Count; Erythropoiesis; Erythropoietin; Hematopoiesis; Humans; Leukocytes; Malaria; Reticulocytes

To study the cellular mechanisms involved in the ineffective erythropoiesis associated with malaria, an in vitro proliferative assay was used to measure the response to erythropoietin (Epo) of erythroid progenitor cells from malaria-infected mice. In this assay, spleen (SP) cells from phenylhydrazine (PHZ)-treated mice (PHZ-SP), enriched for erythroid progenitor cells, respond to Epo in a dose-dependent manner. Despite a similar degree of anemia, SP and bone marrow (BM) cells from Plasmodium berghei- or P. vinckei-infected mice did not show a significant response to Epo in this assay. When SP or BM cells from malaria-infected mice were added to cultures of SP or BM cells from PHZ-treated mice the response to Epo of these cells was significantly inhibited. Removal of parasitized red blood cells (pRBC) from SP cells of P. berghei-infected mice had no effect on the ability of the cells to inhibit the response to Epo. Adherent SP cells and SP cells positive for the Mac-1 antigen, from malaria-infected mice, were shown to be enriched for cells that could inhibit the response to Epo. Cell-free conditioned media (CM) prepared from SP cells of P. berghei- or P. vinckei-infected mice or from normal SP cells incubated with pRBC were also able to inhibit the response to Epo of SP cells from PHZ-treated mice. These investigations have shown that during the course of malaria infection, cells appear in the SP and BM capable of inhibiting, via soluble mediators, the response to Epo of erythroid progenitor cells. The cells responsible are probably macrophages. The nature of the factor(s) and its mechanism of action are not known. Through the ability to inhibit erythropoiesis, soluble factors may, in part, mediate the anemia associated with malaria.

Topics: Animals; Antigens, Differentiation; Bone Marrow; Cell Adhesion; Cell Separation; Culture Media; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Growth Inhibitors; Kinetics; Macrophage-1 Antigen; Malaria; Mice; Mice, Inbred BALB C; Plasmodium berghei; Spleen

This work characterizes the erythropoietic interplay of the spleen, blood, and bone marrow in a lethal murine malaria, strain 17XL P. yoelii. This malaria runs a fulminant 7 day course in BALB/c/ByJ mice, marked by high levels of parasitized reticulocytes with death likely due to anemia. We have quantitated the levels of burst forming units-erythroid (BFU-E), the early, niche-seeking, largely erythropoietin-unresponsive erythropoietic precursors, and of colony forming units-erythroid (CFU-E), the more differentiated sessile erythropoietin-responsive precursors, in bone marrow, blood, and spleen, through the course of this malaria. A decline in marrow BFU-E began on day 2, but recovered, relatively, after day 3. Marrow cellularity declined, being but 75% normal on day 6. Spleen weight increased about 5-fold within 6 days with enlargement of erythroid, lymphoid, macrophage, and stromal compartments. Splenic BFU-E increased in the first 24 hr and 5-fold by day 6. Splenic CFU-E increased in the first 24 hr and into day 4. They then declined and showed a secondary, large-scale, sustained rise interrupted by death. Because the spleen was enlarging, a greater than 60-fold increase in the absolute number of splenic CFU-E occurred at the time of death. Marrow CFU-E followed the same pattern as splenic CFU-E, but the terminal increase represented but a 4-fold absolute increase because of declining marrow cellularity. High levels of erythropoietin occurred only late in the course of disease, likely in response to profound anemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bone Marrow; Colony-Forming Units Assay; Culture Techniques; Erythrocytes; Erythropoiesis; Erythropoietin; Hematopoiesis, Extramedullary; Malaria; Male; Mice; Mice, Inbred BALB C; Plasmodium yoelii; Spleen; Stimulation, Chemical; Time Factors

The causes of anemia and immunosuppression, major outcomes of malaria, are not well established. This study was undertaken to investigate whether erythropoietin (EP) production is adequate and whether the hemopoietic stem cells (CFU-S) were affected during the course of infection. Groups of female Balb/c mice infected with Plasmodium vinckei vinckei, Plasmodium berghei, or Plasmodium chabaudi adami were exposed to five hours of simulated altitude equivalent to 22,000 ft. Plasma samples were collected for EP bioassay and radioimmunoassay (RIA). Using radioiron incorporation as an index of erythropoiesis, differences in response to infection with different species of plasmodia were observed. In general, decreases in erythropoietic activity were observed in bone marrow and spleen as the infection progressed and continued to be depressed after apparent resolution of a nonlethal infection with P. chabaudi adami. Marrow from infected and control femurs were tested for CFU-S content using the spleen colony assay. The cellularity and CFU-S content of the femoral marrow decrease as the parasitemia increases. All three species of plasmodia stimulate EP production during peak parasitemias, indicating that adequate amounts of EP are available to the erythron during malarial infection. Depletion of CFU-S and probable lack of compensatory turnover of CFU-S may contribute to the disease characteristics of malaria.

Topics: Animals; Erythropoietin; Female; Hematopoietic Stem Cells; Malaria; Mice; Mice, Inbred BALB C

An impaired erythropoietic response to anemia has been noted in human patients with malaria and in rodents experimentally infected with Plasmodium berghei. We have attempted to characterize the erythropoietic response in mice with a fatal P berghei infection, with particular emphasis on changes in marrow hematopoietic stem cells. Mice infected with P berghei had dramatic decreases in bone marrow cellularity, erythroblasts, BFU-E, and CFU-E as early as 24 hours postinfection and before there was any change in hematocrit. With development of anemia, marrows became erythropoietic with some expansion of the CFU-E compartment, but the BFU-E pool remained depleted and reticulocyte response was inadequate. There was no significant change in CFU-S from marrows of malaria-infected mice one day after infection. The lethality of malaria infection may take three weeks to be revealed, but it may be determined within hours of the infection by the irreparable changes in marrow erythroid stem cells.

Topics: Animals; Bone Marrow Cells; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hematopoietic Stem Cells; Malaria; Mice; Mice, Inbred C57BL; Plasmodium berghei; Reticulocytes; Spleen

Erythropoietin, the hormone responsible for stimulating erythrocyte production, was shown to increase significantly in the serum of mice during virulent malaria infection. Although erythropoiesis was enhanced, it did not keep pace with the rate of erythocyte destruction; hence all Plasmodium berghei-infected mice quickly succumbed to the deleterious consequences of severe uncompensated hemolytic anemia. Since this apparently inadequate rate of erythropoiesis is not attributed to impaired erythropoietin generation, mechanisms relating to (i) hemopoietic stem-cell resistance to endogenous erythropoietin, (ii) deficits in numbers of hemopoietic stem cells, and/or (iii) ineffective erythropoiesis are of interest.

Topics: Anemia, Hemolytic; Animals; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Malaria; Mice; Plasmodium berghei