Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity

Abstract

Pregnancy-associated malaria, including placental malaria, causes significant morbidity and mortality worldwide. Recently, it has been suggested that in utero exposure of the fetus to malaria antigens may negatively impact the developing immune system and result in tolerance to malaria. Here, we review our current knowledge of fetal immunity to malaria, focusing on the dynamic interactions between maternal malaria infection, placental development, and the fetal immune system. A better understanding of the long-term impact of in utero malaria exposure on the development of natural immunity to malaria, immune responses to other childhood pathogens, and vaccine immunogenicity is urgently needed. This may guide the implementation of novel chemoprevention strategies during pregnancy and facilitate the push toward malaria vaccines.

Keywords: fetal immune system; fetal tolerance; placental malaria; pregnancy-associated malaria.

Published by Elsevier Ltd.

Figures

Figure 1. Gestational Timeline of Fetal Immune Development and Maternal Factors Influencing Placental Malaria

Fetal immune development (blue) begins as early as gestational week (GW) 3–4, with the emergence of antigen-presenting cells (APCs). Thymic development occurs between GW 8–10, followed by the appearance of secondary lymphoid structures, such as the spleen and lymph nodes (LNs). Naïve T cells can first be detected in the periphery around GW 12 and initially the T cell pool is predominated by γδ T cells. The proportion of γδ T cells declines with gestational age, concurrent with expansion of the αβ T cell population, which constitutes the majority at birth. The placenta is also growing rapidly during early gestation. A key turning point in placental growth is the perfusion of the placenta with maternal blood, which occurs between GW 6–12, and theoretically represents the first opportunity for malaria parasites to access the placenta for sequestration (maroon). Pregnant women are more susceptible than non-pregnant adults to malaria infection; however, the highest rates of infection and highest parasite densities seem to occur between 9–20 weeks (tan) in primigravidas. Collectively, these overlapping factors suggest that the first window of vulnerability for placental malaria infection and fetal immune exposure may occur late in the first trimester or early in the second trimester (~GW 10–16).

Figure 2 (Key Figure). Factors Influencing the Fetal Immune Response to Pregnancy-Associated Malaria

Maternal, placental and fetal factors all influence how the fetal immune system will respond to in utero antigen exposure. Maternal factors play a role in when and how often parasites are present in circulation and have access to the placenta. This includes the frequency and gestational timing of infections during pregnancy. The severity of these infections and the ability of parasites to infiltrate the placenta are also impacted by maternal immunity and gravidity, particularly the generation of Var2CSA antibodies with increasing parity. Parasite sequestration in the placenta is influenced by the stage of placental development, and is dependent upon the flow of maternal blood into the placenta. The extent of placental histopathology and inflammation, including disruption of the syncytiotrophoblast (STB) layer, also play a key role in both the amount, and the timing of malaria antigen translocation into fetal circulation. Finally, the stage of fetal immune development when malaria antigen exposure occurs may greatly impact the magnitude and type of response that is mounted, as the number and function of APCs and T cells gradually change throughout gestation. In particular, predisposition toward regulatory T cell (Treg) differentiation may occur as an intrinsic property of developing fetal T cells, or could be impacted by the balance between inflammatory vs. suppressive cytokines in the microenvironment.