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Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. Plasma concentrations of P. falciparum Histidine-Rich Protein 2 ( Pf HRP2) have diagnostic and prognostic value in severe malaria. We investigate the potential use of plasma Pf HRP2 and the sequestration index (the ratio of Pf HRP2 to parasite density) as quantitative traits for case-only genetic association studies of severe malaria. Data from 2198 Kenyan children diagnosed with severe malaria, genotyped for 14 major candidate genes, show that polymorphisms in four major red cell genes that lead to hemoglobin S, O blood group, α-thalassemia, and the Dantu blood group, are associated with substantially lower admission plasma Pf HRP2 concentrations, consistent with protective effects against extensive parasitized erythrocyte sequestration. In contrast the known protective ATP2B4 polymorphism is associated with higher plasma Pf HRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for the mechanism of protection of ATP2B4 . Numerous candidate malaria protective gene polymorphisms have been proposed. Here, Uyoga et al. investigate associations between malaria-protective red blood cell polymorphisms and total parasite biomass estimated from plasma concentrations of Pf HRP2, in a cohort of Kenyan children suffering from severe malaria. They suggest that plasma Pf HRP2 and the ratio of the plasma Pf HRP2 to the peripheral parasite density (sequestration index) as powerful quantitative phenotypic traits for severe malaria.

The changes in mental status during cerebral malaria, heat stroke, and recovery from major surgery are clinically similar, and are associated with high circulating concentrations of cytokines that can induce nitric oxide generation in vascular walls. This vascular nitric oxide could diffuse across the bloodbrain barrier, causing functional changes that include inhibition of glutamate-induced calcium entry, reduced activity of the calcium-dependent nitric oxide synthase, and thus reduced nitric oxide formation, in post-synaptic neurons. Certain general anaesthetics and ethanol reduce glutamate-induced calcium entry into post-synaptic cells, and so would also reduce the rate of formation of neuronal nitric oxide. In view of the apparent importance of glutamate-induced nitric oxide in excitatory neurotransmission, a reduction in neuronal nitric oxide could help explain why these otherwise unrelated influences alter central nervous system function in a similar manner. In particular, this reduction could rationalise why heat stroke, ethanol excess, morphine poisoning, and conditions with high blood ammonia concentrations are easily confused clinically with cerebral malaria.

The genetic basis for susceptibility to malaria has been studied widely in African populations but less is known of the contribution of specific genetic variants in Asian populations. We genotyped 67 single-nucleotide polymorphisms (SNPs) in 1030 severe malaria cases and 2840 controls from Vietnam. After data quality control, genotyping data of 956 cases and 2350 controls were analysed for 65 SNPs (3 gender confirmation, 62 positioned in/near 42 malarial candidate genes). A total of 14 SNPs were monomorphic and 2 (rs8078340 and rs33950507) were not in Hardy–Weinberg equilibrium in controls ( P <0.01). In all, 7/46 SNPs in 6 genes ( ICAM1, IL1A, IL17RC, IL13, LTA and TNF ) were associated with severe malaria, with 3/7 SNPs in the TNF/LTA region. Genotype–phenotype correlations between SNPs and clinical parameters revealed that genotypes of rs708567 ( IL17RC ) correlate with parasitemia ( P =0.028, r 2 =0.0086), with GG homozygotes having the lowest parasite burden. Additionally, rs708567 GG homozygotes had a decreased risk of severe malaria ( P =0.007, OR=0.78 (95% CI; 0.65–0.93)) and death ( P =0.028, OR=0.58 (95% CI; 0.37–0.93)) than those with AA and AG genotypes. In summary, variants in six genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese. Further replicative studies in independent populations will be necessary to confirm these findings.

Evidence from autopsy and in vitro binding studies suggests that adhesion of erythrocytes infected with Plasmodium falciparum to the human host intercellular adhesion molecule (ICAM)-1 receptor is important in the pathogenesis of severe malaria. Previous association studies between polymorphisms in the ICAM1 gene and susceptibility to severe malarial phenotypes have been inconclusive and often contradictory. We performed genetic association studies with 15 single nucleotide polymorphisms (SNPs) around the ICAM1 locus. All SNPs were screened in a family study of 1071 trios from The Gambia, Malawi and Kenya. Two key non-synonymous SNPs with previously reported associations, rs5491 (K56M or ‘ICAM-1 Kilifi ’) and rs5498 (K469E), were tested in an additional 708 Gambian trios and a case-control study of 4058 individuals. None of the polymorphisms were associated with severe malaria phenotypes. 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. We assess the available epidemiological, population genetic and functional evidence that links ICAM-1 Kilifi to severe malaria susceptibility.

Autoimmune disease is generally rare in tropical rural populations. Plasma concentrations of nitrite plus nitrate (reactive nitrogen intermediates), reflecting high nitric-oxide production somewhere in the body, can be high in patients who have cerebral malaria, but even higher in symptom-free parasitised individuals, who are termed malaria-tolerant. We propose that the nitric oxide causing high serum levels of reactive nitrogen intermediates in malaria-tolerant individuals is generated in macrophages during the establishment and maintenance of malarial tolerance, and makes autoimmune disease rare in many tropical rural populations by minimising proliferation of autoreactive T cells. Conversely, innately low levels of nitric-oxide generation in these populations, selected by malarial disease in tropical areas, could rationalise their high frequency of autoimmune disease and hypertension when living in western societies.

We describe the haplotypic structure of the interferon regulatory factor-1 (IRF-1) locus in two West African ethnic groups, Fulani and Mossi, that differ in their susceptibility and immune response to Plasmodium falciparum malaria. Both populations showed significant associations between IRF-1 polymorphisms and carriage of P. falciparum infection, with different patterns of association that may reflect their different haplotypic architecture. Genetic variation at this locus does not therefore account for the Fulani-specific resistance to malaria while it could contribute to parasite clearance's ability in populations living in endemic areas. We then conducted a case–control study of three haplotype-tagging single nucleotide polymorphisms (htSNPs) in 370 hospitalised malaria patients (160 severe and 210 uncomplicated) and 410 healthy population controls, all from the Mossi ethnic group. All three htSNPs showed correlation with blood infection levels in malaria patients, and the rs10065633 polymorphism was associated with severe disease ( P =0.02). These findings provide the first evidence of the involvement in malaria susceptibility of a specific locus within the 5q31 region, previously shown to be linked with P . falciparum infection levels.

Adverse reactions following treatment of onchocerciasis and bancroftian filariasis are common and frequently severe. They are generally caused not by direct drug toxicity but by host inflammatory responses to dying microfilariae. To define the responsible mechanism, serial blood levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were studied in 15 microfilaria-positive patients (10 with bancroftian filariasis, 5 with onchocerciasis) and 4 microfilaria-negative persons after diethylcarbamazine treatment. Elevations in IL-6 correlated with the occurrence and severity of clinical symptoms after treatment; for the onchocerciasis patients IL-6 levels directly reflected pretreatment intensity of infection. Serum TNF levels also rose but did not correlate directly with infection intensity or reaction severity. Microfilaria-negative controls remained asymptomatic with no significant rise in either cytokine. These findings suggest an etiologic role for systemically elevated cytokines in the inflammatory reactions developing after treatment of filarial infections in humans.