title: The host inflammatory response in the pathogenesis of malaria in Gambian children
Creators: name: McGuire, William
Publisher: name: University of Glasgow
Year: 1998
Subjects: subject: Immunology, pathology.

description: The host inflammatory response may be involved in the pathogenesis of severe malaria. High plasma levels of pro-inflammatory cytokines, notably tumour necrosis factor (TNP), are found in African children with cerebral malaria. Experimental evidence also implicates TNF in the pathogenic process of severe malarial anaemia. We have examined the association of polymorphisms in the TNF gene promoter region with severe malaria in a large case-control study of Gambian children. Cerebral malaria, but not severe malarial anaemia, was found to be associated with the TNF-308 A promoter allele (TNF2). Homozygotes for this allele had a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria and this association was independent of variation in the neighbouring HLA class I and class II alleles. In the same population severe malarial anaemia was associated with the TNF-238 A promoter allele with an odds ratio of 2.5 after stratification for HLA type. These data suggest that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection and that severe malarial anaemia and cerebral malaria are influenced by separate genetic factors situated in the neighbourhood of the TNF gene. TNF is an endogenous pyrogen and a critical mediator of malaria fever. However, high plasma levels of TNF are sometimes found in afebrile African children with Plasmodium falciparum parasitaemia. A proposed mechanism for this apparent clinical tolerance is that soluble forms of TNF receptors (sTNF-R55 and sTNF-R75), that are known to inhibit TNF bioactivity in vitro, modulate the pyrogenic effect of TNF in vivo. We have measured the plasma levels of TNF, sTNF-R55 and sTNF-R75 in relation to episodes of malaria fever detected in a cross-sectional study of rural Gambian children during the malaria transmission season. TNF levels were significantly higher in children who were both parasitaemic and febrile, compared to those who were parasitaemic but afebrile and those who had no detectable parasitaemia. In contrast, soluble TNF receptor levels did not differ between these clinical groups and, in a logistic regression model that included level of parasitaemia, TNF but not soluble TNF receptor levels was 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. Sequestration of parasitised erythrocytes in post-capillary venules in critical areas of the brain is believed to be a critical step in the pathogenesis of cerebral malaria. High levels of pro-inflammatory cytokine production may exacerbate sequestration by up-regulating the expression of the specific endothelial receptors to which parasitised erythrocytes bind. One of the best characterised of these receptors is intercellular adhesion molecule-1 (ICAM-1). An indirect measure of ICAM-1 expression may be provided by the amount of circulating ICAM-1 (cICAM-1) in the plasma. In a case-control study of severe malaria, we have found that the plasma levels of cICAM-1 to be higher in Gambian children with acute malaria than in those with non-malarial illnesses. cICAM-1 levels correlated with levels of TNF, interleukin-1 alpha (IL-1) and interferon-gamma, supporting the view that these cytokines are responsible for a general up-regulation of ICAM-1 expression in malaria. However, in contrast to the finding for TNF and IL-1, cICAM-1 levels were unrelated to malaria disease severity. The tissue distribution of ICAM-1 expression, rather than the total level of expression may be the more important determinant of whether an individual child develops cerebral malaria. The host acute inflammatory response to malaria parasitaemia may provide a useful surrogate measure of disease activity. Two such potential measures of malarial morbidity are (i) elevated plasma C-reactive protein (CRP) plus detectable parasitaemia, as an indicator of the malaria-induced acute-phase response; and (ii) reduced plasma haptoglobin, which in children resident in malaria endemic areas of sub-Saharan Africa indicates malaria- induced intravascular haemolysis. We have compared these indices with the traditional malariometric indices in a cross-sectional survey that was undertaken to determine the impact of bed net usage in 1505 rural Gambian children. At the end of the malaria transmission season the proportion of children who had parasitaemia plus elevated CRP was significantly lower than in those who had slept under insecticide-treated bed nets compared to those who did not use a bed net. The proportion with a low haptoglobin differed similarly. We conclude that these indices could be useful for the assessment of the impact of intervention programmes on malarial morbidity in rural African communities.