Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyclonal B-cell activation and hypergammaglobulinemia are prominent features of human malaria. We report here that Plasmodium falciparum-infected erythrocytes directly adhere to and activate peripheral blood B cells from nonimmune donors. The infected erythrocytes employ the cysteine-rich interdomain region 1alpha (CIDR1alpha) of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to interact with the B cells. Stimulation with recombinant CIDR1alpha induces proliferation, an increase in B-cell size, expression of activation molecules, and secretion of immunoglobulins (immunoglobulin M) and cytokines (tumor necrosis factor alpha and interleukin-6). Furthermore, CIDR1alpha binds to Fab and Fc fragments of human immunoglobulins and to immunoglobulins purified from the sera of different animal species. This binding pattern is similar to that of the polyclonal B-cell activator Staphylococcus aureus protein A. Our findings shed light on the understanding of the molecular basis of polyclonal B-cell activation during malaria infections. The results suggest that the var gene family encoding PfEMP1 has evolved not only to mediate the sequestration of infected erythrocytes but also to manipulate the immune system to enhance the survival of the parasite.
 ...
PMID:Identification of a polyclonal B-cell activator in Plasmodium falciparum. 1532 39

Inflammatory cytokines play an important role in human immune responses to malarial disease. However, the role of these mediators in disease pathogenesis, and the relationship between host protection and injury remains unclear. A total of 248 cases of severe Plasmodium falciparum malaria among children aged 3 months to 14 years residing in Bandiagara, Mali, were matched to cases of uncomplicated malaria and healthy controls. Using modified World Health Organization criteria for defining severe malaria, we identified 100 cases of cerebral malaria (coma, seizure, and obtundation), 17 cases of severe anemia (hemoglobin, <5 g/dl), 18 cases combined cerebral malaria with severe anemia, and 92 cases with hyperparasitemia (asexual trophozoites, >500,000/mm3). Significantly elevated levels (given as geometric mean concentrations in picograms/milliliter) of interleukin-6 (IL-6; 485.2 versus 54.1; P = <0.001), IL-10 (1,099.3 versus 14.1; P = <0.001), tumor necrosis factor alpha (10.1 versus 7.7; P = <0.001), and IL-12(p70) (48.9 versus 31.3; P = 0.004) in serum were found in severe cases versus healthy controls. Significantly elevated levels of IL-6 (485.2 versus 141.0; P = <0.001) and IL-10 (1,099.3 versus 133.9; P = <0.001) were seen in severe malaria cases versus uncomplicated malaria controls. Cerebral malaria was associated with significantly elevated levels of IL-6 (754.5 versus 311.4; P = <0.001) and IL-10 (1,405.6 versus 868.6; P = 0.006) compared to severe malaria cases without cerebral manifestations. Conversely, lower levels of IL-6 (199.2 versus 487.6; P = 0.03) and IL-10 (391.1 versus 1,160.9; P = 0.002) were noted in children with severe anemia compared to severe malaria cases with hemoglobin at >5 g/dl. Hyperparasitemia was associated with significantly lower levels of IL-6 (336.6 versus 602.1; P = 0.002). These results illustrate the complex relationships between inflammatory cytokines and disease in P. falciparum malaria.
 ...
PMID:Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. 1538 60

Peroxisome proliferator-activated receptor gamma-retinoid X receptor (PPARgamma-RXR) agonists had minimal effects on the surface levels of CD36, intercellular cell adhesion molecule-1, or platelet-endothelial cell adhesion molecule-1 and had no effect on the cytoadherence of infected erythrocytes to either human umbilical vein endothelial cells or human microvascular endothelial cells or on malaria-induced interleukin-6 secretion from these cells. PPARgamma-RXR agonists do not significantly modify malaria-infected erythrocyte-endothelial cell interactions in vitro.
 ...
PMID:Peroxisome proliferator-activated receptor gamma and retinoid X receptor agonists have minimal effects on the interaction of endothelial cells with Plasmodium falciparum-infected erythrocytes. 1566 66

Polyparasitism is common in the developing world, and interactions that alter disease severity may occur. We previously demonstrated that infection with Schistosoma hematobium was associated with protection against Plasmodium falciparum infection in children who were 4 to 8 years old. In this study, we determined whether underlying helminth infections affected the cytokine responses to acute falciparum malaria. A total of 338 schistosomiasis-positive [Sch(+)] children who were 4 to 14 years old were matched by age, residence, and sex with 338 schistosomiasis-negative [Sch(-)] children and monitored for a malaria transmission season (25 weeks). Serologic cytokine levels were measured at the time of the first clinical malaria episode and in children who did not contract malaria. Elevated background levels of interleukin-6 (IL-6) (37.1 pg/ml versus 10.9 pg/ml [P = 0.04]), IL-4 (27.7 pg/ml versus 6.9 pg/ml [P = 0.02]), IL-10 (18.2 pg/ml versus 7.2 pg/ml [P < 0.001]), and gamma interferon (18.2 pg/ml versus 4.7 pg/ml [P = 0.006]) were noted in Sch(+) children compared to Sch(-) children without malaria. IL-6 and IL-10 levels were elevated in association with acute malaria, but the levels appeared to be blunted in Sch(+) children compared to Sch(-) children who were 4 to 8 years old (for IL-6, 96.2 pg/ml versus 137.2 pg/ml [P = 0.08]; for IL-10, 195.9 pg/ml versus 282.2 pg/ml [P = 0.06]). The level of IL-10 was similarly lower in Sch(+) children than in Sch(-) children who were 9 to 14 years old (91.2 pg/ml versus 141.2 pg/ml [P = 0.03]). IL-4 levels were inversely correlated with the time until the first malaria infection in both the Sch(+) children (P < 0.001) and the Sch(-) children (P < 0.001) who were 4 to 8 years old. We postulate that the Th2-enriched environment induced by schistosomiasis protects against malaria and alters the cytokine milieu during an actual infection.
 ...
PMID:Effects of concomitant Schistosoma haematobium infection on the serum cytokine levels elicited by acute Plasmodium falciparum malaria infection in Malian children. 1698 48

