Inhibition of tumour necrosis factor (TNF) production by antimalarial drugs used in cerebral malaria.
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Antimalarials↗
Biomedical subjects
D Kwiatkowski
Publications and source records attributed to D Kwiatkowski.
Circulating ICAM-1 levels in falciparum malaria are high but unrelated to disease severity.
Intercellular adhesion molecule 1 (ICAM-1) mediates the binding of Plasmodium falciparum to vascular endothelium. In a case-control study of falciparum malaria in Gambian children, we have looked for evidence that a generalized increase in expression of ICAM-1 is associated with cerebral malaria. Plasma levels of circulating ICAM-1 (cICAM-1) were significantly higher in 246 children with acute malaria than in 156 children with non-malarial illnesses. cICAM-1 levels correlated with levels of tumour necrosis factor (TNF), interleukin 1 alpha (IL-1 alpha) and interferon gamma, supporting the view that these cytokines are responsible for a general upregulation of ICAM-1 expression in malaria. However, while it has been previously shown that TNF and IL-1 alpha levels were related to disease severity, this was not the case for cICAM-1. It may be that differences in the distribution of ICAM-1, rather than its total level of expression, are critical in determining the clinical outcome in malaria.
Case-Control Studies↗
C-reactive protein and haptoglobin in the evaluation of a community-based malaria control programme.
When cross-sectional surveys are used to evaluate malaria intervention programmes in the community, the prevalence of morbidity is difficult to assess because of the fluctuating nature of malarial fever. We have therefore investigated the impact of bed net usage on 2 surrogate markers of malarial morbidity: (i) elevated C-reactive protein (CRP) (> 8 mg/L) plus detectable parasitaemia, as an indicator of malaria-induced acute-phase response; and (ii) reduced haptoglobin levels (< 180 mg/L), which in this population indicates malaria-induced intravascular haemolysis. Among 1505 Gambian children 1-5 years old, examined on a single occasion at the end of the malarial transmission season, 5% had parasitaemia plus fever, while 24% had parasitaemia plus elevated CRP, and 35% had low haptoglobin. The proportion of children who had parasitaemia plus elevated CRP was significantly lower among those who had slept under insecticide-treated bed nets than among those who did not use a bed net (16% vs. 34%, P < 0.003), and the proportion with low haptoglobin differed similarly (24% vs. 49%, P < 0.003). Use of an untreated bed net had a weaker effect on both indices (22% had parasitaemia plus elevated CRP, 34% had low haptoglobin). CRP and haptoglobin are simple and inexpensive to measure in large numbers of people, and these results suggest that they could be useful for the assessment of malaria intervention programmes.
Bedding and Linens↗
Levels of tumour necrosis factor and soluble TNF receptors during malaria fever episodes in the community.
The pyrogenic cytokine, tumour necrosis factor (TNF), is a mediator of malaria fever. Since high plasma levels of TNF are sometimes found in afebrile individuals with Plasmodium falciparum parasitaemia, it has been suggested that soluble forms of TNF receptors (sTNF-R55 and sTNF-R75) in the plasma may act to inhibit the pyrogenic effect of TNF. We have investigated plasma levels of TNF, sTNF-R55 and sTNF-R75 in relation to episodes of malaria fever detected in a cross-sectional study of 313 rural Gambian children during the malaria transmission season. Levels of TNF were significantly higher in the 20 children who had parasitaemia associated with fever than in 120 children who were afebrile despite malaria infection and 173 who had no detectable parasitaemia. In contrast, soluble TNF receptor levels did not differ between these clinical groups and, in a logistic regression model which included level of parasitaemia, we found TNF but not soluble TNF receptor levels to be associated with the presence of fever. These data support the role of TNF in malaria fever but suggest that soluble TNF receptors are not a major factor in modulating the fever.
Child, Preschool↗
Absence of an association between intercellular adhesion molecule 1, complement receptor 1 and interleukin 1 receptor antagonist gene polymorphisms and severe malaria in a West African population.
Many genes have been shown to be involved in host susceptibility to the severe forms of Plasmodium falciparum malaria but it is likely that a large number of malaria-susceptibility genes remain to be determined. We conducted a large case-control study of children with the severe forms of this disease-cerebral malaria and severe malarial anaemia--to attempt to identify these genes. Over 1200 children in The Gambia were typed for polymorphisms of the intercellular adhesion molecule 1 (ICAM-1), complement receptor 1 (CR-1) and interleukin 1 receptor antagonist (IL-IRA) genes. None of the polymorphisms typed was significantly associated with severe disease. These data differed significantly from the results of a previous study (Chi 2 = 8.81; P = 0.003) in which the ICAM-1 gene polymorphism was shown to be significantly associated with cerebral malaria in a case-control study of 547 subjects in Kenya. This suggests that there may be heterogeneity in genetic susceptibility to this condition between these 2 African populations.
Case-Control Studies↗
Inherited variability of tumor necrosis factor production and susceptibility to infectious disease.
Tumor necrosis factor (TNF) is a critical mediator of host defense against infection but may cause severe pathology when produced in excess. Individuals vary in the amount of TNF produced when their peripheral blood mononuclear cells are stimulated in vitro, and family studies indicate that much of this variability is genetically determined. Since the TNF response to infection is partly regulated at the transcriptional level, TNF promoter polymorphisms have been the subject of intense interest as potential determinants of disease susceptibility. A single nucleotide polymorphism at nucleotide -308 relative to the transcriptional start site has been associated with susceptibility to severe malaria, leishmaniasis, scarring trachoma, and lepromatous leprosy. Some experimental data indicate that this polymorphism acts to upregulate TNF transcription, but this remains controversial. Detailed analysis of multiple genetic markers at this locus and more sophisticated investigations of TNF transcriptional regulation, in different cell types and with a wide range of stimuli, are required to understand the molecular basis of these disease associations.
Case-Control Studies↗