In Utero B Cell Responses to Plasmodium falciparum and Risk of Malaria during the First Year of Life.

Abstract

The fetal origin of disease hypothesis asserts that childhood predisposition to disease can be conditioned by intrauterine factors which, thus far, have not been well characterized. In malaria-endemic areas, fetuses of women infected with the malaria parasite Plasmodium falciparum (Pf) can be exposed to Pf antigens in utero during the second and third trimesters of gestation. The present dissertation comprises pioneer studies investigating the timing of acquisition antibody responses to Pf antigens in utero and the influence of the amount Pf antigen to which the fetus is exposed, on susceptibility to malaria during the first year of life. Our data show that the human fetus is not immunologically hyporesponsive as specific IgM to a wide breadth of Pf antigens were made by fetal B cells as early as 22 weeks of gestation and fetal B cells were capable of class-switching from Pf IgM to Pf IgG production towards term gestation. We also demonstrated that exposure to low and not high amount of Pf antigens in utero is associated with increased susceptibility to malaria since infants born to mothers with low placental parasitemia had a significantly higher number of infections during the first year of life and shorter time to first postnatal infection compared to infants of uninfected mothers or of mothers with high placental parasitemia. In addition, the infants of low placental parasitemia mothers did not make antibodies to Pf antigens during the first postnatal infection, while infants of high placental parasitemia mothers made a recall antibody response characterized by boosting of IgG and not IgM to the Pf MSP1 antigen. The data suggest that Pf-specific memory B cells can be generated in utero but a threshold amount of Pf antigen exposure may be required. Collectively, our data confirm that prentatal factors can modify risk of malaria after birth and demonstrate that low placental parasitemia at birth is as a major predictor of increased susceptibility of infants to malaria. Therefore, malaria control interventions during pregnancy should aim to eliminate and not reduce placental Pf parasitemia.