The efficacy of vaccine adjuvants can be influenced by the immunological environment of the host, depending on the mechanism(s) by which they exert their immunopotentiating activities. Interleukin-6 is a pleiotropic cytokine that has a broad range of biological activities on immune and non-immune cells. We investigated the role of IL-6 on the ability of nine adjuvant formulations to induce antibody responses to the Plasmodium falciparum MSP1-19 malaria vaccine, using IL-6-/- (KO) mice. Results showed that some adjuvants, i.e. MPL-SE, CFA/IFA, ISA720/QS21/MPL, depended on IL-6 for their efficacy, while others exhibited increased potency in its absence. The efficacy of adjuvants in the IL-6 KO environment cannot be solely attributed to their ability to stimulate antigen-specific cellular responses, suggesting that other biological activities of IL-6 are also important. The results further suggest that two adjuvants utilized dissimilar pathways to potentiate the same type of immune response.
 ...
PMID:Interleukin-6 has differential influence on the ability of adjuvant formulations to potentiate antibody responses to a Plasmodium falciparum blood-stage vaccine. 1768 75

Hepatosplenomegaly among Kenyan schoolchildren has been shown to be exacerbated where there is transmission of both Schistosoma mansoni and Plasmodium falciparum. This highly prevalent and chronic morbidity often occurs in the absence of ultrasound-detectable periportal fibrosis and may be due to immunological inflammation. For a cohort of school-age children, whole-blood cultures were stimulated with S. mansoni soluble egg antigen (SEA) or soluble worm antigen (SWA). Responses to SWA were found to be predominantly Th2 cytokines; however, they were not significantly associated with either hepatosplenomegaly or infection with S. mansoni or P. falciparum. In comparison, SEA-specific Th2 cytokine responses were low, and the levels were negatively correlated with S. mansoni infection intensities and were lower among children who were coinfected with P. falciparum. Tumor necrosis factor alpha levels in response to stimulation with SEA were high, and a negative association between presentation with hepatomegaly and the levels of the regulatory cytokines interleukin-6 and transforming growth factor beta(1) suggests that a possible mechanism for childhood hepatomegaly in areas where both malaria and schistosomiasis are endemic is poor regulation of an inflammatory response to schistosome eggs.
 ...
PMID:Hepatosplenomegaly is associated with low regulatory and Th2 responses to schistosome antigens in childhood schistosomiasis and malaria coinfection. 1828 96

CD163 is an acute-phase-regulated monocyte/macrophage membrane receptor expressed late in inflammation. It is involved in the haptoglobin-mediated removal of free hemoglobin from plasma, has been identified as a naturally soluble plasma glycoprotein with potential anti-inflammatory properties, and is possibly linked to an individual's haptoglobin phenotype. High levels of soluble CD163 (sCD163) in a malaria episode may therefore downregulate inflammation and curb disease severity. In order to verify this, the relationships between sCD163 levels, malaria severity, and selected inflammatory mediators (tumor necrosis factor alpha [TNF-alpha], interleukin-6 [IL-6], and IL-10) were assessed by enzyme-linked immunosorbent assay using plasma samples obtained from pediatric malaria patients with uncomplicated malaria (UM [n = 38]), cerebral malaria (CM [n = 52]), and severe malarial anemia (SA [n = 55]) during two consecutive malaria transmission seasons (2002 and 2003). Median sCD163 levels were higher in UM (11.9 microg/ml) patients than in SA (7.7 microg/ml; P = 0.010) and CM (8.0 microg/ml; P = 0.031) patients. Levels of sCD163 were also higher in all patient groups than in a group of 81 age-matched healthy controls. The higher sCD163/TNF-alpha ratio in UM patients, coupled with the fact that sCD163 levels correlated with TNF-alpha levels in UM patients but not in CM and SA patients, suggests inflammatory dysregulation in the complicated cases. The study showed that sCD163 levels are elevated during acute malaria. High sCD163 levels in UM patients may be due to the induction of higher-level anti-inflammatory responses, enabling them to avoid disease complications. It is also possible that UM patients simply lost their CD163 receptors from macrophages in inflammatory sites while complicated-malaria patients still had their receptors attached to activated macrophages, reflecting ongoing and higher-level inflammation associated with complicated malaria.
 ...
PMID:Levels of soluble CD163 and severity of malaria in children in Ghana. 1863 18

