Here we review the role of ICAM-1 and EPCR receptor adhering falciparum-parasites in the development of severe malaria; we discuss our current research to understand the factors involved in the pathogenesis of cerebral malaria and the feasibility of developing a vaccine targeted specifically to prevent this disease.
<i>Plasmodium falciparum</i> erythrocyte membrane protein 1 (PfEMP1) mediates parasite sequestration to the cerebral microvasculature via binding of DBLβ domains to intercellular adhesion molecule 1 (ICAM1) and is associated with severe cerebral malaria.
Natural and Vaccine-Induced Acquisition of Cross-Reactive IgG-Inhibiting ICAM-1-Specific Binding of a Plasmodium falciparum PfEMP1 Subtype Associated Specifically with Cerebral Malaria.
The tumor necrosis factor-alpha protein level and caspase activity, which is related to CM pathogenesis, was significantly reduced in the minocycline-treated group.
Children presenting with acute CM had significantly higher concentrations of TNF-α (<i>P</i> < 0.001), interferon gamma (IFN-γ) (<i>P</i> = 0.0019), IL-2 (<i>P</i> = 0.0004), IL-6 (<i>P</i> < 0.001), IL-8 (<i>P</i> < 0.001), and IL-10 (<i>P</i> < 0.001) in sera than healthy controls.
Further tests for association with severe malaria using genotype models controlling for age, parasitaemia and HbAS showed a significant association of the TNF-238 polymorphism with susceptibility to severe malaria (95% CI=1.43-6.02, OR=2.94, p=0.003237) The GG genotype of TNF-238 significantly increased the risk of developing cerebral malaria from asymptomatic malaria and uncomplicated malaria (95% CI=1.99-18.17, OR=6.02, p<0.001 and 95% CI=1.78-8.23, OR=3.84, p<0.001 respectively).
Up-regulated TNF-α expression has also been found in various neurodegenerative diseases such as cerebral malaria, AIDS dementia, Alzheimer's disease, multiple sclerosis, and stroke, suggesting a potential pathogenic role of TNF-α in these diseases as well.
Our results show that increased binding to CD36 is associated with uncomplicated malaria while ICAM-1 adhesion is raised in parasites from cerebral malaria cases.
Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes.
Pooled results across our studies for ICAM-1(Kilifi) were, in severe malaria, odds ratio (OR) 1.02, 95% confidence interval (CI) 0.96-1.09, P=0.54, and cerebral malaria OR 1.07, CI 0.97-1.17, P=0.17.
The frequency of the TNF U04 allele designated -1031C, -863C, and -857C was found to be significantly greater in patients with cerebral malaria than in patients with mild malaria (12.6%, cerebral malaria vs 5.6%, mild malaria; odds ratio =2.5; P=0.002).
The frequency of the TNF U04 allele designated -1031C, -863C, and -857C was found to be significantly greater in patients with cerebral malaria than in patients with mild malaria (12.6%, cerebral malaria vs 5.6%, mild malaria; odds ratio =2.5; P=0.002).
The hypothesis that tumor necrosis factor (TNF) aggravates malaria in children is supported by observations that TNF polymorphisms and high TNF levels have been associated with cerebral malaria.
An intercellular adhesion molecule-1 polymorphism (ICAM-1(Kilifi)) is present at a high frequency across sub-Saharan Africa, and its presence may increase susceptibility to cerebral malaria.
A number of endothelial receptors have been identified, and there is evidence that one of these, intercellular adhesion molecule-1 (ICAM-1), may play an important role in the pathology of cerebral malaria.
TNFalpha receptors are upregulated in CM, with TNF receptor 2 (TNFR2) showing a higher upregulation than TNFR1 in vivo; (iv). in murine CM, low doses of TNFalpha seem to protect from CM, whereas excess TNFalpha induces CM and anti-TNFalpha therapies (antibodies, pentoxifylline) did not show any efficiency in protection from CM.
Recently we described a mutation within the coding region of the first N-terminal immunoglobulin-like domain of ICAM-1, present at high frequency within African populations, which increased the risk of cerebral malaria.
This report of RT-PCR on postmortem human tissues infected with CM demonstrates induction of the proinflammatory cytokines TNF-alpha and IL-1beta in the brain.