MECHANISMS OF SCHISTOSOME ASSOCIATED TROPHOBLAST INJURY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this proposal is to understand the mechanism(s) of poor pregnancy outcome in schistosome infected women. Healthy, successful pregnancies are characterized by a placental microenvironment that is biased toward a T-helper cell type 2 (Th2) cytokine milieu [1, 2]. Human infection with schistosomiasis results in the elaboration of pro-inflammatory cytokines including TNF-? [11-15], IL-6 [16], and IFN-? [12, 17] that are detected in the systemic circulation. Each of these cytokines has been implicated in fetal growth restriction in human studies [18-21]. In a pilot study in N=97 pregnant women living in a Schistosoma japonicum endemic area of the Philippines, we demonstrated that women with moderate or high intensity S. japonicum infection gave birth to newborns with birth weights that were 460 grams lower than women with low intensity or no infection, after adjusting for maternal height, gestational age, and geo-helminth infections (N=60, P = 0.06). Furthermore, moderately infected women had increased placental blood pro-inflammatory cytokine levels, increased trophoblast production of pro-inflammatory cytokines, and increased trophoblast apoptosis compared to uninfected women. In this proposal, we will utilize a murine model of S. mansoni to understand the mechanisms of trophoblast activation during schistosome infection. We hypothesize that schistsomes secret ligands into the maternal circulation that activate Toll-like receptors (TLRs) on trophoblasts.