Plasmodium falciparum infection results in adhesion of infected erythrocytes to blood vessel endothelium, and acute endothelial cell activation, together with sequestration of platelets and leucocytes. We have previously shown that patients with severe infection or fulminant cerebral malaria have significantly increased circulatory levels of the adhesive glycoprotein von Willebrand factor (VWF) and its propeptide, both of which are indices of endothelial cell activation. In this prospective study of patients from Ghana with severe (n = 20) and cerebral (n = 13) P. falciparum malaria, we demonstrate that increased plasma VWF antigen (VWF:Ag) level is associated with disproportionately increased VWF function. VWF collagen binding (VWF:CB) was significantly increased in patients with cerebral malaria and severe malaria (medians 7.6 and 7.0 IU/ml versus 1.9 IU/ml; p<0.005). This increased VWF:CB correlated with the presence of abnormal ultra-large VWF multimers in patient rather than control plasmas. Concomitant with the increase in VWF:Ag and VWF:CB was a significant persistent reduction in the activity of the VWF-specific cleaving protease ADAMTS13 (approximately 55% of normal; p<0.005). Mixing studies were performed using P. falciparum patient plasma and normal pooled plasma, in the presence or absence of exogenous recombinant ADAMTS13. These studies demonstrated that in malarial plasma, ADAMTS13 function was persistently inhibited in a time-dependent manner. Furthermore, this inhibitory effect was not associated with the presence of known inhibitors of ADAMTS13 enzymatic function (interleukin-6, free haemoglobin, factor VIII or thrombospondin-1). These novel findings suggest that severe P. falciparum infection is associated with acute endothelial cell activation, abnormal circulating ULVWF multimers, and a significant reduction in plasma ADAMTS13 function which is mediated at least in part by an unidentified inhibitor.
 ...
PMID:Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition. 1930 Apr 93

Complement receptor 1 (CR1/CD35) levels on erythrocytes and related CR1 polymorphisms have been associated with response to falciparum malaria in populations inhabiting malaria-endemic regions. Differences in disease association profiles of its low expression alleles have been observed in populations from different regions of the world. We analyzed the influence of CR1 levels and associated SNPs on susceptibility/resistance to falciparum malaria in Indian populations. Two CR1 SNPs [exon 22 (A/G) and intron 27 (A/T)] define the low expression (L) CR1 allele in populations inhabiting a Plasmodium falciparum-endemic and a nonendemic region of India. Populations of the endemic region have very low red blood cell surface CR1 levels and higher frequencies of the exon 22 and intron 27 mutant L alleles. Whereas low CR1 levels correlated with susceptibility to severe malaria in the nonendemic region, high CR1 levels were associated with manifestation of disease in the endemic region. In addition, the exon 22 L allele was a risk factor for severe malaria in the nonendemic region. Absence of correlation between levels of tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 with CR1 levels in patients with severe disease indicated that RBC CR1 levels in individuals are not the major determinants of pro-inflammatory cytokine release during infection. Our results are interpreted in the context of differences in the pathogenesis of severe malaria in the malaria-endemic and nonendemic region.
 ...
PMID:CR1 levels and gene polymorphisms exhibit differential association with falciparum malaria in regions of varying disease endemicity. 1948 Aug 40

The human immune response to Plasmodium falciparum infection involves the release of cytokines that may contribute to the control of the parasites' replication. These cytokines are also involved in the pathogenesis of the malaria caused by the infection, leading to the appearance of symptoms of varying severity. In a cross-sectional study, the expression of the genes that code for pro-inflammatory cytokines (tumour necrosis factor, interferon-gamma, interleukin-6 and interleukin-12) and anti-inflammatory cytokines (interleukin-10 and interleukin-4) among 80 children infected with P. falciparum (from a malaria-endemic area of Sudan) and five healthy controls (from a non-endemic area) was explored. The infected children were either non-sicklers, with severe malaria (18 children), mild malaria (30) or no symptoms of malaria (18), or asymptomatic sicklers (14). Interleukin-12 was found to be weakly expressed by all the groups of children. In general, compared with the other groups, the asymptomatic non-sicklers had lower expression of all the cytokines studied. The asymptomatic sicklers had significantly lower expression of tumour necrosis factor than the non-sicklers with severe malaria, but these two groups showed similar expression of interferon-gamma, interleukin-4 and interleukin-6. Gene expression of the regulatory cytokine, interleukin-10, by the asymptomatic sicklers was significantly lower than that by the non-sicklers with severe malaria but higher than that recorded in the non-sicklers with mild malaria. Their regulation of cytokine release appears to protect sicklers from clinical malaria.
 ...
PMID:Differential expression of cytokine genes among sickle-cell-trait (HbAS) and normal (HbAA) children infected with Plasmodium falciparum. 1950 46


<< Previous 1 2 3 4 5 6 7 Next >>