TLR Mediated Trophoblast Injury and Poor Pregnancy Outcomes in S. japonica

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DESCRIPTION (provided by applicant): Human schistosomiasis infects 200 million individuals, including 40 million women of child bearing age, and is a significant cause of morbidity and mortality in areas where the parasite is endemic. Treatment with praziquantel (PZQ) is the standard of care for many of those suffering from schistosome infections, however pregnant women have been systematically excluded from this treatment option. Although rodent models of schistosome infection during pregnancy clearly demonstrate adverse birth outcomes, there remains little examination of such a phenomenon in humans. Data from our pilot study suggests schistosome infection in humans can result in increased trophoblast TNF-a; production and apoptosis, as well as lower birth weights. This application is novel in its evaluation of the effect of schistosome-released soluble egg antigen (SEA) on human trophoblasts. We hypothesize that SEA will activate toll-like receptors (TLR)-2 and -4 on the surface of the human syncytiotrophoblast (STB), leading to induction of a pro-inflammatory cascade by this cell layer. We will utilize the most relevant model system available, primary trophoblasts isolated at term from women living in a region of The Philippines in which S. japonicum is endemic. Trophoblasts will be examined after differentiation, as the STB is the cell in direct contact with maternal blood, and thus most likely to be exposed to SEA in vivo. Specific Aim 1 will isolate term cytotrophoblasts from healthy, uninfected women. After in vitro syncytialization the cells will be exposed to SEA and TLR activation assessed through apoptosis rates, intracellular TNF-a; levels, cytokine production, MAPK and NF?B activation. Completion of Specific Aim 1 will allow us to report on specific effects of SEA on STBs in humans. Specific Aim 2 will isolate term cytotrophoblasts from infected women PZQ treatment given during the first trimester. These samples are being collected as part of an ongoing, U01 funded, randomized controlled trial evaluating PZQ treatment in the first trimester in women with schistosomiasis. STB will be cultured and TLR activation assessed as in Specific Aim 1. Despite PZQ treatment, the tissue egg burden does not immediately decrease, thus completion of Specific Aim 2 will identify effects of remaining schistosome eggs as well as PZQ treatment on the STB. Specific Aim 3 will utilize a murine model to determine the specific TLR(s) activated by SEA on trophoblast cells. Based on data in other physiological systems, we hypothesize that both TLR2 and -4 will be activated. This will be examined by trophoblast response to schistosome infection in genetic models deficient in either TLR2 or -4. Findings from Specific Aim 3 will advance mechanistic understanding in the field, allowing for better care of pregnant women with schistosomiasis. To our knowledge, this application will be the first to evaluate STBs for a specific response to antigens released into circulation during schistosome infection. This work is crucial in that it will allow for more comprehensive care of women and their offspring affected by schistosomiasis during pregnancy. PUBLIC HEALTH RELEVANCE: Approximately 40 million women of childbearing age suffer from schistosome infection globally at any given time. Multiple studies in rodent models, as well as a few reports in humans, suggest that schistosome infection results in poor pregnancy outcomes. The mechanisms of this phenomenon are unclear, and will be investigated in this application in order to enhance the treatment and health of pregnant women with schistosomiasis, as well as that of their affected offspring.