Malaria is a global problem, and there is a critical need for further understanding of the disease process. When malarial parasites invade and develop within the bloodstream, they stimulate a profound host response whose main clinical sign is fever. To explore this response, we measured host gene expression in whole blood from Kenyan children hospitalized with either acute malaria or other febrile illnesses. Genomewide analysis of expression identified 2 principal gene-expression profiles related to neutrophil and erythroid activity. In addition to these general acute responses, a third gene-expression profile was associated with host parasitemia; mediators of erythrophagocytosis and cellular stress were notable components of this response. The delineation of subjects on the basis of patterns of gene expression provides a molecular perspective of the host response to malaria and further functional insight into the underlying processes of pathogenesis.

The ability of Plasmodium falciparum-infected erythrocytes to adhere to host endothelial cells via receptor molecules such as ICAM-1 and CD36 is considered a hallmark for the development of severe malaria syndromes. These molecules are also expressed on leukocytes such as dendritic cells. Dendritic cells are antigen-presenting cells that are crucial for the initiation of adaptive immune responses. In many human diseases, their frequency and function is perturbed. We analyzed the frequency of peripheral blood dendritic cell subsets and the plasma concentrations of interleukin-10 (IL-10) and IL-12 in Kenyan children with severe malaria and during convalescence and related these parameters to the adhesion phenotype of the acute parasite isolates. The frequency of CD1c ؉ dendritic cells in children with acute malaria was comparable to that in healthy controls, but the frequency of BDCA3 ؉ dendritic cells was significantly increased. Analysis of the adhesion phenotypes of parasite isolates revealed that adhesion to ICAM-1 was associated with the frequency of peripheral blood CD1c ؉ dendritic cells, whereas the adhesion of infected erythrocytes to CD36 correlated with high concentrations of IL-10 and low concentrations of IL-12 in plasma.

These results indicate that PfMIF is released during blood-stage malaria and potentially modulates the function of monocytes during acute P. falciparum infection.

Background: Genetic heterozygosity is increasingly being shown to be a key predictor of fitness in natural populations, both through inbreeding depression, inbred individuals having low heterozygosity, and also through chance linkage between a marker and a gene under balancing selection. One important component of fitness that is often highlighted is resistance to parasites and other pathogens. However, the significance of equivalent loci in human populations remains unclear. Consequently, we performed a case-control study of fatal invasive bacterial disease in Kenyan children using a genome-wide screen with microsatellite markers.

The high frequencies of both alpha+ thalassemia and the sickle cell trait (hemoglobin AS [HbAS]) found in many tropical populations are thought to reflect selection pressure from Plasmodium falciparum malaria. For HbAS, but not for alpha+ thalassemia, protection appears to be mediated by the enhanced phagocytic clearance of ring-infected erythrocytes. We have investigated the genotype-specific distributions of peripheral blood leukocyte populations in two groups of children living on the coast of Kenya: a group of healthy P. falciparum parasite-negative children sampled at cross-sectional survey during a period of low malaria transmission, and a group of children attending the hospital with acute malaria. We report distinctive distributions of peripheral blood myeloid dendritic cells and monocytes in children with alpha+ thalassemia and HbAS during healthy periods and disease, and suggest ways in which these might relate to the mechanisms of protection afforded by these conditions.