Schistosome Egg Antigens Elicit a Proinflammatory Response by Trophoblast Cells of the Human Placenta

Abstract

f Schistosomiasis affects nearly 40 million women of reproductive age. Many of these women are infected while pregnant and lactating. Several studies have demonstrated transplacental trafficking of schistosome antigens; however, little is known regarding how these antigens affect the developing fetus and placenta. To evaluate the impact of schistosomiasis on trophoblasts of the human placenta, we isolated primary trophoblast cells from healthy placentas delivered at term. These trophoblasts were placed in culture and treated with Schistosoma japonicum soluble egg antigens (SEA) or plasma from S. japonicum-infected pregnant women. Outcomes measured included cytokine production and activation of signal transduction pathways. Treatment of primary human trophoblast cells with SEA resulted in upregulation of the proinflammatory cytokines interleukin 6 (IL-6) and IL-8 and the chemokine macrophage inflammatory protein 1␣ (MIP-1␣). Cytokine production in response to SEA was dose dependent and reminiscent of production in response to other proinflammatory stimuli, such as Toll-like receptor 2 (TLR2) and TLR4 agonists. In addition, the signaling pathways extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal protein kinase (JNK), p38, and NF-B were all activated by SEA in primary trophoblasts. These effects appeared to be mediated through both carbohydrate and protein epitopes of SEA. Finally, primary trophoblasts cocultured with plasma from S. japonicum-infected pregnant women produced increased levels of IL-8 compared to trophoblasts cocultured with plasma from uninfected pregnant women. We report here a direct impact of SEA on primary human trophoblast cells, which are critical for many aspects of a healthy pregnancy. Our data indicate that schistosome antigens can activate proinflammatory responses in trophoblasts, which might compromise maternal-fetal health in pregnancies complicated by schistosomiasis.

Schistosoma japonicum Soluble Egg Antigens Attenuate Invasion in a First Trimester Human Placental Trophoblast Model

“…Our data are consistent with previous work from our laboratory regarding schistosome induced pro-inflammatory cytokine production across different models of trophoblast cells [19]. Outside of pregnancy, we and others have related these responses to nutritional, hepatic and hematologic morbidities in infected individuals [43]–[46].…”

“…Previously, we demonstrated that SEA can cause pro-inflammatory cytokine production in primary human trophoblast cells taken at term and allowed to syncytialize in vitro [19]. However, placentation is a dynamic process requiring trophoblast populations distinct in time and differentiation lineage to behave in specific and unique ways.…”

“…All experiments were performed with the addition of SEA (25 µg/ml) in complete media for 24 h or media only control, unless otherwise noted. This dose was chosen based on dose response curves performed previously in our laboratory using purified primary trophoblast cells [19].…”

Helminth Infections

“…36 In vitro schistosome egg antigens can activate proinflammatory responses in trophoblasts. 37 Accordingly, the WHO now recommends praziquantel to women with schistosomiasis who are pregnant and lactating, 26 whereas a WHO informal consultation has further recommended that "women of childbearing age should not be excluded from population-based chemotherapy programmes for schistosomiasis." 38…”

Maternal helminth infections and the shaping of offspring immunity

“…Up to now, evidence of schistosome‐egg‐derived as well as filarial antigens in the cord blood, breastmilk and placentas of infected women and their newborns was provided by several studies . Further studies investigating possible effects of such transferred antigens have demonstrated firstly stimulatory effects on human trophoblast cells and placental inflammation leading to IL‐6, IL‐8 and MIP‐1alpha secretion, secondly that sensitization had occurred in terms of measurable antigen‐specific T‐cell responses in cord blood mononuclear cells (CBMCs) as well as activation of B cells and thirdly protection against reinfection . In general, maternal schistosomiasis leads to a more activated status of the innate as well as adaptive cell compartments of CBMCs, whereas filariasis during pregnancy seems to lead to tolerance with rather increased susceptibility of the offspring to develop filariasis during childhood indicating a certain longevity of the maternally imprint .…”