Genetic analysis of ID1-DBL2X predicts its validity as a vaccine candidate in Colombia and supports at least two independently introduced Plasmodium falciparum populations in the region.

Pregnancy-associated malaria (PAM) poses a threat to both the mother and fetus, increasing the risk of severe maternal anemia, fetal growth restriction and low birth weight infants. Two vaccines are currently in development to protect women from Plasmodium falciparum in pregnancy. Both vaccine constructs target the ID1-DBL2X domain of VAR2CSA, a protein expressed on the surface of infected erythrocytes (IEs) that mediates parasite sequestration in the placenta. Although development of an effective vaccine may be hampered by ID1-DBL2X polymorphisms expressed by field isolates, a recent study showed that genetic variation of this domain in South American parasite populations is much lower than in other geographical locations. This suggests that a recombinant vaccine designed to be efficacious in Africa and Asia is likely to be efficacious in South America. However, these studies did not include Colombian parasite populations in their analyses, which are known to be genetically distinct from other South American parasite populations due to their independent introduction from Africa. Therefore, we sought to determine the genetic variation of the ID1-DBL2X domain in Colombian parasites to assess the potential efficacy of the vaccine against PAM in this region. Through sequence analysis and population genetics, we show that there is a low degree of genetic variation amongst Colombian parasite populations and that a vaccine containing conserved antigen variants for worldwide populations is likely to be protective against PAM in Colombia. Our analysis also points towards an African origin for Colombian parasite populations, and suggests that their introduction into Colombia was a recurrent process encompassing multiple introduction events.

Dexamethasone increases RAMP1 and CRLR mRNA expressions in human vascular smooth muscle cells.

A recent report has shown that in vitro the RAMP2/CRLR complex is a functional adrenomedullin receptor in human endothelial and vascular smooth muscle cells. However, in vivo, it is well known that CGRP receptors are expressed in human coronary arteries and that a beneficial effect is observed in patients after CGRP infusion of patients with congestive cardiac failure. This contrast may be explained by the in vivo impregnation of major hormones, so we have tested if glucocorticoids were able in vitro to enhance the expression of the RAMP1/CRLR expression leading to functional CGRP receptors. The expression of RAMP1, RAMP2, CRLR, and adrenomedullin was evaluated by semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR) using (33)P in human coronary arteries vascular smooth muscle cells (VSMC) cultured in the presence of dexamethasone. Under basal conditions, the CRLR mRNA was expressed, but RAMP2 mRNA was clearly more abundant than RAMP1 mRNA. Increases in CRLR and RAMP1 mRNA expressions occurred 4 h after treatment of VSMC with 10(-7) M dexamethasone and no change was found for RAMP2 mRNA. Adrenomedullin mRNA increased later, i.e., 8 and 16 h after dexamethasone treatment. The RAMP1 mRNA expression was elevated with doses of dexamethasone ranging from 10(-10) to 10(-7) M, thus a 5-fold increase in the ratio between RAMP1 and RAMP2 was observed with the lowest dose of dexamethasone and a 2-fold rise at 10(-7) M. CRLR mRNA levels were half-reduced with the two lowest doses of dexamethasone (10(-10) and 10(-9) M), but increased from 10(-8) to 10(-7) M. Thus, we suggest that, in vivo, glucocorticoids are involved in the expression of CGRP receptors by human coronary VSMC.