Abstract. Recent work suggests that IgG and IgM from nonimmune human serum (natural antibodies) bind to the surface of Plasmodium falciparum−infected erythrocytes and contribute to rosette formation by stabilizing the interaction between infected and uninfected erythrocytes. Here we show, in both laboratory clones and field isolates, that only IgM but not IgG is detected on the surface of infected cells. In field isolates, there was a strong positive correlation between IgM binding and rosette formation (Spearman's rank correlation coefficient ‫ס‬ 0.804, P < 0.001). Both rosette formation and IgM binding were associated with severe malaria, although statistical analysis indicates that rosette formation is the more strongly associated variable. Rosette formation, but not IgM binding, was also associated with malarial anemia. We conclude that IgM is the predominant class of natural antibodies binding to the surface of infected erythrocytes. However, we could not confirm previous suggestions that infected erythrocytes are coated with nonimmune IgG, which could lead to their interaction with host Fc␥ receptors.

Abstract. Plasmodium falciparum isolates that form rosettes with uninfected red cells are associated with severe malaria in African children, although the mechanism by which rosetting contributes to severe disease is unknown. Here we have analyzed the relationship between rosetting and parasitemia in two samples of clinical isolates from children with malaria in Kilifi, Kenya. A consistent positive correlation was found between rosetting and parasitemia (Spearman's rank correlation coefficent ‫ס‬ 0.467, P < .001, n ‫ס‬ 154, for 1993 study; ‫ס‬ .407, P < .001, n ‫ס‬ 74, for 2000 study). Rosetting may enhance parasite growth and survival by facilitating invasion or promoting immune evasion, thus allowing higher parasitemia to develop and increasing the likelihood of severe malaria.

The interaction between the mammalian host and its resident gut microbiota is known to license adaptive immune responses. Nutritional constituents strongly influence composition and functional properties of the intestinal microbial communities. Here, we report that omission of a single essential amino acid - tryptophan – from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction results in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiota, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation.

Complement receptor-type 1 (CR1, CD35) is the immune-adherence receptor, a complement regulator, and an erythroid receptor for Plasmodium falciparum during merozoite invasion and subsequent rosette formation involving parasitized and non-infected erythrocytes. The non-uniform geographical distribution of Knops blood group CR1 alleles Sl1/2 and McCa/b may result from selective pressures exerted by differential exposure to infectious hazards. Here, four variant short recombinant versions of CR1 were produced and analyzed, focusing on complement control protein modules (CCPs) 15–25 of its ectodomain. These eleven modules encompass a region (CCPs 15–17) key to rosetting, opsonin recognition and complement regulation, as well as the Knops blood group polymorphisms in CCPs 24–25. All four CR1 15–25 variants were monomeric and had similar axial ratios. Modules 21 and 22, despite their double-length inter-modular linker, did not lie side-by-side so as to stabilize a bent-back architecture that would facilitate cooperation between key functional modules and Knops blood group antigens. Indeed, the four CR1 15–25 variants had virtually indistinguishable affinities for immobilized complement fragments C3b (K D = 0.8–1.1 µM) and C4b (K D = 5.0–5.3 µM). They were all equally good co-factors for factor I-catalysed cleavage of C3b and C4b, and they bound equally within a narrow affinity range, to immobilized C1q. No differences between the variants were observed in assays for inhibition of erythrocyte invasion by P. falciparum or for rosette disruption. Neither differences in complement-regulatory functionality, nor interactions with P. falciparum proteins tested here, appear to have driven the non-uniform geographic distribution of these alleles.