Serological Evidence of Discrete Spatial Clusters of Plasmodium falciparum Parasites

BACKGROUND: Malaria transmission may be considered to be homogenous with well-mixed parasite populations (as in the classic Ross/Macdonald models). Marked fine-scale heterogeneity of transmission has been observed in the field (i.e., over a few kilometres), but there are relatively few data on the degree of mixing. Since the Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) is highly polymorphic, the host's serological responses may be used to infer exposure to parasite sub-populations. METHODS AND FINDINGS: We measured the antibody responses to 46 individual PfEMP1 domains at four time points among 450 children in Kenya, and identified distinct spatial clusters of antibody responses to individual domains. 35 domains showed strongly significant sero-clusters at p = 0.001. Individuals within the high transmission hotspot showed the greatest diversity of anti-PfEMP1 responses. Individuals outside the hotspot had a less diverse range of responses, even if as individuals they were at relatively intense exposure. CONCLUSIONS: We infer that antigenically distinct sub-populations of parasites exist on a fine spatial scale in a study area of rural Kenya. Further studies should examine antigenic variation over longer periods of time and in different study areas

Somatic mutations in the angiopoietin-receptor TIE2 can cause both solitary and multiple sporadic venous malformations

The vascular endothelial cell (EC)-specific receptor tyrosine kinase (RTK) TIE2 plays a crucial role in angiogenesis and cardiovascular development. In man, heterozygous TIE2 substitutions that induce in vitro ligand-independent hyperphosphorylation cause hereditary mucocutaneous venous malformations (VMCM, OMIM 600195), characterized by multifocal small bluish cutaneous and mucosal lesions, composed of enlarged, tortuous venous channels. We now identified a somatic, lesion-associated TIE2 “2nd-hit” alteration in one resected VMCM, from a patient (Sa-I.4) carrying the germline R849W. Unlike inherited intracellular TIE2 mutations, the somatic deletion mutant (“Del”) was not hyperphophorylated in vitro, nor did it exacerbate hyperphosphorylation of R849W in trans. In retrovirally transfected HUVECs, Del-TIE2 is retained in endoplasmic reticulum (ER), and shows no ability to respond to Ang1 by increased phosphorylation or translocation and clustering. Thus, the somatic deletion mutant acts as a null-allele, causing local loss-of-function of wild-type TIE2. We assessed for whether such localized, tissue-specific events play a role in the etiology of the far more common sporadic VM, characterized by extensive, unifocal lesions. Eight somatic TIE2 mutations were identified in lesions from 28 out of 57 patients (49.1%), not detected in their blood or in control tissues. They were all located within the first TK or KID of TIE2. The somatic mutations included a frequent L914F change, and a series of double-mutations that occurred in cis, all of which show varying degrees of ligand-independent hyperphosphorylation in vitro, with double-mutants showing even higher levels as compared to their constituent single-mutant forms. The most common of these mutants (germline R849W and somatic L914F), also profoundly affect receptor compartmentalization, and response to ligand. Like the wild-type, R849W shows an even cellular distribution, and is translocated to the cell-rear and retraction fibers in response to ligand; however, it shows significantly higher levels of activation than wild-type in these fibers. L914F, on the other hand, accumulates in an activated state in the Golgi and ER, and is incompletely translocated upon stimulation. Phosphorylation levels in L914F-HUVEC retraction-fibers is nevertheless significantly greater than with the wild-type. In conclusion, these data illustrate that a sporadic disease may be explained by somatic changes in a gene causing rare, inherited forms, and pinpoint TIE2 pathways as potential therapeutic targets for VM. ([email protected]